Can CBD oil help with anxiety, and if so, how?

  • A 2015 review published in the journal Neurotherapeutics demonstrated CBD’s efficacy in reducing anxiety behaviors linked to multiple disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder (PD)(1)
  • Researchers of a 2019 study published in the Brazilian Journal of Psychiatry found that CBD’s anti-anxiety effect might help reduce the response to stressful environmental factors(2)
  • Published in CNS and Neurological Disorders – Drug Targets, a study showed that CBD, a cannabis Sativa constituent with great psychiatric potential, had therapeutic uses as an anxiolytic-like and an antidepressant-like compound(3).
  • Researchers of a study published in The Permanente Journal in 2019 measured sleep and anxiety scores in human subjects and found that CBD could hold benefits for anxiety-related disorders(4)
  • Results of a study published in the Neuropharmacology Journal suggested that CBD might block anxiety-induced sleep disturbances through its anti-anxiety effect on the brain(5).

Best CBD Oils for Anxiety

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    FormOil Tincture
    IngredientsOrganic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier OilOrganic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price Range$89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsOrganic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forNew CBD users
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Organic

Nuleaf Naturals 725mg Full Spectrum CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
Nuleaf Naturals 725mg Full Spectrum CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health conscious
  • Summary

    Natural remedy for various illnesses. There are approximately 300 drops in this 0.5 FL OZ bottle, where 1 drop = 2.4 mg of CBD.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsUSDA Certified Organic Hemp Oil, Full Spectrum Hemp Extract
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take itUnder the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    725mg of CBD per 0.5 FL OZ (15ml)
    Carrier OilOrganic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    48.33mg to a max of 51.82mg per 1ml
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursNatural
    Price Range$99.00 - 1-pack, $434.00 - 6-pack
    $/mg CBD
    Price ($/mg)
    1-pack - $0.13, 6-pack - $0.59
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsNo additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    AllergensNot specified
    Refund policyWithin 30 days
    Recommended forHealth conscious
    Countries servedUSA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Parguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

Sabaidee Super Good Vibes CBD Oil

Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

Check Latest Price
Read our review

Why People Are Turning to CBD for Anxiety

CBD has been known for its numerous health benefits, from helping to reduce chronic pain to alleviating cancer symptoms(6). 

There have also been other studies conducted to understand better the anxiolytic (anti-anxiety) characteristics of CBD.

CBD’s potential for anxiety relief is also linked to its ability to help with sleep problems, reduce stress, and manage depression

Esther Blessing, Ph.D. of New York University, led a group of researchers in 2015 and investigated the benefits of CBD in helping with anxiety. Their review of 49 studies yielded promising results(7). 

Blessing noted that animal studies conclusively demonstrated CBD’s efficacy in reducing anxiety behaviors linked to multiple disorders. 

These disorders include panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

Blessing added that the results were supported by human experimental findings, which also suggested CBD’s minimal sedative effects and excellent safety profile.

Unlike THC (tetrahydrocannabinol), another well-known compound of the cannabis plant, CBD (cannabidiol), is non-addictive and does not get users high, making it an appealing option for most people dealing with anxiety.

However, the results could not confirm that treatment with CBD would have comparable effects for those with chronic anxiety. Further tests are needed to determine the impact of prolonged CBD use on individuals. 

Meanwhile, researchers of a 2019 study, published in the Brazilian Journal of Psychiatry, looked at CBD’s effects on anxiety and stress. 

The study demonstrated that CBD might help reduce the response to stressful environmental factors when given in the optimal dosage(8).

Orrin Devinsky, M.D., director of NYU Langone’s Comprehensive Epilepsy Center in New York City and a principal investigator in the Epidiolex trials, says there is growing evidence that CBD can ease anxiety. 

This disorder sometimes accompanies attention-deficit/hyperactivity disorder (ADHD)(9).

A study published in the Neuropsychopharmacology journal simulated public speaking and demonstrated that a single dose of CBD could decrease the discomfort in people with a social anxiety disorder(10). 

A review published in the Brazilian Journal of Psychiatry in 2019 yielded similar effects on healthy people in anxiety-inducing situations(11).  

Researchers are also exploring CBD as a means of soothing anxiety in people with an autism spectrum disorder (ASD). 

In a study published in Frontiers in Pharmacology in 2019, the authors found an increase in the use of cannabidiol in children with ASD(12). 

Based on the parents’ reports, the findings suggest that CBD may be useful in improving ASD symptoms, such as anxiety, aggression, and hyperactivity. 

However, the authors also note that CBD’s efficacy and safety need large-scale clinical trials and further evaluation in children with ASD.

Orrin Devinsky is also involved in two clinical trials that aim to test whether CBD can meaningfully reduce the irritability and anxiety of those with autism(13). 

In another study, published in the Brazilian Journal of Psychiatry, researchers suggested that the therapeutic benefits from the use of CBD oil may be attributed to its anti-anxiety and sleep-inducing effects(14). 

Results of an animal study published in the Neuropharmacology Journal in 2012 also had comparable results that supported the use of CBD treatment. 

The findings suggested that CBD might block anxiety-induced sleep disturbances through its anxiolytic effect on the brain(15). 

A case report in The Permanente Journal, meanwhile, noted the effectiveness of CBD oil for anxiety and insomnia as part of post-traumatic stress disorder (PTSD)(16). 

The authors of the 2016 study found that CBD oil reduced the feelings of anxiety and reduced the insomnia of one 10-year old girl.

The strength of this particular case is that the child was receiving no prescription medications other than the nonprescription diphenhydramine. 

With only nutritional supplements and the CBD oil to control her symptoms, her scores on the sleep and anxiety scales consistently and steadily decreased over 5 months. 

Ultimately, she was able to sleep on most nights in her room, behave appropriately, and become less anxious at school and home. 

For people who deal with the misery of insomnia, studies suggest that CBD may help with both falling asleep and staying asleep(17).

A study published in Pharmaceuticals (Basel) in 2012 even compared CBD with a sleep aid called nitrazepam(18). 

The authors found that a high dose of 160 milligrams of CBD (equivalent to 0.16 milliliter of CBD) increased the subject’s duration of sleep.

Similarly, a 2017 study published in the Current Psychiatry Reports noted that at moderate to high doses of CBD, the compound might have therapeutic potential for the treatment of insomnia(19).

Researchers of a study published in The Permanente Journal in 2019 measured sleep and anxiety scores in human subjects and found that CBD could hold benefits for anxiety-related disorders(20). 

A 2018 study published in the Frontiers in Immunology Journal demonstrated CBD as a potential remedy to depression(21). 

In the study, researchers examined the experimental and clinical use of CBD. They found that CBD showed anti-anxiety, anti-epileptic, and antipsychotic properties that might help reduce depression linked to stress.

CBD is a cannabis Sativa constituent with great psychiatric potential, including uses as an anxiolytic-like and an antidepressant-like compound, as a 2014 study published in CNS and Neurological Disorders – Drug Targets suggested(22).

In one study, results showed that CBD could induce rapid-acting antidepressant-like effects and enhance neurotransmission(23). Neurotransmission is the process of communication between nerve cells.

How CBD Works to Help With Anxiety

To fully understand how CBD works to help with anxiety, one must understand how the endocannabinoid system (ECS) works. 

The therapeutic effects of cannabinoids, such as CBD, are realized by their interaction with the body’s ECS and its specialized cannabinoid receptors. 

The ECS, integral to the body’s physiologies, is responsible for regulating a wide range of body functions, including pain sensation, immune response, anxiety, sleep, mood, appetite, metabolism, and memory.

CB1 and CB2 are the two main types of receptors found in specific parts of the human body. These receptors each have particular roles in the ECS.

CB1 receptors are mostly located in the brain and central nervous system. However, they are also found in the reproductive organs, gastrointestinal and urinary tracts, liver, lungs, and retina(24). 

 CB1 receptors play a role in motor regulation, memory processing, appetite, pain sensation, mood, and sleep(25). 

The activation of CB1 receptors has also been related to neuroprotective responses. 

This activity suggests the cannabinoids with a higher affinity for CB1 receptors could help in the treatment and prevention of neurodegenerative conditions, such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.

Meanwhile, CB2 receptors are primarily situated on cells in the immune system and its associated structures.

When CB2 receptors are triggered, they stimulate a response that fights inflammation, reducing pain, and minimizing damage to tissues.

These anti-inflammatory responses are useful for treating inflammation-related conditions, such as chronic inflammatory demyelinating polyneuropathy (CIDP), Crohn’s disease, arthritis, and inflammatory bowel syndrome(26).  

CBD acts indirectly against cannabinoid agonists. Agonists are substances that attach to a receptor and cause the same action as the substances that typically bind to the receptor.

CBD also interacts with several other receptors in the body, such as the 5-HT1A receptor, which is linked to serotonin, a neurotransmitter found to be a contributor to feelings of well-being. It is through this interaction that these cannabinoids promote healing and balance(27).

A 2005 research published in the Neurochemical Research Journal indicated that cannabidiol could inhibit the reuptake of serotonin in the brain, making serotonin more available for the body(28). 

Serotonin occurs throughout the body, and it impacts a variety of body and psychological functions. In the brain, serotonin influences levels of anxiety, mood, and happiness. 

The researchers believe that with better regulation of serotonin, CBD could help stabilize mood and reduce anxiety.

In the Translational PsychiatryJournal, a 2012 study demonstrated CBD’s ability to trigger the endocannabinoid system (ECS) in the body to produce more of its natural cannabinoids, including anandamide, which regulates emotions(29). 

Results showed that anandamide levels were higher in subjects exposed to CBD.

The ECS plays a vital role in the human body due to its ability to maintain homeostasis or state of balance, as explained in a 2018 research published in the Journal of Young Investigators(30). 

Increased anandamide production in the brain is believed to guard against the effects of stress while reducing behavioral signs of anxiety and fear, according to a 2019 study published in the Journal of Neuroscience(31). 

In another 2019 study published in the journal Current Psychiatry Reports, results indicated that CBD might have the potential to help elevate anandamide levels for the treatment of anxiety-related disorders in the future (32). 

Studies in the journal Cannabis and Cannabinoid Research showed that CBD might stimulate the hippocampus, a part of the brain important for memory, to regenerate neurons (nerve cells)(33). 

Preclinical studies have shown some evidence suggesting that the pro-neurogenic action of CBD through the hippocampus might trigger its anxiolytic (anti-anxiety) effects(34). 

The Pros and Cons of CBD Oil for Anxiety

The Pros

  • Studies have shown that CBD might be beneficial in alleviating anxiety, stress, and depression.
  • Unlike the commonly prescribed medications for anxiety, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and benzodiazepines, CBD oil may be purchased without a prescription in locations where it is legally available.
  • CBD is non-addictive, says Nora Volkow, director of the National Institute on Drug Abuse (NIDA) in a 2015 article(35). This characteristic makes CBD an appealing option for people with anxiety. 
  • CBD “is generally well tolerated with a good safety profile,” as the World Health Organization (WHO) states in a critical review(36). 
  • In a 2017 review published in the Cannabis and Cannabinoid Research Journal, the authors found CBD to be well-tolerated at doses of up to 1,500 mg per day(37). 

The Cons

  • Studies are too limited to determine whether or not CBD is an effective treatment for conditions other than the ones approved by the U.S. Food and Drug Administration (FDA). 

The FDA has only approved Epidiolex, a drug for seizures that has CBD as its main ingredient(38). 

  • As with the use of any natural chemical compound, there are risks involved in using CBD. Possible side effects of CBD use include diarrhea, fatigue, and changes in appetite and weight. CBD can also alter how the body breaks down certain medications(39).  
  • Research published in Medicines Journal in 2019 indicates that the CYP450 family of enzymes is responsible for breaking down several phytocannabinoids (cannabinoids that exist naturally in the cannabis plant), including CBD(40). 

Thus, taking CBD in combination with medications that have a grapefruit warning is not recommended(41). 

  • CBD products marketed online and in dispensaries are mostly unregulated, making it difficult to determine whether the CBD oil tinctures, CBD gummies, CBD balms, and CBD softgels contain the amount of CBD the product labels claim(42). 

A 2107 review published in the Journal of the American Medical Association revealed labeling inaccuracies among CBD products(43). Some products had less CBD than stated, while others had more.

How CBD Oil Compares to Alternative Treatments for Anxiety

Yoga and massage are alternative treatments for anxiety.

According to an article posted by Harvard Health Publishing of the Harvard Medical School of Harvard University, yoga functions like other self-soothing techniques, such as relaxation, exercise, meditation, or even socializing with friends(44).  

By decreasing levels of perceived stress and anxiety, yoga modulates stress response systems, which consequently leads to a decreased heart rate, reduced blood pressure, and natural respiration.

Self-soothing methods also include massages or other types of tactile treatments which represent different kinds of relationships with other living beings, like pets. 

Oxytocin, a hormone produced in the brain, is released in response to several kinds of massage(45). 

Oxytocin is linked to increased levels of social interaction, well-being, and anti-stress effects, according to a 2015 study published in the journal Frontiers in Psychology (46). 

Although using oxytocin to treat mental health conditions has not yet been studied sufficiently, low oxytocin levels have been linked to depression, says the Endocrine Society(47).

The benefits of aromatherapy and essential oils include reducing anxiety and depression symptoms and improving sleep, according to a 2012 study(48). 

CBD used in aromatherapy and massage takes advantage of the cannabis plant’s terpenes that are used to create an essential oil. 

Terpenes are responsible for the flavors and aroma of cannabis and influence its effects by interacting with cannabinoids.

When combined with other essential oils, CBD stimulates one’s sense of smell and heightens the soothing benefits of a massage. 

When applied topically, CBD oil gets absorbed into the skin and targets cannabinoid receptors found in the skin’s mast cells and nerve fibers. 

The reaction gives a calming, anti-inflammatory effect with localized benefits all over the skin and muscles. 

Massages are used as a wellness and healing practice, and with an infusion of pure CBD hemp extract, the therapeutic benefits increase.

Studies have found that massage can also help relieve pain in people with cancer, as it helps relieve anxiety, fatigue, and stress(49). 

Meanwhile, according to an article published by the American Massage Therapy Association (AMTA), the potential value of massage therapy for individuals with depression comes from interrupting the pattern of symptoms regularly. 

Each time one interrupts the pattern and experiences calm, it is easy to remember what it is like to live in a healthy state, providing hope that it is possible(50). 

How to Choose the Right CBD for Anxiety

Full-spectrum CBD oil contains all phytonutrients from hemp, including trace amounts of THC, terpenes, flavonoids, fatty acids, and essential oils. 

Broad-spectrum CBD oils are like full-spectrum oils without THC.

Meanwhile, CBD isolates carry only pure, isolated cannabidiol.

For individuals allergic to specific components of the hemp plant, or do not want any amount of THC in their system, CBD isolates are an option.

Regardless of the form of CBD products that one chooses, careful consideration must be employed in selecting the best CBD oil for anxiety that is suitable for his or her lifestyle and preferences.

The following factors are essential to ensure the safety and reliability of the CBD products purchased:

  1. Research on the exact legal stipulations applicable to CBD in the area where it would be purchased and used.
  2. Purchase only high-quality, non-GMO, organic hemp-derived CBD products from legitimate and reliable CBD brands. The majority of companies that manufacture the best CBD oil products grow their hemp from their own farms, or they purchase from licensed and reputable hemp producers. Popular CBD brands, like NuLeaf Naturals, CBDistillery, and CBDPure, source their hemp from Colorado. Colorado in the United States has been at the forefront of hemp production as producers have benefited from the State’s favorable regulations. 
  3. When buying from an online store, research product reviews. When buying from a physical store or dispensary, check whether the store is authorized by the government to sell CBD.
  4. Knowing the extraction methods used in making the CBD oil is also essential. Researchers of a study indicate that the Supercritical-CO2 extraction process is recognized as safe by the U.S. Food and Drug Administration (FDA) in pharmaceutical manufacturing(51). 
  5. One important thing to look for in CBD products is certification codes. Several certification authorities approve certain products only after some thorough screening tests. 
  6. Compare company claims about their products’ potency with that of the third-party lab testing reports. 
  7. Consulting with a trusted medical professional who is experienced in CBD use is ideal before trying any CBD brands or cannabis products. 

Best CBD Oils for Anxiety

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    FormOil Tincture
    IngredientsOrganic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier OilOrganic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price Range$89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsOrganic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forNew CBD users
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Organic

Nuleaf Naturals 725mg Full Spectrum CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
Nuleaf Naturals 725mg Full Spectrum CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health conscious
  • Summary

    Natural remedy for various illnesses. There are approximately 300 drops in this 0.5 FL OZ bottle, where 1 drop = 2.4 mg of CBD.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsUSDA Certified Organic Hemp Oil, Full Spectrum Hemp Extract
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take itUnder the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    725mg of CBD per 0.5 FL OZ (15ml)
    Carrier OilOrganic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    48.33mg to a max of 51.82mg per 1ml
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursNatural
    Price Range$99.00 - 1-pack, $434.00 - 6-pack
    $/mg CBD
    Price ($/mg)
    1-pack - $0.13, 6-pack - $0.59
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsNo additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    AllergensNot specified
    Refund policyWithin 30 days
    Recommended forHealth conscious
    Countries servedUSA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Parguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

Sabaidee Super Good Vibes CBD Oil

Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

Check Latest Price
Read our review

CBD Dosage for Anxiety

Several factors determine the correct dose for an individual, including body weight, the amount of CBD is in each product, and the desired results.

Still, the guidelines for the correct dosage of CBD for specific medical conditions are unclear.

The U.S. Food and Drug Administration (FDA) has not approved cannabidiol as a supplement. 

Researchers of the 2016 study that was published in The Permanente Journal say they have no foundation to suggest dosages of CBD based on the data from their studies(52). 

However, in their experience, the CBD supplement given in different dosages of 12 mg to 25 mg of CBD once daily appears to offer relief of key symptoms, such as anxiety and sleep problems, with nominal side effects

Notably, the subject of their study did report any complaints or discomfort from the use of CBD

While CBD is considered generally safe, as the 2011 review in the Current Drug Safety Journal suggests, the long-term effects are yet to be examined further(53). 

How to Take CBD Oil for Anxiety

CBD oil capsules and edibles, such as brownies, gummies, and lozenges, are a convenient and straightforward way to take CBD oil, especially for beginners.

Meanwhile, CBD oil tinctures or drops may be a practical option for those who seek fast results and maximum dosage control. 

CBD oil tinctures may be directly discharged under the tongue by using a dropper, allowing the oil to be absorbed into the bloodstream.

Sublingual (under the tongue) absorption is an efficient way of consuming CBD tinctures. According to studies, CBD oil has a sublingual bioavailability of 13% to 19%, with some studies putting it as high as 35%(54).

Bioavailability is the extent and rate to which a compound or an active drug ingredient is absorbed and becomes readily available for the body to use(55). 

In a 2010 review, published in the International Journal of Pharmacy and Pharmaceutical Sciences, researchers found that peak blood levels of most substances given sublingually are achieved in 10 to 15 minutes, which is faster than when those same drugs are ingested orally(56). 

For those who find the taste of pure CBD hemp extract unappealing, there are CBD gummies that come in many delicious flavors. 

Each gummy also comes in a fixed dose, making it an excellent way to give CBD, even to kids with anxiety.

CBD oil can also be mixed with other foods and beverages. However, keep in mind that oil and water do not mix.

Given that CBD is a highly lipophilic (soluble in lipids or oils) molecule, it may dissolve in the fat content of food, increasing its solubility and absorption, according to a 2018 study published in the journal Frontiers in Pharmacology(57). 

An additional fat, like milk, may be necessary for the oil to bind and completely dissolve while maintaining the smooth consistency of the drink. 

CBD may also be used in massage therapies or applied as a lotion, cream, balm, or salve. There is, however, limited absorption through the skin with topical CBD oil.

For topical products, look for keywords on the product labels that indicate that the product uses nano technology, encapsulation, or micellization of CBD. 

These words indicate that their solution can carry CBD through the dermal layers, rather than staying on the skin.

CBD vapes, meanwhile, are one of the quickest ways to get CBD into the body since it enters the bloodstream through the lungs without going through the digestive system. 

However, vaping is not for everyone. Experts are not sure if vaping indeed caused lung problems but believe the most likely culprit is a contaminant, not an infectious agent. 

Possibilities include chemical irritation or allergic or immune reactions to various chemicals or other substances in the inhaled vapors(58). 

Thus, individuals contemplating vaping CBD for the first time must proceed with caution and first consult with a doctor experienced in cannabis use.

A Close Look at Anxiety Disorders

The U.S. Department of Health & Human Services lists five significant types of anxiety disorders(59):

Generalized Anxiety Disorder (GAD)

GAD is characterized by exaggerated worry, chronic anxiety, and tension, even when there is little or nothing to provoke it.

Generalized anxiety disorder symptoms include:

  • Restlessness and irritability
  • Fatigue
  • Difficulty concentrating
  • Muscle tension
  • Sleep problems(60)

Obsessive-Compulsive Disorder (OCD)

OCD is characterized by recurrent, unwanted thoughts or obsessions and repetitive behaviors or compulsions. 

Repetitive behaviors, like hand washing and counting, are often done in the hope of making them go away. 

Doing these so-called rituals, however, provides only temporary relief, while not performing them increases anxiety.

People with OCD may also have other mental disorders, such as depression, anxiety, and body dysmorphic disorder, in which someone believes a part of his or her body is abnormal(61). 

Panic Disorder

Panic disorder is described by unexpected and repeated episodes of intense fear.

People with panic disorder sometimes worry about when the next attack can happen and try to prevent future attacks by avoiding certain places, situations, or behaviors they link to the panic attacks.

Worrying about panic attacks and exerting too much effort trying to avoid attacks cause significant problems in various aspects of life.

During a panic attack, people may experience:

  • Heart palpitations or an accelerated heart rate
  • Trembling or shaking
  • Sweating
  • Sensations of shortness of breath or choking
  • Feelings of impending doom and being out of control(62)

Post-Traumatic Stress Disorder (PTSD)

PTSD may develop after exposure to a terrifying ordeal or event in which severe physical harm occurred.

Traumatic events that can trigger PTSD also include violent personal assaults, natural or human-caused disasters, accidents, or military combat(63). 

Anyone can develop PTSD at any age. Those at risk include war veterans, children, and people who have been through a physical or sexual assault, abuse, accident, and disaster. 

According to the National Center for PTSD, 7 or 8 out of every 100 people experience PTSD at some point in their lives(64). 

Women are more likely to have PTSD than men. Also, some genes can make some people more likely to develop PTSD than others.

Not everyone with PTSD has experienced a dangerous event, however. Some people may develop PTSD after a friend or family member experiences danger or harm. The unexpected or sudden passing of a loved one can also lead to PTSD.

Social Phobia or Social Anxiety Disorder (SAD)

SAD is characterized by overwhelming anxiety and excessive self-consciousness in everyday social situations(65). 

Social phobia may be limited to one type of situation, such as a fear of speaking during formal situations or eating in front of others.

In its most severe form, a person with SAD may experience symptoms almost anytime they are around other people.

FAQs on CBD

How is CBD different from THC?

CBD comes from cannabis and is naturally found in hemp plants. CBD is one of more than 100 cannabinoids that occur naturally within the plant. This compound is also commonly used to produce CBD hemp oil supplements. 

Cannabis oil is a term used to refer to any extract of the cannabis plant, including marijuana plant and hemp plant, that removes the plant’s naturally thick, viscous oil from dried or fresh cannabis.

Medical marijuana, also called medical cannabis, is made of dried parts of the Cannabis sativa plant.

Hemp seed oil is produced by extracting the oil from the seeds of the hemp plant itself. This oil is abundant in nutrients, such as omega-3 and omega-6 fatty acids, making it ideal for digestion. 

Although some people refer to “hemp extract” as hemp oil, the term “hemp oil” is synonymous with the term “hemp seed oil.”

Chemical compounds in cannabis, called cannabinoids, have shown various potential benefits by activating the body’s endocannabinoid system (ECS)

The ECS is involved in regulating a variety of body processes and functions, including sleep, appetite, pain, and immune system response(66). 

The body produces endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors in the nervous system.

The medicinal efficacy of cannabis can be optimized by incorporating the various cannabinoids, flavonoids, and terpenes that are intrinsic components of cannabis plants.

CBD is non-psychoactive, contrasting with THC (delta-9-tetrahydrocannabinol), another primary cannabinoid

THC is the most significant factor contributing to the high associated with using cannabis. 

Consuming CBD without any THC does not produce those effects, which means that nearly everyone should be able to function as they usually do when taking CBD. 

The lack of high lets one continue with work, school, and other commitments without a decrease in performance. 

The absence of psychoactive effects also makes CBD oil safe to take, even for those who must pass regular or random drug tests.

CBD oil must not contain any THC for CBD not to induce psychoactive effects. 

Products containing CBD isolates do not have THC, while full-spectrum CBD oil products do. 

The full spectrum of cannabinoids, terpenes, fatty acids, and essential oils extracted from the plant all work together in synergy. 

This synergy magnifies the therapeutic benefits of individual cannabinoids and produces a phenomenon known as the “entourage effect.”

Any product that one buys should also state the percentage of THC, information which one can also get from its certificate of analysis.

What are the FDA-approved drugs that contain CBD and synthetic cannabinoids?

CBD is used in the treatment of some types of epilepsy, such as Dravet’s Syndrome, a complex disorder in children that is associated with a high rate of mortality and drug-resistant seizures.

Epidiolex (cannabidiol) oral solution is the first drug approved by the FDA for the treatment of seizures in individuals two years of age and older(67). 

The scientific study of cannabinoids has led to two FDA-approved drugs, dronabinol and nabilone. These medications contain THC in pill form(68).   

Is CBD safe?

Side effects of CBD include fatigue, nausea, and irritability. CBD can intensify the level of the blood thinner coumadin in the bloodstream, and it can raise levels of certain other medications in the system.

Another significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication(69). 

Currently, the FDA does not regulate the purity and safety of dietary supplements. Thus, consumers cannot know for sure that the product they are buying has active ingredients at the dose printed on the label. The product may also contain other unknown elements. 

Although the World Health Organization says that CBD is safe and well-tolerated, it is not clear how much to take or how often a person should use it for any particular problem. 

High doses of CBD may interact with other medications, such as blood thinners, antidepressants, and immune suppressors(70).

CBD is readily obtainable in many parts of the United States, although its exact legal status continually changes. 

In December 2015, the FDA eased the regulatory stipulations to allow researchers to conduct CBD investigations and trials. Currently, many people are able to get CBD online without a medical cannabis license(71). 

The government’s position on CBD is confusing, and it depends in part on whether the CBD comes from hemp or marijuana(72).

The legality of CBD is expected to change. Currently, there is a bipartisan consensus in Congress to make the hemp crop legal, which would make CBD difficult to prohibit, says Dr. Peter Grinspoon, the author of Free Refills: A Doctor Confronts His Addiction, in a 2019 article published by Harvard Health(73). 

Many states and Washington, D.C., have passed cannabis-related laws, making medical marijuana with high levels of THC legal. Still, marijuana may require a prescription from a licensed physician(74).

Also, several states have made recreational use of marijuana and THC legal. One should be able to buy CBD in states where marijuana is legal for recreational or medical purposes.

To get more information on state laws and penalties, click here(75).

Individuals who possess cannabis-related products in a state where they are illegal or do not have a medical prescription in states where the products are legal for medical treatment could face legal penalties.

For a complete list of legal medical marijuana states and D.C., including the corresponding laws, fees, and possession limits, click here(76).

What does a Farm Bill have to do with CBD?

The 2018 Farm Bill legalized industrial hemp and hemp-derived products at the federal level, removing them from the jurisdiction of the Drug Enforcement Administration (DEA). 

Since hemp is no longer categorized under controlled substances, it is now the job of the United States Department of Agriculture (USDA) to regulate the crop as it does other agricultural commodities. 

The law defined “agricultural hemp” as cannabis strains that contain less than 0.3% THC. Additionally, the Farm Bill explicitly legalized the “extracts, cannabinoids, and derivatives” of hemp. 

Does CBD show up on a drug test? 

CBD products from hemp sold online and in retail stores are not supposed to contain over 0.3 percent THC, the compound in marijuana that can get the user high.

However, sometimes, CBD products contain more THC than the amount printed on the label, says Barry Sample, senior director of science and technology at Quest Diagnostics, the largest administrator of drug tests in the U.S.(77).

It is also possible that, eventually, the trace amounts of THC allowed in CBD products could accumulate in the body to detectable levels, Sample explains.

THC is fat-soluble, adds Norbert Kaminski, Ph.D., professor of pharmacology and toxicology at Michigan State University in East Lansing. Thus, THC that is not immediately broken down by the body is stored in fat tissues(78). 

Over time, THC and THC metabolites (substances made when the body breaks down chemicals) are slowly released,” Kaminski says. As a result, it is possible to test positive for THC and not pass a drug test, even after one has stopped taking the product.

Conclusion

CBD has shown therapeutic efficacy in reducing both physiological and behavioral measures of stress and anxiety(79). 

In addition, in small clinical trials, CBD has shown benefits in helping to reduce symptoms of anxiety with few or no adverse effects

Research on cannabidiol oil (CBD oil) is still in its infancy. However, there has been mounting scientific evidence to suggest that it can help provide anxiety relief or reduce anxiety symptoms.

Still, the long-term side effects of CBD are unknown, and longitudinal scientific research is still lacking.

Thus, consult with a doctor experienced in the use of cannabis products before using CBD as an adjunct anxiety therapy or as a remedy for anxiety and other medical conditions.


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DOXEFAZEPAM
(Group 3)
For definition of Groups, see Preamble Evaluation.

VOL.: 66 (1996) (p. 97)

CAS No.: 40762-15-0
Chem. Abstr. Name: 7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-1-(2-hydroxyethyl)-2H-1,4-benzodiazepin-
2-one

5. Summary of Data Reported and Evaluation
5.1 Exposure data
Doxefazepam is a benzodiazepine hypnotic that was used in the past to a limited extent in the short-term management of insomnia.

5.2 Human carcinogenicity data

No data were available to the Working Group.

5.3 Animal carcinogenicity data

Doxefazepam was tested for carcinogenicity in one experiment in rats by oral administration in the diet. A slight dose-related increase in the incidence of hepatocellular adenomas was observed.

5.4 Other relevant data

Doxefazepam disposition has received little study. In humans, the drug was eliminated in urine mainly as a conjugate, and two oxidative metabolites were identified. The elimination half-life was 3-4 h. No satisfactory metabolism studies in animals were available. Data on human toxicity were not available. In rats treated with 60 mg/kg bw per day for 26 weeks, increased liver weights were reported without other clinical, haematological or histopathological signs of toxicity. In a single study, doxefazepam was not teratogenic in rats or rabbits. The few data available on genetic effects were negative.

5.5 Evaluation

There is inadequate evidence in humans for the carcinogenicity of doxefazepam.

There is limited evidence in experimental animals for the carcinogenicity of doxefazepam.

Overall evaluation

Doxefazepam is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Synonyms

N-1-Hydroxyethyl-3-hydroxyflurazepam
Doxans
SAS 643
Last updated 05/22/97

See Also:
Doxefazepam (PIM 924)

See Also:
Doxefazepam (PIM 924)

INTOX Home Page

MONOGRAPH FOR UKPID

AMITRIPTYLINE HYDROCHLORIDE

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review group: Directors of the UK National Poisons Information
Service.

MONOGRAPH FOR UKPID

Drug name

Amitriptyline hydrochloride.

Chemical group

Tricyclic antidepressant.

Origin of substance

Synthetic.

Name

UK Brand name(s)

e.g. Lentizol(R), Tryptizol(R), Domical(R), Elavil(R).
Also available in compound preparations with perphenazine as
Triptafen(R) and Triptafen-M(R).

Synonyms

Common names/street names

Pharmacotherapeutic group

Drug acting upon CNS; antidepressant; tricyclic.

Reference number

Product licence

Lentizol(R) 25 mg capsules: 0018/0173R
Lentizol(R) 50 mg capsules: 0018/0174R
Tryptizol(R) 10 mg tablets: 0025/0093
Tryptizol(R) 25 mg tablets: 0025/0094
Tryptizol(R) 50 mg tablets: 0025/0095
Tryptizol(R) injection: 0025/5036
Tryptizol(R) syrup: 0025/5037

Other

CAS 549-18-8

Manufacturer

of Lentizol(R)
Name Parke-Davis Medical
Address Lambert Court, Chestnut Avenue, Eastleigh, Hampshire
SO53 3ZQ
Telephone 01703 620500
Fax 01703 629812

of Tryptizol(R)
Name Thomas Morson Pharmaceuticals (a subsidiary of Merck
Sharp & Dohme Ltd)
Address Hertford Road, Hoddesdon, Hertfordshire EN11 9BU
Telephone 01992 467272
Fax 01992 451006

of Domical(R)
Name Berk Pharmaceuticals (a subsidiary of Approved
Prescription Services Ltd)
Address Brampton Road, Hampden Park, Eastbourne, East Sussex
BN22 9AG
Telephone 01323 501111
Fax 01232 520306

of Elavil(R)
Name DDSA Pharmaceuticals Ltd
Address 310 Old Brompton Road, London SW5 9JQ
Telephone 0171 373 7884
Fax 0171 370 4321

Supplier/importer

In addition to the branded products listed above, non-proprietary
products are available from Antigen, APS and Cox.

Name Antigen Pharmaceuticals Ltd
Address Antigen House, 82 Waterloo Rd, Hillside, Southport,
Merseyside, PR8 4QW
Telephone 01704 562777
Fax 01704 562888

Name APS (Approved Prescription Services Ltd)
Address Brampton Road, Hampden Park, Eastbourne, East Sussex
BN22 9AG
Telephone 01323 501111
Fax 01323 520306

Name AH Cox & Co Ltd
Address Whiddon Valley, Barnstaple, Devon EX32 8NS
Telephone 01271 311257
Fax 01271 321326

Presentation

Form

Oral tablets, modified release capsules, and mixture. Injection for
intramuscular or intravenous administration.

Formulation details

Tablets of 10 mg, 25 mg, and 50 mg.
Modified release capsules of 25 mg and 50 mg.
Mixture (as amitriptyline embonate) equivalent to 10mg/5ml.
Injection of 10mg/ml.

Pack size(s)

Lentizol(R)
25 mg and 50 mg modified release capsules: blister packs of 56 or
100.
Tryptizol(R)
10 mg tablets: blister packs of 30,
25 mg tablets: blister packs of 30,
50 mg tablets: blister packs of 30,
mixture: bottle of 200 ml,
injection: vials of 10 ml.

Packaging

Lentizol(R) 25 mg: pink capsules of 25 mg amitriptyline hydrochloride
in a modified release form, marked ‘LENTIZOL 25’,
Lentizol(R) 50 mg: pink/red capsules of 50 mg amitriptyline
hydrochloride in a modified release form, marked ‘LENTIZOL 50’.

Tryptizol(R) 10 mg: blue tablets of 10 mg amitriptyline hydrochloride
marked ‘MSD23′,
Tryptizol(R) 25 mg: yellow tablets of 25 mg amitriptyline
hydrochloride marked’ MSD 45′,
Tryptizol(R) 50 mg: brown tablets of 50 mg amitriptyline hydrochloride
marked ‘MSD 102′,
Tryptizol(R) syrup: pink suspension of amitriptyline embonate
equivalent to 10 mg/5 ml amitriptyline,
Tryptizol(R) injection: colourless solution for injection containing
10mg/ml amitriptyline hydrochloride.

Compound preparations

Triptafen(R): pink tablets of 25 mg amitriptyline hydrochloride and 2
mg perphenazine.
Triptafen-M(R): pink tablets of 10 mg amitriptyline hydrochloride and
2 mg perphenazine.

Amitriptyline is also available in generic and branded-generic
formulations, the appearance of which will differ from the branded
products listed.

Physico-chemical properties

Solubility in water

Freely soluble (Martindale 1996).

Solubility in ether

Practically insoluble (Martindale 1996).

Solubility in other solvents

Freely soluble in alcohol, chloroform, methyl alcohol and
methylene chloride (Martindale 1996).

Chemical structure

3-(10,11-Dihydro- 5H-dibenz-[ a,d]cyclohepten-5-
ylidene)propyldimethylamine hydrochoride

C20H23N,HCl = 313.9

Uses

Indication

Symptomatic treatment of depressive illness especially where sedation
is required. Nocturnal enuresis in children.

Therapeutic dosage

in adults
In depression
by mouth: 75-150 mg daily in single or divided doses (lower doses in
elderly and adolescents).
by IM or IV injection: 10-20 mg four times daily.

in children
For nocturnal enuresis:
6-10 years: 10-20 mg daily by mouth.
11-16 years: 25-50 mg daily by mouth.
Modified release preparations are not licensed for use in children.

Contra-indications

Recent myocardial infarction or coronary artery insufficiency. Heart
block or other cardiac arrhythmia. Mania. Severe liver disease.
Co-administration with monoamine oxidase inhibitors. Hypersensitivity
to amitriptyline. Lactation. Children under 6 years of age.

Abuses

Pharmacokinetics

Absorption

Amitriptyline is well absorbed orally with maximum plasma
concentrations being reached after approximately 3 hours (Schulz et
al. 1985). It undergoes extensive first-pass metabolism, the systemic

bioavailability being in the region of 45%(Schulz et al. 1985).
Little information is available on the disposition of amitriptyline
following parenteral administration.

Distribution

Amitriptyline is widely distributed throughout the body with an
apparent volume of distribution of about 19 L/kg (Schulz et al. 1985).
Approximately 95% of amitriptyline in the plasma is bound to proteins
(Schulz et al. 1985). The plasma protein binding of tricyclic
antidepressants is pH sensitive, with a small reduction in plasma pH
being associated with large increases in unbound (pharmacologically
active) drug (Nyberg & Martensson 1984).

Metabolism

There is wide individual variation in the pharmacokinetic profile of
amitriptyline. Amitriptyline is metabolised in the liver, the primary
routes of metabolism being demethylation, hydroxylation and
conjugation. It is considered that the metabolic pathways are mediated
by the enzymes CYP2D6 and CYP2C19, although other enzymes are probably
also involved (Schmider et al. 1995). The major active metabolites
formed are nortriptyline, 10-hydroxyamitriptyline, and
10-hydroxynortriptyline. Both nortriptyline and
10-hydroxynortriptyline contribute significantly to the antidepressant
effect (Bertilsson et al. 1979).

Elimination

Amitriptyline is excreted mainly in the urine as conjugated and
unconjugated metabolites. Less than 5% is excreted as unchanged drug
(Dollery 1991).
Significant gastric and biliary secretion of amitriptyline and its
metabolites occurs, resulting in enteroenteric and enterohepatic
circulations (Gard et al. 1973).
Dialysis as a means of promoting drug and metabolite elimination is
ineffective (Dawling et al. 1982).

Half-life

substance

Amitriptyline: 21 hours (range 13-36 hours)(Schulz et al. 1985).

metabolite(s)

Nortriptyline: 25 hours (Dawling et al. 1982).
10-hydroxynortriptyline: 26 hours (Dawling et al. 1982).

Special populations

Elderly: metabolic changes in the elderly result in higher plasma
amitriptyline concentrations than in younger populations (Schmider et
al. 1995).

Renal impairment: reduced metabolite clearance in renal impairment
results in accumulation, particularly of the hydroxymetabolites
(Dawling et al. 1982).
Hepatic impairment: reduced metabolic capacity in liver impairment
results in accumulation of amitriptyline (Hrdina et al. 1985).
Gender: there is some evidence to suggest that higher plasma
concentrations of amitriptyline occur in females over the age of 50
than in males of a similar age, but factors other than gender
complicate the picture (Preskorn & Mac 1985, Schmider et al. 1995).

Breast milk

Amitriptyline and its metabolites are secreted into breast milk. In
one patient the amounts of amitriptyline and nortriptyline in the
breast milk and serum were approximately equal (Bader & Newman 1980).
In a second patient the concentrations of amitriptyline, nortriptyline
and 10-hydroxynortriptyline in breast milk were about 50%, 75%, and
70% of the maternal serum concentrations respectively (Breyer-Pfaff et
al. 1995). The doses to the infants in these two cases are
approximately 3% and 1% of the maternal doses respectively.

Toxicokinetics

Absorption

In a study of 27 tricyclic overdose patients, peak plasma
concentrations occurred within 3 hours of the overdose (Bramble et al.
1985).
There was no evidence of prolonged absorption from the gut following
amitriptyline overdose in 9 patients (Hulten et al. 1992).

Distribution

Amitriptyline is rapidly distributed into body tissues with plasma
drug concentrations beginning to fall within 3 hours of overdose
(Bramble et al. 1985).
The value for protein binding remains within the range observed with
therapeutic doses and is likewise pH sensitive (Hulten et al. 1992).

Metabolism

A comparison of half-life values for amitriptyline following overdose
with values after therapeutic dosing suggests that saturation of
metabolic process may occur. Insufficient data are available to draw
firm conclusions.

Elimination

There is evidence to show that enterohepatic or enteroenteral
circulation of the metabolite nortriptyline occurs (Hulten et al.
1992).
Less than 5% of a dose is excreted in urine during the first 24 hours
after overdose (Gard et al. 1973).

Half-life

substance

Following overdose, half-life values between 15 hours and 81 hours
have been reported (Hulten et al. 1992, Spiker & Biggs 1976).

metabolite(s)

Special populations

Breast milk

Adverse effects

Antimuscarinic effects, sedation, ECG changes, arrhythmias, postural
hypotension, tachycardia, syncope, sweating, tremor, rashes,
hypersensitivity reactions, behavioral disturbances, hypomania or
mania, confusion, interference with sexual function, blood sugar
changes, weight gain, convulsions, movement disorders and dyskinesias,
fever, hepatic and haematological reactions.

Interactions

Pharmacodynamic

a) A potentially hazardous interaction may occur between a tricyclic
antidepressant and a monoamine oxidase inhibitor (including
moclobemide and selegiline) resulting in increased amounts of
noradrenaline and serotonin at the synapse. Coma, hyperthermia,
convulsions, delirium, or death may result (White & Simpson 1984).

b) There is an increased risk of cardiotoxicity when administered with
other drugs which prolong the QT interval e.g. anti-arrhythmics,
astemizole, halofantrine, terfenadine.

c) The pharmacology of amitriptyline suggests that concomitant
ingestions of selective serotonin reuptake inhibitors, phenothiazines,
sympathomimetics, or other tricyclic antidepressants will enhance its
toxicity.

Pharmacokinetic

a) The metabolism of tricyclic antidepressants is inhibited by most
selective serotonin reuptake inhibitors resulting in elevated
tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and
paroxetine appear to exert a greater effect than sertraline. Limited
data suggest that citalopram does not inhibit tricyclic metabolism
(Baettig et al. 1993, Taylor 1995).

b) As the metabolism of amitriptyline is mediated by cytochrome P450
microsomal enzymes, particularly CYP2D6 and CYP2C19, the potential
exists for interactions with drugs which are substrates of these
pathways.

c) Cimetidine reduces the metabolic clearance of amitriptyline by
inhibition of liver enzymes, resulting in higher plasma amitriptyline
concentrations (Stockley 1996).

Ethanol

Plasma concentrations of amitriptyline are higher when ingested with
ethanol, probably as a result of reduced first-pass metabolism (Shoaf
& Linnoila 1991).

Summary

Type of product

A tricyclic antidepressant.

Ingredients

Amitriptyline tablets: 10 mg, 25 mg, 50 mg.
Amitriptyline in a modified release capsule: 25 mg, 50 mg.
Amitriptyline mixture: equivalent to 10mg/5ml.
Amitriptyline injection: 10mg/ml.

Summary of toxicity

Patients with only mild signs of toxicity may rapidly develop life-
threatening complications. Where major toxic events occur these
usually develop within 6 hours of overdose, the risk of toxicity being
greatest 2-4 hours after ingestion.

Amitriptyline overdose must be managed on a clinical basis rather than
on the amount ingested, but as a guide, doses of 750 mg in adults have
been associated with severe toxicity. Ingestions of tricyclic
antidepressants in children indicate that doses of 15 mg/kg may prove
fatal to a child, although recovery has followed reported ingestions
of over 100 mg/kg.

Sinus tachycardia, hypotension, and anticholinergic symptoms are
common features. Cardiotoxicity, impaired consciousness, seizures,
acidosis, and respiratory insufficiency are associated with severe
toxicity. The occurrence of seizures may precipitate the onset of
cardiac arrhythmias and hypotension. Delirium may be a complication on
recovery.

Common features

Dry mouth, blurred vision, dilated pupils, urinary retention, sinus
tachycardia, drowsiness, hypothermia, and confusion. Hypoxia,
acidosis, hypotension, convulsions, cardiac arrhythmias, and coma.

Uncommon features

Skin blisters, rhabdomyolysis, disseminated intravascular coagulation,
adult respiratory distress syndrome, and absent brain stem reflexes.

Summary of management

SUPPORTIVE

1. Maintain a clear airway and adequate ventilation if consciousness
is impaired.

2. If within 1 hour of the ingestion and more than 300 mg has been
taken by an adult or more than 1mg/kg by a child, give activated
charcoal.

3. Carry out arterial blood gas analysis, and correct any acidosis
and hypoxia.

4. Monitor the cardiac rhythm and blood pressure.

5. Single, brief convulsions do not require treatment but if they
are prolonged or recurrent, they should be controlled with
intravenous diazepam.

6. Other measures as indicated by the patient’s clinical condition.

Epidemiology

Over an 11 year period between 1975 and 1985, more than 1,200 deaths
were attributable to amitriptyline poisoning in the UK, or 47 deaths
per million prescriptions dispensed (Montgomery et al. 1989).
Fatalities tend to occur in older rather than younger patients. In
both fatal and non-fatal overdose, there are a greater number of
ingestions in females than in males (Crome 1986).
The overall incidence of serious cardiac complications in patients who
are admitted to hospital following tricyclic overdose is reported to
be less than 10%. Some degree of coma occurs in about 50% of cases,
but is only unresponsive to painful stimuli in about 10-15% of cases
(Crome 1986). Convulsions occur in approximately 6% of patients
(Taboulet 1995). The death rate in patients admitted to hospital is
estimated to be 2%-3% (Dziukas & Vohra 1991).

Mechanism of action/toxicity

Mechanism of action

The precise mechanism of antidepressant action is unclear, but results
from the potent inhibition of noradrenaline and serotonin reuptake
into presynaptic neurones, and adaptive changes in receptor
sensitivity (Richelson 1994).

Amitriptyline inhibits the reuptake of noradrenaline and serotonin
with similar potency, whilst the metabolite nortriptyline inhibits the
reuptake of noradrenaline to a greater degree than serotonin. The
hydroxy metabolites of amitriptyline and nortriptyline inhibit
noradrenaline reuptake, but to a lesser degree than the parent drugs.
They do not have any significant effect on serotonin reuptake
(Bertilsson et al. 1979).

Amitriptyline is a potent antagonist of both peripheral and central
muscarinic cholinergic receptors. It has also relatively potent
antagonist activity at H1 histamine and a1 adrenergic receptors.
These antagonist actions account for its anticholinergic, sedative,
and hypotensive properties (Richelson 1994).

Mechanism of toxicity

Toxicity is due to depression of myocardial function (a quinidine-like
effect), central and peripheral muscarininic receptor blockade, a1
adrenergic receptor blockade, and respiratory insufficiency.
The risk of toxicity is greatest 2-4 hours after ingestion when plasma
levels are maximal.

Features of poisoning

Acute

Ingestion

Mild to moderate toxicity: dilated pupils, sinus tachycardia,
drowsiness, dry mouth, blurred vision, urinary retention, absent bowel
sounds, confusion, agitation, body temperature disturbances,
twitching, delirium, hallucinations, nystagmus, and ataxia.
Increased tone and hyperreflexia may be present with extensor plantar
responses (Callaham 1979, Crome 1986, Dziukias & Vohra 1991).

Severe toxicity: coma, hypotension, convulsions, supraventricular
and ventricular arrhythmias, hypoxia, metabolic/respiratory acidosis,
and cardiac arrest (Crome 1986, Dziukias & Vohra 1991).

ECG changes (in the usual order of appearance) include non-specific ST
or T wave changes, prolongation of the QT, PR, and QRS intervals,
right bundle branch block, and atrioventricular block. The terminal
0.04 second frontal plane QRS axis often shows a right axis deviation
(Dziukas & Vohra 1991).

Delayed features: adult respiratory distress syndrome (Varnell et
al. 1989).

Uncommon features: skin blisters, rhabdomyolysis, disseminated
intravascular coagulation, gaze paralysis, and absent brain reflexes
(Dziukias & Vohra 1991, White 1988, Yang & Dantzker 1991). See case
report 1.

Inhalation

Dermal

Ocular

Other routes

Chronic

Ingestion

Inhalation

Dermal

Ocular

Other routes

At risk groups

Elderly

There is an increased risk of toxicity resulting from impaired drug
metabolism (Schmider et al. 1995).

Pregnancy

There is relatively wide experience with the therapeutic use of
amitriptyline during pregnancy. Although a few birth defects have been
reported, the number is insufficient to support an association with
amitriptyline administration (Briggs 1994).

Children

Ingestions in children result in features similar to those following
adult ingestion (Crome & Braithwaite 1978, Goel & Shanks 1974, James &
Kearns 1995). See case report 2.

Enzyme deficiencies

The metabolism of amitriptyline is in part mediated by the microsomal
enzymes CYP2D6 and CYP2C19 which are subject to genetic polymorphism
(Schmider et al. 1995). Metabolic processes will differ in individuals
deficient in these enzymes and there is a risk of amitriptyline
accumulation.

Enzyme induced

The metabolism of amitriptyline is increased in the presence of enzyme
inducing drugs, but is of doubtful clinical relevance as the
metabolites formed also have pharmacological activity.

Others

Renal impairment: increased risk of toxicity due to accumulation of
metabolites.
Hepatic impairment: increased risk of toxicity due to impaired
amitriptyline metabolism.
Cardiac disease: increased risk of cardiotoxicity due to underlying
disease.
Epilepsy: increased risk of seizures.

Management

Decontamination

In cases where more than 300 mg has been taken by an adult or more
than 1mg/kg by a child, activated charcoal should be given to reduce
the absorption if administered within one hour of the drug ingestion.
Adult dose; 50 g, child dose; 1 g/kg. If the patient is drowsy this
should be administered via a nasogastric tube, and if there is no gag
reflex present, using a cuffed endotracheal tube to protect the
airway.

Supportive care

General

Clear and maintain the airway, and give cardiopulmonary resuscitation
where necessary. Evaluate the patient’s condition and provide support
for vital functions.

Management of the symptomatic patient

1. Administer intravenous sodium bicarbonate to correct any
acidosis.

Adult dose: 50 ml of 8.4%sodium bicarbonate by slow intravenous
injection; child dose: 1 ml/kg of 8.4% sodium bicarbonate by slow
intravenous injection.

Subsequent bicarbonate therapy should be guided by arterial blood pH
which should be monitored frequently.

2. Maintain adequate ventilation to prevent hypoxia with
supplemental oxygen or artificial ventilation as appropriate.

3. Carefully maintain plasma potassium levels to prevent
hypokalaemia.

In mixed overdoses where a benzodiazepine has also been ingested,
the use of the competitive benzodiazepine antagonist flumazenil is
contraindicated (Mordel et al. 1992).

Where symptoms develop following mild to moderate overdose, they may
persist for 24 hours. Prolonged or delayed complications following
severe toxicity may require the patient to be hospitalised for several
days.

Specific

Management of cardiotoxicity.

GENERAL NOTE: in practice it is seldom necessary or advisable to use
specific drug treatment for arrhythmias. If hypoxia and acidosis are
reversed and adequate serum potassium levels maintained, then the
majority of patients show improvement with supportive measures.

SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment
required (Pimentel & Trommer 1994).

VENTRICULAR ARRHYTHMIAS: give sodium bicarbonate (even in the absence
of acidosis) before considering antiarrhythmic drug therapy. Where an
antiarrhythmic is considered necessary, lignocaine is the preferred
drug (Pimentel & Trommer 1994).

ADULT DOSE: 50-100 mg given by IV bolus over a few minutes,
followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2
mg/minute for 2 hours, then 1 mg/minute (BNF 1998).
The use of quinidine, disopyramide, procainamide, and flecainide are
all contra-indicated as they depress cardiac conduction and
contractility. The use of beta-blockers should also be avoided as they
decrease cardiac output and exacerbate hypotension. The efficacy of
other antiarrhythmic agents (e.g bretylium, amiodarone, calcium
channel blockers) has not been studied in tricyclic antidepressant
poisoning (Pimentel & Trommer 1994).

BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited
success as the cardiotoxicity of amitriptyline results from depression
of contractility rather than failure of cardiac pacemakers.

CARDIAC ARREST: manage in the standard manner but with continuing
resuscitative measures as some patients have recovered after receiving
several hours of external cardiac massage (Orr & Bramble 1981).

Management of coma

Good supportive care is essential.

Management of hypotension

Hypotension should be managed by the administration of intravenous
fluids and by physical means. The majority of patients ingesting
amitriptyline have otherwise healthy cardiovascular systems and
providing cardiac output is good it is unnecessary to use specific
drug therapy.

If there is evidence of poor cardiac output (after correction of
acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive
agent may need to be considered. Noradrenaline has been shown to be
helpful in a number of studies (including cases where dopamine therapy
has failed) (Pimentel & Trommer 1994, Teba et al. 1988, Yang &
Dantzker 1991).

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via
a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute
adjusted according to response (BNF 1998).

CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
microgram/kg/minute of noradrenaline base) in glucose 5% or
glucose/saline via a central venous catheter (Guy’s, Lewisham & St
Thomas Paediatric Formulary, 1997).

Management of seizures

Administer intravenous diazepam to control frequent or prolonged
convulsions.

ADULT DOSE: 10 mg,
CHILD DOSE: 0.25-0.4 mg/kg,
Both by slow IV injection preferably in emulsion form.

Where seizure activity proves difficult to manage, paralyse and
ventilate the patient. Continue to monitor the cerebral function to
ensure the cessation of seizure activity.

Other management

Catheterisation may be required to relieve distressing urinary
retention and to allow continuous monitoring of urine output as a
means of assessing cardiac output (Crome 1986).
Respiratory complications should be managed conventionally with early
respiratory support.
Control delirium with oral diazepam. Large doses may be required (20-
30 mg two-hourly in adults).

Monitoring

Monitor the cardiac rhythm, arterial blood gases, serum electrolytes,
blood pressure, respiratory rate and depth, and urinary output.

Observe for a minimum of 6 hours post-ingestion where:
i) more than 1 mg/kg has been ingested by a child,
ii) more than 300 mg has been ingested by an adult,
iii) the patient is symptomatic.

Antidotes

None available.

Elimination techniques

Due to the large volume of distribution and high lipid solubility of
amitriptyline, haemodialysis and haemoperfusion do not significantly
increase drug elimination (Lieberman et al. 1985).

Investigations

Following severe toxicity:

i) a chest X-ray will be needed to exclude pulmonary complications,
ii) measure serum creatine kinase and other skeletal muscle enzyme
activity (e.g. AST, ALT, and lactic dehydrogenase),
iii) assess renal function,
iv) assess haematological status.

Management controversies

Gastric lavage is not recommended as the procedure may be associated
with significant morbidity, and there is no evidence that it is of any
greater benefit than activated charcoal used alone (Bosse et al.
1995).
If the procedure is used (i.e. in cases where activated charcoal
cannot be administered), a cuffed endotracheal tube should be used to
protect the airway if the patient is drowsy, and activated charcoal
left in the stomach following the lavage.

Repeat doses of oral activated charcoal may prevent the reabsorption
of tricyclic antidepressants and their metabolites secreted in gastric
juices and bile (Swartz & Sherman 1984). However, it would not be
expected from the large volume of distribution of amitriptyline that
clinically significant increases in body clearance would result.

Physostigmine salicylate is a short acting reversible cholinesterase
inhibitor which has been used historically in the management of
tricyclic overdoses to reverse coma and antimuscarinic effects.
Reports of serious complications from its use include severe
cholinergic activity, convulsions, bradycardia, and asystole (Newton
1975, Pentel & Peterson 1980). The use of physostigmine is no longer
recommended.

The use of dopamine in the management of hypotension has been
advocated, but the pressor effect of this indirect acting inotrope may
be diminished in tricyclic overdosed patients due to depleted levels
of noradrenaline (Buchman et al. 1990, Pimentel & Trommer 1994, Teba
et al. 1988).

The use of intravenous glucagon has been proposed in cases where
hypotension is unresponsive to volume expansion and sodium bicarbonate
administration, because of its positive inotropic effect and possible
antiarrhythmic property. Its place in therapy has not been established
(Senner et al. 1995).

Adult dose: 10 mg by IV bolus followed by an infusion of 10 mg
over 6 hours (unlicensed indication and dose).

There are a number of reports of severe arrhythmias or sudden death
occurring up to 1 week after tricyclic overdose, but a review of the
cases show that the patients had continuing toxicity, underlying
disease, or abnormalities (Stern et al. 1985). See case report 3.

Several predictors of clinical severity in tricyclic overdoses have
been suggested, including:

1. a maximal limb-lead QRS duration of 0.1 second or longer as a
predictor of the risk of seizure (Boehnert & Lovejoy 1985),
2. a maximal limb-lead QRS duration of 0.16 second or longer as a
predictor of the risk of ventricular arrhythmias (Boehnert & Lovejoy
1985),
3. plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart
1991),
4. the ECG terminal 40-ms frontal plane QRS axis of more than 120°
(Wolfe et al. 1989).
5. plasma drug concentrations in excess of 2 mg/L as a predictor of
the development of lung injury (Roy et al. 1989).

Whilst none of these features in isolation are predictive of
life-threatening toxicity, they may be helpful in assessing patient
risk.

Case data

Case report 1

Massive ingestion of amitriptyline in an adult.

A 46 year old woman took an estimated 9 g of amitriptyline. One hour
later she suffered a grand mal seizure. Diazepam, phenobarbitone and
physostigmine were administered. Her blood pressure was 98/66 mm Hg,
and the pulse was 94 beats per minute. Arterial blood gas values
showed a pH of 7.16, PaCO2 of 31 mm Hg, and PaO2 of 373 mm Hg on 100
percent oxygen. The ECG revealed a widened QRS complex of 160 ms. She
had metabolic acidosis and an anion gap of 24. Dopamine and adrenaline
were given to maintain blood pressure. At this time the woman was
transferred to intensive care facilities as she failed to respond to
pressor therapy. She was comatose with no response to painful stimuli,
without spontaneous respiration, and corneal and oculocephalic
reflexes were absent. The serum amitriptyline level was 2.35 mg/L. Her
blood pressure remained low (75/50) despite an infusion of 30

micrograms/kg/min of dopamine, but rose to 130/70 when noradrenaline
was substituted for dopamine. Spontaneous respiration returned after
24 hours, and during the next 3 days corneal, pupillary, and
oculocephalic reflexes also returned. The patient regained full
consciousness five days after the ingestion (Yang & Dantzker 1991).

Case report 2

Ingestion of 1.15 g amitriptyline in a young child.

A 20-month-old girl reportedly ingested 23 tablets of amitriptyline 50
mg. She was cyanotic, comatose, and had continuous clonic-tonic
seizures. Her rectal temperature was 34.7°C, the heart rate was 115
beats/min, and her blood pressure was 59/27 mm Hg. The ECG tracing was
consistent with ventricular tachycardia. After extensive resuscitative
measures, including mechanical ventilation, the girl recovered and was
discharged home one week later (Beal & May 1989).

Case Report 3

Unexpected death 7 days after overdose in adult.

A 34 year old woman was admitted to hospital following an intentional
overdose of amitriptyline and diazepam. She was comatose, had a sinus
tachycardia, nonspecific ST and T wave changes, and was normotensive.
Her electrolyte levels were normal except for a potassium value of 3.3
mmmol/L. During 44 hours of monitoring no arrhythmias occurred and her
mental status returned to normal. On the second day her usual
hydrochlorothiazide diuretic therapy was restarted, the potassium
level being 4 mmmol/L at this time. Five days after admission her
potassium level was 3.2 mmmol/L. Seven days after recovery from
overdose the patient was found unresponsive and in refractory
ventricular fibrillation. Venous blood samples during unsuccessful
resuscitative efforts showed a potassium level of 2.6 mmmol/L.
Post-mortem plasma amitriptyline and nortriptyline levels were both
0.2 mg/L. An autopsy did not reveal an anatomic cause of death (Babb &
Dunlop 1985).

Analysis

Agent/toxin/metabolite

There is no clear relationship between plasma amitriptyline
concentration and clinical response or toxicity. Consequently the
measurement of plasma drug concentration following overdose is not
routinely advised, although it may have diagnostic value.

Sample container

Storage conditions

Transport

Interpretation of data

There is considerable variation in plasma concentrations of
amitriptyline and its metabolites between individuals.
As a guide, a therapeutic range for amitriptyline of 0.15-0.25 mg/L
has been proposed, whilst moderate to severe toxicity is associated
with combined amitriptyline and nortriptyline concentrations of 1 mg/L
or greater (Bramble et al. 1985, Preskorn & Mac 1985).

Conversion factors

1 mg/L = 3.186 micromoles/L
1 micromole/L = 0.314 mg/L

Other

The molecular weight of amitriptyline hydrochloride is 313.9

Other toxicological data

Carcinogenicity

Tumour-inducing effects have not been reported (Dollery 1991).

Reprotoxicity

Teratogenicity

There are occasional reports suggesting an association between
amitriptyline and congenital abnormalities (particularly limb
reductions), but analysis of over 500,000 births failed to confirm
such an association.
A surveillance study between 1985 and 1992 involving over 200,000
completed pregnancies exposed to amitriptyline (of which 467 were
during the first trimester) observed 25 major birth defects (20
expected in a control population). These data do not support an
association between amitriptyline and congenital defects (Briggs
1994).

Relevant animal data

There is evidence of amitriptyline-induced teratogenicity in some
animals. Encephaloceles and bent tails in hamsters, and skeletal
malformations in rats have been reported (Briggs 1994).

Relevant in vitro data

Authors

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph was produced by the staff of the Leeds Centre of the
National Poisons Information Service in the United Kingdom. The work
was commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review was undertaken by the Directors of the UK National Poisons
Information Service.

Prepared September 1996
Updated May 1998

References

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Value of the QRS duration versus the serum drug level in predicting
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The use of vasoactive agents in the treatment of refractory
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Tricyclic antidepressant overdose. J Am Coll Emerg Phys 1979; 8:
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Demographic and electrocardiographic factors associated with severe
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Dawling S, Lynn K, Rosser R, Braithwaite R.
Nortriptyline metabolism in chronic renal failure: metabolite
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Dziukas LJ, Vohra J.
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Gard H, Knapp D, Hanenson I, Walle T, Gaffney T.
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Amitriptyline and amitriptyline metabolites in blood and cerebrospinal
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James LP, Kearns GL.
Cyclic antidepressant toxicity in children and adolescents. J Clin
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Lieberman JA, Cooper TB, Suckow RF, Steinberg H, Borenstein M, Brenner
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Martindale, The Extra Pharmacopeia. 31st ed.
Ed Reynolds, JEF. London: The Royal Pharmaceutical Society, 1996.

Montgomery SA, Baldwin D, Green M.
Why do amitriptyline and dothiepin appear to be so dangerous in
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Mordel A, Winkler E, Almog S, Tirosh M, Ezra D.
Seizures after flumazenil administration in a case of combined
benzodiazepine and tricyclic antidepressant overdose. Crit Care Med
1992; 20: 1733-1734.

Newton RW.
Physostigmine salicylate in the treatment of tricyclic antidepressant
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Nyberg G, Martensson E.
Determination of free fractions of tricyclic antidepressants. Arch
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Orr DA, Bramble MG.
Tricyclic antidepressant poisoning and prolonged external cardiac
massage during asystole. Br Med J 1981; 283: 1107-1108.

Pentel P, Peterson CD.
Asystole complicating physostigmine treatment of tricyclic
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Preskon SH, Mac DS.
Plasma levels of amitriptyline: effect of age and sex. J Clin
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Roy TM, Ossorio MA, Cipolla LM, Fields CL, Snider HL, Anderson WH.
Pulmonary complications after tricyclic antidepressant overdose. Chest
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Schmider J, Deuschle M, Schweiger U, Korner A, Gotthardt U, Heuser IJ.
Amitriptyline metabolism in elderly depressed patients and normal
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Schulz P, Dick P, Blaschke TF, Hollister L.
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Response to glucagon in imipramine overdose. Clin Toxicol 1995; 33:
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Interaction of ethanol and smoking on the pharmacokinetics and
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Spiker DG, Biggs JT.
Tricyclic antidepressants: prolonged plasma levels after overdose. J
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Stern TA, O’Gara PT, Mulley AG, Singer DE, Thibault GE.
Complications after overdose with tricyclic antidepressants. Crit Care
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Stockley IH.
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The treatment of tricyclic antidepressant overdose with repeated
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Cardiovascular repercussions of seizures during cyclic antidepressant
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Beneficial effect of norepinephrine in the treatment of circulatory
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Adult respiratory distress syndrome from overdose of tricyclic
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White A.
Overdose of tricyclic antidepressants associated with absent
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The combined use of MAOI’s and tricyclics. J Clin Psychiatry 1984; 45:
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Terminal 40-ms frontal plane QRS axis as a marker for tricyclic
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Reversible brain death: a manifestation of amitriptyline overdose.
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INTOX Home Page
Moclobemide
1. NAME
1.1 Substance
1.2 Group
1.3 Synonyms
1.4 Identification numbers
1.4.1 CAS number
1.4.2 Other numbers
1.5 Main brand names, main trade names
1.6 Main manufacturers, main importers
2. SUMMARY
2.1 Main risks and target organs
2.2 Summary of clinical effects
2.3 Diagnosis
2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
3.2 Chemical structure
3.3 Physical properties
3.3.1 Colour
3.3.2 State/Form
3.3.3 Description
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Storage conditions
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
4.2 Therapeutic dosage
4.2.1 Adults
4.2.2 Children
4.3 Contraindications
5. ROUTES OF EXPOSURE
5.1 Oral
5.2 Inhalation
5.3 Dermal
5.4 Eye
5.5 Parenteral
5.6 Other
6. KINETICS
6.1 Absorption by route of exposure
6.2 Distribution by route of exposure
6.3 Biological half-life by route of exposure
6.4 Metabolism
6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
7.1.2 Pharmacodynamics
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
7.2.1.2 Children
7.2.2 Relevant animal data
7.2.3 Relevant in vitro data
7.3 Carcinogenicity
7.4 Teratogenicity
7.5 Mutagenicity
7.6 Interactions
7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analysis
8.1.1.2 Biomedical analysis
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analysis
8.1.1.5 Other (unspecified) analysis
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analysis
8.1.2.2 Biomedical analysis
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analysis
8.1.2.5 Other (unspecified) analysis
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analysis
8.1.3.2 Biomedical analysis
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analysis
8.1.3.5 Other (unspecified) analysis
8.2 Toxicological analysis and their interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
8.2.1.2 Advanced qualitative confirmation test(s)
8.2.1.3 Simple quantitative method(s)
8.2.1.4 Advanced quantitative method(s)
8.2.2 Test for biological specimens
8.2.2.1 Simple qualitative test(s)
8.2.2.2 Advanced qualitative confirmation test(s)
8.2.2.3 Simple quantitative method
8.2.2.4 Advanced quantitative method(s)
8.2.2.5 Other dedicated method(s)
8.2.3 Interpretation of toxicological analysis
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analysis
8.3.3 Haematological analysis
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their interpretation
8.5 Overall interpretation of all toxicological analysis and toxicological investigations
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
9.1.2 Inhalation
9.1.3 Skin exposure
9.1.4 Eye contact
9.1.5 Parenteral exposure
9.1.6 Other
9.2 Chronic poisoning
9.2.1 Ingestion
9.2.2 Inhalation
9.2.3 Skin exposure
9.2.4 Eye contact
9.2.5 Parenteral exposure
9.2.6 Other
9.3 Course, prognosis, cause of death
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
9.4.2 Respiratory
9.4.3 Neurological
9.4.3.1 Central nervous system
9.4.3.2 Peripheral nervous system
9.4.3.3 Autonomic nervous system
9.4.3.4 Skeletal and smooth muscle
9.4.4 Gastrointestinal
9.4.5 Hepatic
9.4.6 Urinary
9.4.6.1 Renal
9.4.6.2 Other
9.4.7 Endocrine and reproductive systems
9.4.8 Dermatological
9.4.9 Eye, ear, nose, throat: local effects
9.4.10 Haematological
9.4.11 Immunological
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
9.4.12.2 Fluid and electrolyte disturbances
9.4.12.3 Others
9.4.13 Allergic reactions
9.4.14 Other clinical effects
9.4.15 Special risks
9.5 Other
9.6 Summary
10. MANAGEMENT
10.1 General principles
10.2 Life supportive procedures and symptomatic/specific treatment
10.3 Decontamination
10.4 Enhanced elimination
10.5 Antidote treatment
10.5.1 Adults
10.5.2 Children
10.6 Management discussion
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

MOCLOBEMIDE

International Programme on Chemical Safety
Poisons Information Monograph 151
Pharmaceutical

1. NAME

1.1 Substance

Moclobemide

1.2 Group

Psycholeptics (N06)/ Antidepressants (N06A)/
Non-hydrazide MAO inhibitors (N06A G02)

1.3 Synonyms

RO 11-1163

1.4 Identification numbers

1.4.1 CAS number

71320-77-9

1.4.2 Other numbers

No data available.

1.5 Main brand names, main trade names

Aurorix (Australia, Austria, Belgium, Germany,
Netherlands, Norway, South Africa, Sweden, Switzerland);
Manerix (Canada, Spain, UK);
Moclamine (France);

1.6 Main manufacturers, main importers

Roche

2. SUMMARY

2.1 Main risks and target organs

Moclobemide is a short-acting, selective and reversible
monoamine oxidase type A inhibitor (RIMA).
It is generally well tolerated in overdose when taken
alone.

The serotonergic effects of moclobemide may be enhanced by
combination with tricyclic antidepressants, other monoamine
oxidase inhibitors, selective serotonin reuptake inhibitors
(SSRIs), lithium or serotonergic substances. A life-
threatening serotonin syndrome consisting of hyperthermia,
tremor and convulsions can develop when moclobemide is
ingested with these drugs.
The concomitant consumption of large amounts of tyramine-rich
foodstuff may result in a moderate increase of systolic blood
pressure (cheese reaction).

2.2 Summary of clinical effects

Agitation, drowsiness, disorientation, slow-reacting
pupils, myoclonic jerks in upper extremities; hypo or
hypertension, tachycardia; nausea, vomiting, abdominal
pain.

2.3 Diagnosis

Diagnosis of moclobemide poisoning is clinical and based
on history of overdose and/or access to moclobemide and the
presence of gastroenterological symptoms and minor
neurological symptoms.
Co-ingestion of tricyclic antidepressants and/or selective
serotonin reuptake inhibitors should be suspected and the
diagnosis of the serotonin syndrome should be considered in
the presence of three or more of the following symptoms:
behavioural change (confusion or hypomania), agitation,
myoclonus, ocular clonus, hyperreflexia, sweating, shivering,
tremor, diarrhoea, motor incoordination, muscle rigidity,
fever. The differential diagnoses include neuroleptic
malignant syndrome, acute poisoning with strychnine, acute
sepsis, or severe metabolic disturbances.

2.4 First aid measures and management principles

Due to the potential for delayed toxicity, any patient
with a history of acute moclobemide overdose, should be
admitted for observation and remain for 24 hours, even in the
absence of initial symptoms.
Management of moclobemide overdose as a single agent consists
primarily of observation and basic supportive care until
symptoms resolve.
Treatment of the serotonin syndrome may require aggressive
supportive care including diazepam, mechanical ventilation,
external cooling and if necessary, curarization. Although
several deaths have been reported, the symptoms of the
serotonin syndrome usually resolve over 1 to 2 days with
supportive care.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Obtained by synthesis.

3.2 Chemical structure

Structural name: 4-Chloro-N (2-morpholinoéthyl)benzamide

Molecular formula: C13H17O2N2Cl

Molecular weight: 268.7

3.3 Physical properties

3.3.1 Colour

Whiteredish

3.3.2 State/Form

Solid-crystals

3.3.3 Description

Weak odour
Solubility (g/100 mL) at 25 °C:
Chloroform: 33.6
Methanol: 11.8
Water: 0.4
Artificial gastric fluid (pH 1.2): 2.6 at 37 °C
Artificial intestinal fluid (pH 6.8): 0.3 at 37 °C
pKa 6.2
Melting point: 138 °C
(Roche lab., 1996)

3.4 Other characteristics

3.4.1 Shelf-life of the substance

3 years at 20 °C

3.4.2 Storage conditions

Keep at 20 °C in polyethylene bottles or foil
packs.

4. USES

4.1 Indications

4.1.1 Indications

Psychoanaleptic Antidepressant Monoamine oxidase inhibitor;
non-selective;
antidepressant

4.1.2 Description

Accepted:
Major mental depression
Dysthymia.
Investigational:
Menopausal flushing (Menkes et al., 1994)
Prophylactic treatment of migraine (Meienberg &
Amsler, 1996)
Smoking cessation and abstinence in heavy dependent
smokers (Berlin et al., 1995).

4.2 Therapeutic dosage

4.2.1 Adults

Usual initial dosage is a total daily dose of
300 mg by mouth after food in 2 or 3 doses. This may
be increased to up to 600 mg daily according to
response (Reynolds, 1996).
Dosage should be reduced by one third or half the
normal dosage in patients with significant hepatic
impairment (Roche lab., 1996).

4.2.2 Children

No data available

4.3 Contraindications

Absolute:
Hypersensitivity to moclobemide.
Children less than 15 years old.
Breast feeding (in the absence of available data on potential
toxic effects to suckling infants): less than 3 % of the
administered dose of moclobemide is excreted in breast
milk.
Co-administration of sumatriptan: hypertensive crises, severe
coronary vasoconstriction may occur.
Co-administration of pethidine (meperidine),
dextromethorphan: the serotonin syndrome may occur.
(Roche lab., 1996)

Moclobemide is contra-indicated in patients with acute
confusional states and in those with phaeochromocytoma.
It should be avoided in excited or agitated patients and in
those with severe hepatic impairment.
(Reynolds, 1996)
Relative:
Co-administration of drugs which increase the levels of
monoamines such as serotonin and noradrenaline: tricyclic
antidepressants, selective serotonin re-uptake inhibitor
antidepressants: a serotonin syndrome may occur.
Alcohol (as for other psychoactive drugs).
Pregnancy (no data available)
(Roche lab., 1996).

5. ROUTES OF EXPOSURE

5.1 Oral

Moclobemide is available as tablets, thus ingestion is
the most common route of exposure.

5.2 Inhalation

Not relevant

5.3 Dermal

Not relevant

5.4 Eye

Not relevant

5.5 Parenteral

No data available

5.6 Other

No data available.

6. KINETICS

6.1 Absorption by route of exposure

Readily absorbed from the gastro-intestinal tract.
Food delays absorption (Fulton and Benfield, 1996).
Peak plasma concentration: 1 to 2 hours after ingestion.
Oral bioavailability was reported as 60 % after a single dose
and 80 % after repeated doses, due to an important and
saturable hepatic first-pass effect (Roche lab., 1996).

6.2 Distribution by route of exposure

Widely distributed throughout the body. Plasma protein
binding is 50 %.
After oral administration of 50 mg to 6 healthy subjects, the
mean volume of distribution was about 1 L/kg (Raaflaub et
al., 1984).
The therapeutic levels range from 0.5 to 1.5 mg/L (Iwersen &
Schmoldt, 1996).
Less than 3 % of the administered dose is excreted in breast
milk (Mayersohn & Guentert, 1995).

6.3 Biological half-life by route of exposure

After single oral doses, plasma half-life is 1 to 2
hours; with long term treatment, the half-life is reported to
increase to 2 to 4 hours (Iwersen & Schmoldt, 1996; Roche
lab., 1996).

6.4 Metabolism

Moclobemide undergoes extensive metabolism, mainly
carbon and nitrogen oxidation in the liver, deamination and
aromatic hydroxylation. Metabolites are inactive (Mayersohn &
Guentert, 1995).

6.5 Elimination and excretion

Systemic plasma clearance: 310 to 750 mL/min.
Renal clearance: 1 to 5 mL/min
Metabolites of moclobemide and a small amount of unchanged
drug (less than 1 %) are excreted in the urine; after an oral
dose of 50 mg radio-labelled moclobemide, 92 % of the dose
was excreted in the urine within 12 hours (Roche lab.,
1996).

7. PHARMACOLOGY AND TOXICOLOGY

7.1 Mode of action

7.1.1 Toxicodynamics

Moclobemide selectively and reversibly inhibits
the activity of the intracellular enzyme monoamine
oxidase A (MAO-A), thus preventing the normal
metabolism of biogenic amines (noradrenaline,
adrenaline, serotonin, dopamine).
Mono amine oxidase inhibitors (MAOIs) exert their
toxic effects by inhibiting the metabolism of
sympathomimetic amines and serotonin, and by
decreasing noradrenaline stores in post-ganglionic
sympathetic neurons. They do not inhibit MAO
synthesis. MAOIs also inhibit enzymes other than MAO,

including dopamine-beta-oxidase, diamine-oxidase,
amino-acid decarboxylase and choline dehydrogenase.
Inhibition of these enzymes occurs only with very high
doses of MAOIs and may be responsible for some of the
toxic effects of MAOIs.
Drugs that enhance serotonin release or reuptake
(tricyclic antidepressants, selective serotonin
reuptake inhibitors) may cause the serotonin syndrome
when they are administered concurrently with the
MAOIs, even at therapeutic doses (Sternbach, 1991;
Livingston & Livingston, 1996).
A toxic reaction to MAOIs may be caused by pressor
amines such as tyramine, resulting in hypertensive
crisis. When the protective role of intestinal and
hepatic MAO is eliminated, increased absorption of
tyramine from certain foods occurs and can cause a
significant increase in blood pressure (“cheese
reaction”) through the release of noradrenaline from
pre-synaptic vesicles (Mayersohn & Guentert,
1995).
Two isoforms of the MAO enzyme have been discovered:
MAO-A and MAO-B. These isoforms differ in anatomical
distribution and preferred substrates. The new MAOIs
such as moclobemide are isoform-selective and
reversibly inhibit MAO-A. Thus having a lower
potential for interactions than non selective MAOIs at
therapeutic doses. Selectivity is lost in overdoses
and in extreme situations such as high-dose
combination therapies and mixed drug overdoses, and
severe toxic reactions may occur (Mayersohn &
Guentert, 1995).

7.1.2 Pharmacodynamics

The MAOs are a group of enzymes that
metabolise, and therefore inactivate endogenous
pressor amines (such as noradrenaline, adrenaline,
dopamine, serotonin) as well as ingested indogenous
amines (such as tyramine). MAOIs inhibit the
degradation of these amines by MAO. The increased
availability of biogenic amines (such as noradrenaline
and serotonin) is thought to be linked with the
improvement in depression accounted for by MAIO
treatment (Livingston & Livingston, 1996).
Two isoforms of the MAO enzyme have been discovered:
MAO-A and MAO-B, which differ in anatomical
distribution and preferred substrates. The MAO type A
enzymes preferentially metabolize serotonin and
noradrenaline and are located primarily in the
placenta, gut and liver. The MAO type B enzymes are
predominant in brain, liver and platelets, and
phenylethylamine, methylhistamine and tryptamine are
their primary substrates. Both MAO-A and MAO-B

metabolize tyramine (Mayersohn & Guentert, 1995).
New MAOIs such as moclobemide, which are isoform-
selective and have reversible inhibition of the enzyme
are called Reversible Inhibitors of MAO-A (RIMA). The
duration of MAO-A inhibition by moclobemide is shorter
(16 to 24 hours) than the inhibition induced by
conventional MAOIs (> 10 days) (Roche lab.,
1996).
The interaction of the newer RIMAs with hepatic
cytochrome P450 appears to be much weaker than with
the irreversible and nonspecific MAOIs. However,
several studies in humans have suggested there is some
involvement of cytochtome P450 in the metabolism of
moclobemide, and also a weak inhibitory effect of
moclobemide for its isoenzyme CYP2D6. The clinical
relevance of this weak interaction is not clear and is
probably of little consequence (Mayersohn & Guentert,
1995).
Like tricyclic antidepressants, SSRIs and other MAOIs,
moclobemide significantly reduces REM (rapid eye
movement) sleep density, REM time and the REM
percentage of total sleep time in patients with major
depression (Roche lab., 1996).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

Myrenfors et al. (1993) reported a
case series of 8 pure moclobemide overdoses.
Patients ingesting up to 2 grams showed no
symptoms or mild gastro-intestinal
disturbances.
Ingestions of 3 to 4 grams were associated
with a slight increase in blood pressure, and
decrease in consciousness.
Fatigue, agitation, tachycardia, increased
blood pressure, and minimally reactive
mydriasis occurred with the ingestion of
moclobemide doses of 7 to 8 grams.
The ingestion of moclobemide with other drugs
produced a more varied and severe clinical
picture, even with moderate doses of
moclobemide.

7.2.1.2 Children

No data available

7.2.2 Relevant animal data

In mice: LD 50 (oral): 1141 mg/kg
LD 50 (intraperitoneal): 527 mg/kg
Symptomatology: sedation, muscle twitching,
respiratory depression, death.

In rats: LD 50 (oral): 4138 mg/kg
LD 50 (intraperitoneal): 678 mg/kg
Symptomatology: sedation, respiratory depression,
death.

In rabbits: LD 50 (oral): 800 mg/kg
Symptomatology: ataxia, decrease in motor activity,
respiratory depression, tremor, seizures, salivation,
death.
(Roche lab., 1996).

7.2.3 Relevant in vitro data

No data available.

7.3 Carcinogenicity

Animal studies: moclobemide was not carcinogenic in
rats at doses ranging from 9 to 225 mg/kg/day orally for 2
years. In mice given 10, 50 or 100 mg/kg/day orally over 80
weeks, no carcinogenic effect was observed (Roche lab.,
1996).

7.4 Teratogenicity

Animal studies:
– doses up to 100 mg/kg/day did not affect fertility in
rats.
– in rabbits and rats oral doses of up to 100 and 200
mg/kg/day respectively did not have embryotoxic or
teratogenic effects
(Roche lab., 1996).

7.5 Mutagenicity

In vitro and in vivo: moclobemide did not show
mutagenicity (Roche lab., 1996).

7.6 Interactions

Drug-food interactions:
the dietary restrictions that need to be followed with
irreversible MAOIs are less stringent with selective
reversible inhibitors of monoamine oxidase type A such as
moclobemide. However, the manufacturer of moclobemide
recommends that since some patients may be more sensitive to
tyramine, the consumption of large amounts of tyramine-rich

foodstuffs should still be avoided; these foods include
chocolate, aged cheeses, beer, chianti, vermouth, pickled
fish and concentrated yeast extracts (Reynolds, 1996; Roche
lab., 1996).

Drug-drug interactions:
Sympathomimetics and anorectic drugs should not be taken with
moclobemide.
Opioid analgesics: Central Nervous System (CNS) excitation or
depression may occur.
Drugs used in anaesthesia: anaesthesia may be performed 24
hours after discontinuation of moclobemide with little
potential for significant interaction (Blom-Peters & Lamy,
1993; Mac Farlane, 1994); when the washout period is not
feasible, the use of pethidine and parenteral
sympathomimetics should be avoided (Roche lab., 1996).
Levodopa: a hypertensive crisis may be precipitated.
Sumatriptan: the manufacturer recommends to not prescribe
moclobemide concominantiantly with sumatriptan which is a
selective agonist at serotonin type 1D receptors, because of
possible hypertensive crises and severe coronary
vasoconstriction, and advises a washout period of 24 hours
after discontinuation of moclobemide; however a clinical
study performed by Blier & Bergeron (1995) involving 103
episodes of migraine, did not show evidence of significant
adverse effects.
The metabolism of moclobemide is inhibited by cimetidine,
leading to a prolonged half-life and increased plasma
concentrations (Livingston & Livingston, 1996); the
manufacturer recommends that the dose of moclobemide be
reduced to half strength in patients who are also given
cimetidine.
The co-administration of drugs that increase the levels of
monoamines such as serotonin and noradrenaline, including
tricyclic antidepressants (mainly clomipramine), selective
serotonin re-uptake inhibitor antidepressants, and
potentially other antidepressants may cause a serotonin
syndrome (Spigset et al., 1993; Kuisma, 1995; Liebenberg et
al., 1996).
Lithium: according to Livingston & Livingston (1996), care
should be taken when co-prescribing RIMAs with lithium, since
it increases serotonin levels, although no interactions have
been reported to date.
Therapy with moclobemide should not be started until at least
7 days following the discontinuation of tricyclic or
serotonin reuptake inhibitor antidepressant treatment (2
weeks in the case of paroxetine; 5 weeks in the case of
fluoxetine) or for at least a week after stopping treatment
with other monoamine oxidase inhibitors (Reynolds, 1996).
Conversely, a washout period of 24 hours is advised when
switching from moclobemide to other antidepressants (Lane &
Fischler, 1995).

Antipsychotics, benzodiazepines, nifedipine and
hydrochlorothiazide may be coprescribed without major
interaction (Livingston & Livingston, 1996).

7.7 Main adverse effects

They include sleep disturbances, dizziness, nausea, and
headache.
Confusional states, restlessness or agitation may occur.
Mild elevations in liver enzyme values have been
reported.
Care is required in patients with thyrotoxicosis as
moclobemide may theoretically precipitate a hypertensive
reaction.
Mental alertness may be impaired, patients under treatment
should not drive or operate machinery (Reynolds, 1996).
Manic episodes may be provoked in patients with bipolar
disorders, moclobemide should be discontinued and
antipsychotic therapy should be initiated (Reynolds, 1996;
Roche lab., 1996).
Less common adverse effects include:
– hypertension, although the role of concomitant
administration of clomipramine, buspirone, thyroxine in the
case series reported by Coulter & Pillans (1995) may have
contributed and cannot be disregarded,
– alopecia (Sullivan & Mahmood, 1997),
– a case of fatal intrahepatic cholestasis was described
(Timmings & Lamont, 1996) in a 85 year-old woman after she
was switched from fluoxetine to moclobemide without a washout
period. The role of moclobemide in causing this adverse
reaction is questionable and it is more likely that the
hepatotoxic effect was associated with co-administration of
both drugs,
– a case of sexual hyperarousal in a female patient was
reported by Lauerma (1995),
– a toxic shock like-syndrome was described by O’Kane &
Gottlieb (1996).

8. TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan

8.1.1 Sampling and specimen collection

8.1.1.1 Toxicological analysis

8.1.1.2 Biomedical analysis

8.1.1.3 Arterial blood gas analysis

8.1.1.4 Haematological analysis

8.1.1.5 Other (unspecified) analysis

8.1.2 Storage of laboratory samples and specimens

8.1.2.1 Toxicological analysis

8.1.2.2 Biomedical analysis

8.1.2.3 Arterial blood gas analysis

8.1.2.4 Haematological analysis

8.1.2.5 Other (unspecified) analysis

8.1.3 Transport of laboratory samples and specimens

8.1.3.1 Toxicological analysis

8.1.3.2 Biomedical analysis

8.1.3.3 Arterial blood gas analysis

8.1.3.4 Haematological analysis

8.1.3.5 Other (unspecified) analysis

8.2 Toxicological analysis and their interpretation

8.2.1 Tests on toxic ingredient(s) of material

8.2.1.1 Simple qualitative test(s)

8.2.1.2 Advanced qualitative confirmation test(s)

8.2.1.3 Simple quantitative method(s)

8.2.1.4 Advanced quantitative method(s)

8.2.2 Test for biological specimens

8.2.2.1 Simple qualitative test(s)

8.2.2.2 Advanced qualitative confirmation test(s)

8.2.2.3 Simple quantitative method

8.2.2.4 Advanced quantitative method(s)

8.2.2.5 Other dedicated method(s)

8.2.3 Interpretation of toxicological analysis

8.3 Biomedical investigations and their interpretation

8.3.1 Biochemical analysis

8.3.1.1 Blood, plasma or serum

8.3.1.2 Urine

8.3.1.3 Other fluids

8.3.2 Arterial blood gas analysis

8.3.3 Haematological analysis

8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their
interpretation

8.5 Overall interpretation of all toxicological analysis and
toxicological investigations

8.6 References

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Patients may display minimal or no symptoms
following pure moclobemide overdose. However, the
ingestion of moclobemide may cause nausea, vomiting,
gastric pain; agitation, disorientation, drowsiness,
impaired reflexes, myoclonic jerks in upper
extremities, slow-reacting pupils; slight rise in
blood pressure or moderate hypotension and tachycardia
(Myrenfors et al., 1993; Iwersen & Schmoldt,
1996).
Co-ingestion of tricyclic antidepressants (primarily
clomipramine), opioids, or SSRIs can result in more
varied and severe symptoms appearing within 2 to 3
hours after ingestion, even with lower doses of
moclobemide. Symptoms include: both CNS depression
(confusion, drowsiness) and excitation (seizure),
tremor, mydriasis, hyperthermia with muscle rigidity,
hypertension and metabolic acidosis (Myrenfors et al.,
1993). Several fatal cases have been reported after a
combination of moclobemide with citalopram,
clomipramine and fluoxetine (Power et al., 1995;
Hernandez et al., 1995) and moclobemide with
citalopram and fluoxetine (Neuvonen et al.,
1993).

9.1.2 Inhalation

Not relevant

9.1.3 Skin exposure

No data available

9.1.4 Eye contact

Not relevant

9.1.5 Parenteral exposure

No data available

9.1.6 Other

No data available

9.2 Chronic poisoning

9.2.1 Ingestion

No data available

9.2.2 Inhalation

Not relevant

9.2.3 Skin exposure

No data available

9.2.4 Eye contact

Not relevant

9.2.5 Parenteral exposure

No data available

9.2.6 Other

No data available

9.3 Course, prognosis, cause of death

Pure moclobemide overdoses usually have a fairly benign
course.
Several fatalities are reported in the literature, all
involving a co-ingestion (Neuvonen et al., 1993; Power et
al., 1995; Hernandez et al., 1995). The clinical course
consisted of euphoria, agitation, then extreme tremor,

followed by convulsions and hyperthermia. Death occured
within 3 to 16 hours after ingestion, after intractable
seizure and/or hyperthermia and its subsequent complications:
disseminated intravascular coagulation and multiple organ
failure.

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Mild to moderate hypertension (Myrenfors et
al., 1993)
Moderate hypotension (Heinze & Sanchez, 1986)
Sinus tachycardia (Myrenfors et al., 1993)

9.4.2 Respiratory

No data available.

9.4.3 Neurological

9.4.3.1 Central nervous system

Mild disorientation, agitation,
slurred speech, anxiety, dizziness; headache;
drowsiness, coma.

9.4.3.2 Peripheral nervous system

No data available.

9.4.3.3 Autonomic nervous system

Slow-reacting pupils, mydriasis
(Myrenfors et al., 1993).

9.4.3.4 Skeletal and smooth muscle

Myoclonic jerks in upper
extremities; muscle rigidity;
rhabdomyolysis.

9.4.4 Gastrointestinal

Dry mouth; nausea, vomiting, gastric pain; diarrhoea.

9.4.5 Hepatic

Mild increases in liver enzymes values.

9.4.6 Urinary

9.4.6.1 Renal

No data available.

9.4.6.2 Other

No data available.

9.4.7 Endocrine and reproductive systems

No data available.

9.4.8 Dermatological

Sweating

9.4.9 Eye, ear, nose, throat: local effects

9.4.10 Haematological

DIC has occurred in a fatal case.

9.4.11 Immunological

No data available.

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

Acidosis is expected in association
with coma and/or convulsions.

9.4.12.2 Fluid and electrolyte disturbances

Hyperkalemia

9.4.12.3 Others

Creatine phosphokinase may be
elevated in patients with muscular
hyperactivity or rigidity.

9.4.13 Allergic reactions

No data available.

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

No data available.

9.5 Other

Abuse potential does exist with MAOIs. Although there
are currently no reported cases of dependence on the RIMAs,
it is wise to be cautious when prescribing these drugs for
individuals who have a substance misuse problem, including
alcohol dependence, or for personality-disordered patients
with poor impulse control (Livingston & Livingston,
1996).

9.6 Summary

10. MANAGEMENT

10.1 General principles

The primary management of isolated moclobemide overdose
consists of the institution of careful observation of vital
signs and neurological status and supportive care until signs
and symptoms resolve. Intravenous access should be
established as soon as practical.
In more severe intoxications or where there are other
substances ingested, more aggressive measures such as
establishment of an airway, ventilation, administration of
intravenous fluids, control of seizures, and control of
hyperthermia may be necessary.

10.2 Life supportive procedures and symptomatic/specific treatment

In pure moclobemide overdose, intensive supportive care
is rarely required. In severe cases or when a serotonin
syndrome occurs, measures that may be required include:
endotracheal intubation and assisted ventilation if coma is
present, intravenous fluid resuscitation if hypotension is
present, pharmacological control of seizures, and cooling if
hyperthermia is present.

10.3 Decontamination

For doses of up to 2000 mg, gastrointestinal
decontamination by administration of a single oral dose of
activated charcoal should be considered. Gastric lavage
followed by activated charcoal should be advocated in
patients who have ingested higher doses and/or when there has
been a co-ingestion.

10.4 Enhanced elimination

There are no effective methods known to enhance the
elimination of moclobemide.

10.5 Antidote treatment

10.5.1 Adults

No data

10.5.2 Children

No data

10.6 Management discussion

Although dantrolene has been used successfully by
Myrenfors et al. (1993), its role in the management of the
serotonin syndrome has yet to be defined.

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

Iwersen & Schmoldt (1996) described a 46-year-old
female who ingested 3000 mg of moclobemide. Gastric lavage
was performed and activated charcoal was administered two
hours after ingestion. The patient was fully orientated. Her
temperature was 37 °C, blood pressure remained within a range
of 110/70 to 143/81 mmHg during 24 hours following admission,
and heart rate remained stable between 58 and 74 bpm. No
abnormalities were observed during the period of continuous
ECG monitoring. After 24 hours the patient was discharged. On
admission, the plasma moclobemide was 60.9 mg/L, 12 hours
later the concentration was 4.6 mg/L.

Myrenfors et al. (1993) described a 24-year-old woman who
ingested a combination of moclobemide (5000 mg) with
clomipramine (625 mg), nitrazepam (20 mg) and one bottle of
wine. Two hours later she was admitted to the emergency
department with mild disorientation, nausea and drowsiness.
Blood pressure was 90/60 mmHg, heart rate 145 bpm, and
respiratory rate 21/minute. ECG showed sinus tachycardia. The
stomach was emptied and activated charcoal was administered.
15 minutes later she developed convulsions. She was intubated
and mechanically ventilated and a continuous infusion of
thiopentone (2 mg/kg) was given. The temperature was 38.7 °C
and mild metabolic acidosis was present. Three hours later
the patient’s temperature rose to 41.9 °C and dantrolene
sodium was given at a dose of 1 mg/kg body weight. Because of
persisting fever and muscle rigidity, another dose was given
2.5 hours later. Within 4.5 hours the temperature had
declined to 37.9 °C and the muscle rigidity was less
pronounced. The patient was extubated 48 hours after
admission, fully alert but complaining of muscular stiffness
and pain, mainly in her legs. A third dose of dantrolene
sodium was given. After developing pneumonia, the patient

recovered uneventfully and was discharged on the 10th day.
The muscle pain and stiffness were still present 1 month
after the intoxication. Biological disturbances included:
increased serum CPK, transient myoglobinuria and increased
liver enzymes.

Neuvonen et al. (1993) reported several fatalities after
moclobemide-clomipramine overdoses. Two patients (male 23-
year-old, female 19-year-old) ingested 1000 to 1500 mg of
moclobemide and 225 to 500 mg of clomipramine in order to get
“high”. 2 to 3 hours later they were euphoric, but within the
next 2 hours both had severe tremors, followed by convulsions
and loss of consciousness. One patient also exhibited
hyperthermia. Both died 9 to 10 hours after taking the
drugs. Blood concentrations of moclobemide and clomipramine
at admission and at necropsy showed only moderate
overdosage.

12. ADDITIONAL INFORMATION

12.1 Specific preventive measures

No data

12.2 Other

No data

13. REFERENCES

Berlin I, Said S, Spreux-Varoquaux O, Launay JM, Olivares R,
Millet V, Lecrubier Y & Puech AJ (1995) A reversible monoamine
oxidase A inhibitor (moclobemide) facilitates smoking cessation
and abstinence in heavy, dependent smokers. Clin Pharmacol Ther,
58: 444-452

Blier P & Bergeron R (1995) The safety of concomitant use of
sumatriptan and antidepressant treatments. J Clin Psychopharmacol,
15: 106-109

Blom-Peters L & Lamy M (1993) Monoamine oxidase inhibitors and
anaesthesia., 44, 2: 57-60

Coulter DM & Pillans PI (1995) Hypertension with moclobemide.
Lancet, 346: 1032

Fulton B & Benfield P (1996) Moclobemide An update of its
Pharmacological Properties and Therapeutic Use. Drug 53(3): 450-
474

Heinze G & Sanchez A (1986) Overdose with moclobemide. J Clin
Psychiatry, 47: 438

Hernandez AF, Montero MN, Pla A, & Enrique V (1995) Fatal
Moclobemide overdose or death caused by serotonin syndrome?
Journal of Forensic Sciences 40(1): 128-130.

Iwersen S & Schmoldt A (1996) Three suicide attempts with
moclobemide. Clin Toxicol, 34: 223-225

Kuisma MJ (1995) Fatal serotonin syndrome with trismus. Ann Emerg
Med, 26, 1: 108

Lane R & Fischler B (1995) The serotonin syndrome: co-
administration, discontinuation and washout periods for the
selective serotonin reuptake inhibitors (SSRIs). J Serotonin
Research, 3: 171-180

Lauerma H (1995) A case of moclobemide-induced hyperorgasmia. Int
Clin Psychopharmacol, 10, 2: 123-124

Liebenberg R, Berk M & Winkler G (1996) Serotonergic syndrome
after concomitant use of moclobemide and fluoxetine. Human
Psychopharmacol: Clin and Experiment, 11: 146-147

Livingston M & Livingston H (1996) Monoamine oxidase inhibitors.
An update on drug interactions. Drug Safety, 14, 4: 219-227

Mac Farlane (1994) Anaesthesia and the new generation monoamine
oxidase inhibitors. Anaesthesia, 49, 7: 597-599

Mayersohn M & Guentert TW (1995) Clinical pharmacokinetics of the
monoamine oxidase-A inhibitor moclobemide. Clin Pharmacokinet, 29,
5: 292-332

Meienberg O & Amsler F (1996) Moclobemide in the prophylactic
treatment of migraine. A retrospective analysis of 44 case. Eur
Neurol, 36: 109-110

Menkes DB, Thomas MC & Phipps RF (1994) Moclobemide for menopausal
flushing. Lancet, 344, 8923: 691-692

Myrenfors PG, Eriksson T, Sansdtedt CS & Sjoberg G (1993)
Moclobemide overdose. J Intern Med, 233: 113-115

Neuvonen P, Pohjola-Sintonen S, Tacke U & Vuori E (1993) Five
fatal cases of serotonin syndrome after moclobemide-citalopram or
moclobemide-clomipramine overdoses. Lancet, 342: 1419

O’Kane GM & Gottlieb T (1996) Severe adverse reaction to
moclobemide. Lancet, 347: 1329-1330

Power BM, Pinder M, Hackett LP & Ilett KF (1995) Fatal serotonin
syndrome following a combined overdose of moclobemide,
clomipramine and fluoxetine. Anaesth Intens Care, 23: 499-502

Raaflaub J, Haefelfinger P & Trautman KH (1984) Single-dose
pharmacokinetics of the MAO-inhibitor moclobemide in man. Arzneim
Forsch, 34: 80-82

Reynolds JEF ed (1996) Martindale: the extra pharmacopoeia, 31st
ed. London, The Pharmaceutical Press

Roche laboratoires: Moclamine. Manufacturer information. 92521
Neuilly sur Seine France, 1996

Spigset O, Mjorndal T & Lovheim O (1993) Serotonin syndrome caused
by a moclobemide-clomipramine interaction. Br Med J, 306, 6872:
248

Sternbach H (1991) The serotonin syndrome. Am J Psychiatry, 148:
705-713

Sullivan G & Mahmood A (1997) Hair loss associated with
moclobemide use. Human Psychopharmacol: Clin and Experiment, 12:
81-82

Timmings P & Lamont D (1996) Intrahepatic cholestasis associated
with moclobemide leading to death. Lancet, 347: 762-763

14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)

Author: MO Rambourg Schepens
Centre Anti-Poisons de Champagne Ardenne
Centre Hospitalier Universitaire
F- 51092 Reims cedex France

Telephone 33 326 862 686
Fax 33 326 865 548
E-mail: [email protected]

Reviewer: WA Watson
Emergency Medicine. Truman Medical Center.
2301 Holmes Street. Kansas City, MO, USA

E-mail: [email protected]

Date: June 1997

Peer review: Oslo (2 July, 1997) Members of group: Marie-Odile
Rambourg, Bill Watson, Rob Dowsett, Barbara Groszek, Michael
Ruse

Editor: Dr. M. Ruse (August, 1997)

———————

MONOGRAPH FOR UKPID

DOTHIEPIN HYDROCHLORIDE

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review group: Directors of the UK National Poisons Information
Service.

MONOGRAPH FOR UKPID

Drug Name

Dothiepin hydrochloride

Chemical group

Tricyclic antidepressant

Origin

Synthetic

Name

UKBrand name(s)

Prothiaden(R), Dothapax(R), Prepadine(R).

Synonyms

Dosulepin hydrochloride (INN).

Common names

Product licence number(s)

Prothiaden(R) 25 mg: 00169/0086
Prothiaden(R) 75 mg: 00169/0087

CAS number

7081-53-0

Manufacturer

Prothiaden(R), Knoll Ltd, 9 Castle Quay, Castle Boulevard, Nottingham,
Nottinghamshire NG7 1FW
Tel no. 0115 912 5000

APS, Ashbourne (Dothapax(R)), Berk (Prepadine(R)), Cox, Generics,
Hillcross, Kent, Pharm and Norton.

Presentation

Form

Capsules, tablets.

Formulation details

Capsules of 25mg.
Tablets of 75mg.

Pack size(s)

25mg capsules – packs of 100 and 600.
75mg tablets – packs of 28 and 500.
Generics or branded generics may have different pack sizes.

Packaging

Prothiaden(R) 25mg – red/brown capsules marked P25
Prothiaden(R) 75 mg – red sugar-coated tablets marked P75
Generic formulations or branded generics will differ in presentation.

Properties

Chemical structure C19H21NS.HCl = 331.9
Chemical name 11-(3-Dimethylaminopropylidene)-6,-11-
dihydrodibenz [b,e]thiepin hydrochloride

Indications

Depressive illness especially where an anti-anxiety effect is
required.

Therapeutic Dosage

ADULTS: 50 mg – 150 mg daily in either divided doses or as a single
dose at night.
In severely depressed patients, doses of up to 225 mg daily have been
used.
CHILD: Not recommended.

Contra-indications

Recent myocardial infarction, heart block or other cardiac arrhythmia,
mania, severe liver disease.

Abuses

Epidemiology

Over a four year period between 1989 and 1992 there were over 600
deaths from dothiepin overdose (ONS 1996). Tricyclic fatalities tend
to occur in older rather than in younger patients. In both fatal and
non-fatal overdose, there are a greater number of tricyclic ingestions
in females than in males (Crome 1986).
The overall incidence of serious cardiac complications in patients who
are admitted to hospital following tricyclic overdose is reported to
be less than 10%. Some degree of coma occurs in about 50% of cases,
but is only unresponsive to painful stimuli in about 10-15% of cases
(Crome 1986). Convulsions occur in approximately 6% of patients
(Taboulet 1995). The death rate in patients admitted to hospital is
estimated to be 2%-3% (Dziukas & Vohra 1991).

Adverse effects

Antimuscarinic effects, sedation, arrhythmias, postural hypotension,
tachycardia, sweating, tremor, rashes, hypomania or mania, confusion,
interference with sexual function, weight gain, convulsions, hepatic
and haematological reactions.

Interactions

Pharmacodynamic:

a) A potentially hazardous interaction may occur between a tricyclic
antidepressant and a MONOAMINE OXIDASE INHIBITOR (including
moclobemide and selegiline) resulting in increased amounts of
noradrenaline and serotonin at the synapse. Coma, hyperthermia,
hypertension, convulsions, delirium, or death may result (Lipman 1981,
White & Simpson 1984).

b) There is an increased risk of cardiotoxicity when administered
with other DRUGS WHICH PROLONG THE QT INTERVAL e.g. anti-arrhythmics,
astemizole, halofantrine, or terfenadine.

c) The pharmacology of dothiepin suggests that concomitant
ingestions of SELECTIVE SEROTONIN REUPTAKE INHIBITORS, PHENOTHIAZINES,
SYMPATHOMIMETICS, or OTHER TRICYCLIC ANTIDEPRESSANTS will enhance its
toxicity.

Pharmacokinetic:

a) The metabolism of tricyclic antidepressants is inhibited by most
SELECTIVE SEROTONIN REUPTAKE INHIBITORS, resulting in elevated
tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and
paroxetine appear to exert a greater effect than sertraline. Limited
data suggest that citalopram does not inhibit tricyclic metabolism
(Baettig et al. 1993, Taylor 1995).

b) As the metabolism of dothiepin is mediated by cytochrome P450
microsomal enzymes, the potential exists for interactions with other
drugs which are substrates of this system.

c) CIMETIDINE reduces the metabolic clearance of tricyclic
antidepressants by inhibition of liver enzymes, resulting in higher
plasma tricyclic concentrations (Stockley 1996).

Ethanol

Information about any interaction between dothiepin and ethanol is
lacking. Two other tricyclic antidepressants (amitriptyline, doxepin)
are known to interact with ethanol resulting in an increased
impairment of psychomotor skills, whilst a number of other tricyclics
appear to interact with ethanol only minimally (Stockley 1996).

Mechanism of action

The precise mechanism of antidepressant action is unclear, but results
from the inhibition of noradrenaline and serotonin reuptake into
presynaptic neurones, and adaptive changes in receptor sensitivity.
In addition to inhibiting the reuptake of noradrenaline and serotonin,
dothiepin is also an antagonist of muscarinic cholinergic receptors,
histamine receptors, and to a lesser extent alpha1 adrenergic
receptors (Rudorfer et al. 1994). These antagonist actions account for
its anticholinergic, sedative, and hypotensive properties.
The contributions of the metabolites nordothiepin and the combined
sulphoxides to the total antidepressant activity are similar to that
of dothiepin itself (Rees 1981).

Mechanism of toxicity

The toxicity of dothiepin in overdose results from depression of the
myocardial function (a quinidine-like effect), anticholinergic
activity, alpha adrenergic receptor blockade, and respiratory
insufficiency. The risk of toxicity is greatest 2-4 hours after
ingestion when plasma levels are at the highest.

Pharmacokinetics

ABSORPTION

Dothiepin is rapidly absorbed after oral administration with maximum
plasma concentrations being reached after approximately 3 hours
(Maguire et al. 1983).
Extensive first-pass metabolism occurs (Rees 1981), the estimated oral
bioavailability of dothiepin being approximately 30% (Yu et al. 1986).

DISTRIBUTION

Dothiepin is widely distributed throughout the body with an apparent
volume of distribution of over 10 L/kg (Rees 1981).
Dothiepin is 80-90% bound to plasma proteins at therapeutic
concentrations (Dollery 1991). The plasma protein binding of tricyclic
antidepressants is pH sensitive with a small reduction in plasma pH
being associated with large increases in unbound (pharmacolgically
active) drug (Nyberg & Martensson 1984).

METABOLISM

The metabolic profile of dothiepin varies widely between individuals.
Dothiepin is metabolised by demethylation and S-oxidation in the
liver, resulting in the active metabolites, nordothiepin (also known
as northiaden or desmethyldothiepin), dothiepin sulphoxide and
nordothiepin sulphoxide, all of which contribute to the antidepressant
effect (Rees 1981).
Inactive conjugated glucuronide metabolites have also been isolated
(Rees 1981).

ELIMINATION

The major route of excretion is in urine, although significant faecal
elimination also occurs. Less than 0.5% of a dose is excreted as
unchanged dothiepin in urine (Rees 1981).
Enteroenteric and enterohepatic recycling of dothiepin and its
metabolites is considered to occur (Pimentel & Trommer 1994, Rees
1981).

HALF LIFE

Dothiepin: 20 hours (Yu et al. 1996).
Active metabolites: 24-40 hours (Yu et al. 1996).

SPECIAL POPULATIONS

ELDERLY:

Metabolic changes in the elderly result in higher plasma
concentrations, longer half-lives, and reduced clearance than in
younger populations (Ogura et al. 1983).

LIVER IMPAIRMENT:

Reduced metabolic capacity in liver disease suggests that accumulation
of dothiepin will occur, but the clinical implications are unclear due
to a corresponding reduction in active metabolite production.

RENAL IMPAIRMENT:

Reduced clearance in renal impairment suggests that accumulation of
active metabolites will occur.

GENDER:

Elimination half-lives for dothiepin and nordothiepin are reported to
be several hours longer in females than in males (Maguire et al.
1983).

BREAST MILK

Dothiepin and its active metabolites are excreted into human breast
milk.
In an early study, a patient treated with dothiepin 25 mg three times
daily for 3 months had milk and serum dothiepin concentrations of
0.011 and 0.033 mg/L respectively (Rees et al. 1976). These data
suggest that a baby would ingest less than 0.2% of the maternal
dothiepin dose based on a daily milk intake of 150 ml/kg, but in this
study no account was taken of active metabolites.
A later study considered both the excretion of dothiepin and its
active metabolites into breast milk. Concentrations of dothiepin,
nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide were measured

in blood and milk samples from five breast feeding women, and in
plasma samples from their infants. The data show that the mean total
infant daily dose is 4.5% of the maternal dothiepin dosage in
dothiepin equivalents (Ilett et al. 1992).

Toxicokinetics

Absorption

Distribution

Metabolism

Elimination

Half life

Dothiepin: 11-29 hours (Ilett et al. 1991)

Special populations

Breast milk

Summary

TYPE OF PRODUCT

A tricyclic antidepressant.

INGREDIENTS

Dothiepin capsules: 25 mg
Dothiepin tablets: 75mg

SUMMARY OF TOXICITY

Patients presenting with only mild signs of toxicity may rapidly
develop life-threatening complications. Where major toxic events occur
these usually develop within 6 hours of overdose, the risk of toxicity
being greatest 2-4 hours after ingestion.

Dothiepin overdose should be managed on a clinical basis rather than
on the amount ingested, but as a guide, doses of 1 g in adults have
been associated with severe toxicity. Ingestions of tricyclic
antidepressants in children indicate that doses of 15 mg/kg may prove
fatal to a child, although recovery has followed reported ingestions
of over 100 mg/kg.

Sinus tachycardia, hypotension, and anticholinergic symptoms are
common features. Cardiotoxicity, impaired consciousness, seizures,
acidosis, and respiratory insufficiency are associated with severe
toxicity. The occurrence of seizures may precipitate the onset of
cardiac arrhythmias and hypotension. Delirium may be a complication on
recovery.

FEATURES

Dry mouth, blurred vision, dilated pupils, urinary retention, sinus
tachycardia, drowsiness, hypothermia, and confusion. Hypoxia,
acidosis, hypotension, convulsions, cardiac arrhythmias, and coma.

UNCOMMON FEATURES

Skin blisters, rhabdomyolysis, disseminated intravascular coagulation,
adult respiratory distress syndrome, and absent brain stem reflexes.

SUMMARY OF MANAGEMENT: SUPPORTIVE

1. Maintain a clear airway and adequate ventilation if consciousness
is impaired.

2. If within 1 hour of the ingestion and more than 300 mg has been
taken by an adult, or more than 1mg/kg by a child, give
activated charcoal.

3. Carry out arterial blood gas analysis, and correct any acidosis
and hypoxia.

4. Monitor the cardiac rhythm and blood pressure.

5. Single, brief convulsions do not require treatment but if they
are prolonged or recurrent, they should be controlled with
intravenous diazepam.

6. Ventricular arrhythmias should be managed with intravenous sodium
bicarbonate and supportive measures. Where these measures fail
and an anti-arrhythmic is considered essential, lignocaine is the
preferred drug.

7. Other measures as indicated by the patient’s clinical condition.

Clinical Features

ACUTE INGESTION

Mild to moderate toxicity: dilated pupils, sinus tachycardia,
drowsiness, dry mouth, blurred vision, urinary retention, absent bowel
sounds, confusion, agitation, body temperature disturbances,
twitching, delirium, hallucinations, nystagmus, and ataxia.
Increased tone and hyperreflexia may be present with extensor plantar
responses.
(Callaham 1979, Crome 1986, Dziukas & Vohra 1991, Noble & Matthews
1969).

Severe toxicity: coma, hypotension, convulsions, supraventricular and
ventricular arrhythmias, hypoxia, metabolic and/or respiratory
acidosis, and cardiac arrest (Crome 1986, Dziukas & Vohra 1991).

ECG changes (in the usual order of appearance) include non-specific ST
or T wave changes, prolongation of the QT, PR, and QRS intervals,
right bundle branch block, and atrioventricular block. The terminal
0.04 second frontal plane QRS axis often shows a right axis deviation
(Dziukas & Vohra 1991).

Delayed features: adult respiratory distress syndrome (Varnell et al.
1989).

Uncommon features: skin blisters, rhabdomyolysis, disseminated
intravascular coagulation, gaze paralysis, and absent brain reflexes
(Dziukas & Vohra 1991, White 1988).

INHALATION

DERMAL

OCULAR

OTHER

CHRONIC

INGESTION

INHALATION

DERMAL

OCULAR

OTHER

At risk groups

ELDERLY

There is an increased risk of toxicity resulting from impaired drug
metabolism and elimination. The elderly are also particularly
susceptible to the central anticholinergic effects such as confusion,
disorientation, acute psychosis and hallucinations (Nolan & O’Malley
1992).

PREGNANCY

The safety of dothiepin (or tricyclic antidepressants in general)
during pregnancy has not been established.
A handful of cases were reported in the early 1970’s linking tricyclic
antidepressant administration during pregnancy to birth defects,
particularly limb deformities. Retrospective studies, subsequently
reported, showed no correlation between tricyclic antidepressant use
and increased malformations. However, a more recent report of a large

case-controlled study found a greater occurrence (not quantified) of
congenital malformation with tricyclic antidepressants than in control
groups (Schardein 1993).
Fetal tachyarrhythmia has been reported where dothiepin has been given
in pregnancy – see case report 1.

CHILDREN

Comparison with other tricyclic antidepressants would suggest that
ingestions in children result in symptoms typical of tricyclic
antidepressant overdose in adults (Crome & Braithwaite 1978, Goel &
Shanks 1974).
See case report 2 for clinical details of dothiepin ingestion in a
young child.

ENZYME DEFICIENCIES

Dothiepin is metabolised by microsomal enzymes in the liver which may
be subject to genetic polymorphism.

ENZYME INDUCED

The metabolism of dothiepin is likely to be increased in the presence
of enzyme inducing drugs, but is of doubtful clinical relevance as the
metabolites formed also have antidepressant activity.

OCCUPATIONS

OTHERS

RENAL IMPAIRMENT: increased risk of toxicity due to accumulation of
metabolites.
HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired
metabolism.
CARDIAC DISEASE: increased risk of toxicity due to underlying disease.
EPILEPSY: increased risk of seizures.

Management

Decontamination

If within one hour of ingestion, and more than 300mg has been taken by
an adult or more than 1mg/kg by a child, activated charcoal should be
given to reduce the absorption.

ADULT DOSE; 50 g,
CHILD DOSE; 1 g/kg.

If the patient is drowsy this should be administered via a nasogastric
tube, and if there is no gag reflex present, using a cuffed
endotracheal tube to protect the airway.

Supportive care

GENERAL MANAGEMENT OF THE SYMPTOMATIC PATIENT

Clear and maintain the airway, and give cardiopulmonary resuscitation
if necessary.
Evaluate the patient’s condition and provide support for vital
functions.

1. Administer intravenous sodium bicarbonate to correct any
acidosis.

ADULT DOSE: 50 ml of 8.4% sodium bicarbonate by slow intravenous
injection; CHILD DOSE: 1 ml/kg of 8.4% sodium bicarbonate by slow
intravenous injection.

Subsequent bicarbonate therapy should be guided by arterial blood pH
which should be monitored frequently.

2. Maintain adequate ventilation to prevent hypoxia with
supplemental oxygen or artificial ventilation as appropriate.

3. Carefully maintain plasma potassium levels to prevent
hypokalaemia.

IN MIXED OVERDOSES WHERE A BENZODIAZEPINE HAS ALSO BEEN INGESTED, THE
USE OF THE COMPETITIVE BENZODIAZEPINE ANTAGONIST FLUMAZENIL IS
CONTRA-INDICATED (Mordel et al. 1992).

Where symptoms develop following mild to moderate overdose, they may
persist for 24 hours. Prolonged or delayed complications following
severe toxicity may require the patient to be hospitalised for several
days.

SPECIFIC MANAGEMENT OF THE SYMPTOMATIC PATIENT

1. CARDIOTOXICITY
GENERAL NOTE: in practice it is seldom necessary or advisable to use
specific drug treatment for arrhythmias. If hypoxia and acidosis are
reversed and adequate serum potassium levels maintained, then the
majority of patients show improvement with supportive measures.

SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment
required (Pimentel & Trommer 1994).

VENTRICULAR ARRHYTHMIAS: give intravenous sodium bicarbonate (even in
the absence of acidosis) before considering antiarrhythmic drug
therapy. Where an antiarrhythmic is considered necessary, lignocaine
is the preferred drug (Pimentel & Trommer 1994).

ADULT DOSE: 50-100 mg lignocaine by IV bolus over a few minutes,
followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2
mg/minute for 2 hours, then 1 mg/minute (BNF 1998).

The use of quinidine, disopyramide, procainamide, and flecainide are
all contra-indicated as they depress cardiac conduction and
contractility. The use of beta-blockers should also be avoided as they
decrease cardiac output and exacerbate hypotension. The efficacy of
other antiarrhythmic agents (e.g bretylium, amiodarone, calcium
channel blockers) has not been studied in tricyclic antidepressant
poisoning (Pimentel & Trommer 1994).

BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited
success as the cardiotoxicity of dothiepin results from depression of
contractility rather than failure of cardiac pacemakers.

CARDIAC ARREST: manage in the standard manner but with continuing
resuscitative measures as some patients have recovered after receiving
several hours of external cardiac massage (Orr & Bramble 1981).

2. COMA
Good supportive care is essential.

3. HYPOTENSION
Hypotension should be managed by the administration of intravenous
fluids and by physical means. The majority of patients ingesting
dothiepin have otherwise healthy cardiovascular systems and providing
cardiac output is good it is unnecessary to use specific drug therapy.
If there is evidence of poor cardiac output (after correction of
acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive
agent may need to be considered. Noradrenaline has been shown to be
helpful in a number of studies (including cases where dopamine therapy
has failed) (Teba et al. 1988, Yang & Dantzker 1991).

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via
a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute
adjusted according to response (BNF 1998).
CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
microgram/kg/minute of noradrenaline base) in glucose 5% or
glucose/saline via a central venous catheter (Guy’s, Lewisham & St
Thomas Paediatric Formulary, 1997).

4. SEIZURES
Administer intravenous diazepam to control frequent or prolonged
convulsions.

ADULT DOSE: 10 mg
CHILD DOSE: 0.25-0.4 mg/kg
Both by slow IV injection preferably in emulsion form.

Where seizure activity proves difficult to manage, paralyse and
ventilate the patient. Continue to monitor the cerebral function to
ensure the cessation of seizure activity.

5. OTHER
Catheterisation may be required to relieve distressing urinary
retention and to allow continuous monitoring of urine output as a
means of assessing cardiac output (Crome 1986).
Respiratory complications should be managed conventionally with early
respiratory support.
Control delirium with oral diazepam. Large doses may be required (20-
30mg two-hourly in adults).

Monitoring

Monitor the heart rate and rhythm, arterial blood gases, blood
pressure, serum electrolytes, body temperature, respiratory rate and
depth, and urinary output.

Observe for a minimum of 6 hours post-ingestion where:

i) more than 1mg/kg has been ingested by a child,
ii) more than 300 mg is known to have been ingested by an adult,
iii) the patient is symptomatic.

Antidotes

None available

Elimination techniques

Dialysis and haemoperfusion are ineffective as means of promoting drug
or metabolite elimination.

Investigations

Following severe toxicity:
i) a chest X-ray will be needed to exclude pulmonary
complications,
ii) measure serum creatine kinase and other skeletal muscle
enzyme activity (e.g. AST, ALT, and lactic dehydrogenase),
iii) assess renal function,
iv) assess haematological status.

Management controversies

Gastric lavage is not recommended as the procedure may be associated
with significant morbidity, and there is no evidence that it is of any
greater benefit than activated charcoal used alone (Bosse et al.
1995).
If the procedure is used (i.e. in cases where activated charcoal
cannot be administered), a cuffed endotracheal tube should be used to
protect the airway if the patient is drowsy, and activated charcoal
left in the stomach following the lavage.

Repeat doses of oral activated charcoal may prevent the reabsorption
of tricyclic antidepressants and their metabolites secreted in gastric
juices and bile (Swartz & Sherman 1984). However, it would not be
expected from the large volume of distribution of the tricyclics that
clinically significant increases in body clearance would result.

Physostigmine salicylate is a short acting reversible cholinesterase
inhibitor which has been used historically in the management of
tricyclic overdoses to reverse coma and antimuscarinic effects.
Reports of serious complications from its use include severe
cholinergic activity, convulsions, bradycardia, and asystole (Newton
1975, Pentel & Peterson 1980). The use of physostigmine is no longer
recommended.

The use of dopamine in the management of hypotension has been
suggested, but the pressor effect of this indirect acting inotrope may
be diminished in tricyclic overdosed patients due to depleted levels
of noradrenaline (Buchman et al. 1990, Teba et al. 1988).

The use of intravenous glucagon has been proposed in cases where
hypotension is unresponsive to volume expansion and sodium bicarbonate
administration, because of its positive inotropic effect and possible
antiarrhythmic property. Its place in therapy has not been established
(Sener et al. 1995).
ADULT DOSE: 10 mg by IV bolus followed by an infusion of 10 mg
over 6 hours (unlicensed indication and dose).

There are a number of reports of severe arrhythmias or sudden death
occurring up to 1 week after tricyclic overdose, but a review of the
cases show that the patients had continuing toxicity, underlying
disease or abnormalities (Stern et al. 1985).

Several predictors of clinical severity in tricyclic overdoses have
been suggested, including:

1. a maximal limb-lead QRS duration of 0.1 second or longer as a
predictor of the risk of seizure (Boehnert & Lovejoy 1985),
2. a maximal limb-lead QRS duration of 0.16 second or longer as a
predictor of the risk of ventricular arrhythmias (Boehnert &
Lovejoy 1985),
3. plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart
1991),
4. the ECG terminal 40-ms frontal plane QRS axis of more than 120°
(Wolfe et al. 1989),
5. plasma drug concentrations in excess of 2 mg/L as a predictor of
the development of lung injury (Roy et al. 1989).

Whilst none of these features in isolation are predictive of
life-threatening toxicity, they may be helpful in assessing patient
risk.

Case data

CASE REPORT 1 – Fetal tachyarrhythmia attributed to maternal drug
treatment with dothiepin.
A 26 year old woman was started on dothiepin 50 mg daily during the
first trimester of pregnancy. This was increased to 75 mg daily at
about 16 weeks of gestation and subsequently reduced to 50 and 25 mg
daily at 30 and 34 weeks respectively. At 37 weeks there had been
little growth over the previous three weeks, the patients weight
remaining the same. The fetal heart rate was irregular with over 180
beats per minute. An ultrasound scan showed a normally grown fetus
with no evidence of cardiac failure. The dothiepin was stopped after a
few days. The frequency and the duration of the tachyarrhythmias
decreased and within four days no abnormalities of the fetal heart
rate were detected. At subsequent review in antenatal clinics no
abnormalities were noted, and the patient delivered a healthy infant
at term (Prentice & Brown 1989).

CASE REPORT 2 – Dothiepin ingestion in an infant.
An 11-month-old child weighing 9.7 kg ingested about 13 dothiepin 75
mg tablets (100 mg/kg). She was drowsy, had muscle twitching and a
generalised convulsion. On admission to hospital one and a half hours
later she was comatose and convulsing. Her pulse was 160 beats/minute,
blood pressure 80/50 mm Hg, respirations regular, and pupils fixed and
dilated. Electrocardiography showed sinus tachycardia. Her convulsions
were controlled with 10 mg IV diazepam and 4 ml IM paraldehyde. She
was intubated and her stomach emptied. She suddenly became bradycardic
(pulse 50 beats/minute, blood pressure unrecordable), with wide QRS
complexes showing on the ECG. Cardiac massage and assisted ventilation
were started. She was unresponsive to IV atropine, and was given
5 mmol sodium bicarbonate and 50 ml plasma protein fraction. Blood gas
analysis showed hypoxia with metabolic and respiratory acidosis.
Further sodium bicarbonate was given (30 mmol) and hyperventilation
started. One hour later blood gas analysis showed correction of her
acidosis, her pulse returned to 104 beats/minute, and her blood
pressure was 75 mm Hg systolic. Over the next few hours there was
narrowing of the QRS complexes, some ST depression, and ventricular
ectopic beats. She was responsive to pain ten hours after ingestion,
and made an uneventful recovery (Hodes 1984).

Analysis

Agent/toxin/metabolite

There is no clear relationship between plasma dothiepin concentration
and clinical response or toxicity. Consequently the measurement of
plasma drug concentration following overdose is not routinely advised,
although it may have diagnostic value.

Sample container

Optimum storage

Transport of samples

Interpretation of data

There is considerable variation in plasma concentration of dothiepin
between individuals.
As a guide, it has been suggested that therapeutic effect is
associated with plasma dothiepin concentrations in excess of 0.1 mg/L
(Rees 1981).
Forensic studies have found lethal tricyclic antidepressant levels
ranging from 1.1 mg/L to 21.8 mg/L (Frommer et al. 1987).

Conversion factors

1 mg/L = 3.013 micromoles/L
1 micromole/L = 0.332 mg/L

The molecular weight of dothiepin hydrochloride is 331.9

Other recommendations

Prevention of poisoning

Other toxicological data

Carcinogenicity

Genotoxicity

Mutagenicity

Reprotoxicity

Teratogenicity

Relevant animal data

Animal tests show no evidence of carcinogenicity, teratogenicity,
genotoxicity, or reprotoxicity (Dollery 1991, Goldstein & Claghorn
1980).

Relevant in vitro data

Laboratory tests involving mammalian cells, human lymphocytes, and
bacteria show no evidence of genotoxicity (Dollery 1991).

Other regulatory standards

NA

Environment

NA

Hazard

NA

Authors

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph was produced by the staff of the Leeds Centre of the
National Poisons Information Service in the United Kingdom. The work
was commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review was undertaken by the Directors of the UK National Poisons
Information Service.

Prepared October 1996
Updated May 1998

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Taylor D.
Selective serotonin reuptake inhibitors and tricyclic antidepressants
in combination: interactions and therapeutic uses. Br J Psychiatry
1995; 167: 575-580.

Teba L, Schiebel F, Dedhia HV, Lazzell VA.
Beneficial effect of norepinephrine in the treatment of circulatory
shock caused by tricyclic antidepressant overdose. Am J Emerg Med
1988: 6: 566-568.

Varnell RM, Godwin JD, Richardson ML, Vincent JM.
Adult respiratory distress syndrome from overdose of tricyclic
antidepressants. Radiology 1989; 170: 667-670.

White A.
Overdose of tricyclic antidepressants associated with absent
brain-stem reflexes.Can Med Assoc J 1988; 139: 133-134.

White K, Simpson G.
The combined use of MAOI’s and tricyclics. J Clin Psychiatry 1984; 45:
67-69.

Wolfe TR, Caravati EM, Rollins DE.
Terminal 40-ms frontal plane QRS axis as a marker for tricyclic
antidepressant overdose. Ann Emerg Med 1989; 18: 348-351.

Yang KL, Dantzker DR.
Reversible brain death: a manifestation of amitriptyline overdose.
Chest 1991; 99: 1037-1038.

Yu DK , Dimmitt DC, Lanman C, Giesing DH.
Pharmacokinetics of dothiepin in humans: a single dose
dose-proportionality study. J Pharm Sci 1986; 75: 582-585.

—————

INTOX Home Page

MONOGRAPH FOR UKPID

HALOPERIDOL DECANOATE

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review group: Directors of the UK National Poisons Information
Service.

MONOGRAPH FOR UKPID

Drug name

Haloperidol decanoate

Chemical group

Butyrophenone

Origin

Synthetic

Name

Brand name

Haldol(R) Decanoate

Synonyms

Common names

Product licence number

Haldol(R) Decanoate 50mg/ml 0242/0094
Haldol(R) Decanoate 100mg/ml 0242/0095

CAS number

74050-97-8

Manufacturer

Janssen-Cilag Limited, PO Box 79, Saunderton, High Wycombe, Bucks HP14
4HJ
Tel no. 01494 567567

Form

Intramuscular depot injection.
NOTE: a separate entry exists for other haloperidol formulations – see
under ‘Haloperidol’.

Formulation details

Injection of haloperidol decanoate equivalent to 50mg/ml or 100mg/ml
of haloperidol for intramuscular administration. Solutions contain
sesame oil and benzyl alcohol as inactive ingredients.

Pack size

50 mg/ml: 5x1ml ampoules
100mg/ml: 5x1ml ampoules

Packaging

Chemical structure

C31H41ClFNO3

Molecular weight = 530.1

Chemical name

4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone
decanoate

Indication

Long term maintenance in schizophrenia, psychoses especially paranoid,
and other mental and behavioural problems.

Therapeutic dosage – adults

By deep IM injection:
50-300 mg every 4 weeks (reduced doses in elderly)

Therapeutic dosage – children

Not recommended

Contra-indications

Use in children, confusional states, coma caused by CNS depressants,
parkinsonism, hypersensitivity to haloperidol, lesions of the basal
ganglia, and during lactation.

Abuses

Epidemiology

Overdose with haloperidol decanoate tends to be limited to accidental
administration and dosage errors.

Adverse effects

Extrapyramidal effects such as acute dystonia, Parkinsonian rigidity,
tremor, and akathisia. Also sedation, agitation, drowsiness, insomnia,
headache, nausea, blurring of vision, urinary retention, hypotension,
depression, confusional states, impairment of sexual function, skin
reactions, epileptic fits, hyperprolactinaemia, ventricular
arrhythmias, and abnormalities of liver function tests.

Tardive dyskinesia, and neuroleptic malignant syndrome have both been
associated with haloperidol therapy.

Interactions

PHARMACODYNAMIC

1. Enhancement of central nervous system depression produced by
other CNS DEPRESSANT drugs.

2. Combination with other antidopaminergic agents, such as
METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of
extrapyramidal effects (Dollery 1991).

PHARMACOKINETIC

1. The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by
haloperidol resulting in higher serum tricyclic levels (Stockley
1996).

OTHER

1. There is limited evidence to suggest that profound drowsiness and
confusion may be associated with combined use of haloperidol and
INDOMETHACIN (Stockley 1996).

2. Combination with high doses of LITHIUM have produced
encephalopathic syndromes and severe extrapyramidal reactions
(Cohen & Cohen 1974, Stockley 1996).

ETHANOL

Possible enhancement of central nervous system depression, and
precipitation of extrapyramidal side effects by ALCOHOL (Stockley
1996).

Mechanism of action

Haloperidol decanoate has no intrinsic activity. The pharmacological
effects are those of haloperidol which is released by bioconversion.
The precise mechanism of antipsychotic action is unclear, but is
considered to be associated with the potent dopamine D2 receptor
blocking activity of haloperidol and the resulting adaptive changes in
the brain.
Haloperidol is also a potent antagonist of opiate receptors, and has
weak antagonist activity at muscarinic, histamine H1,
alpha-adrenergic, and serotonin receptors (Dollery 1991).

Mechanism of toxicity

Toxicity is due to an extension of the pharmacological actions. The
various receptor antagonist actions of haloperidol result in
extrapyramidal reactions, orthostatic hypotension, a reduction of

seizure threshold, hypothermia, QT and PR prolongation on the ECG,
sedation, and antimuscarinic effects.

Pharmacokinetics

ABSORPTION

Haloperidol decanoate is slowly released into the circulation where it
is hydrolysed releasing active haloperidol. Peak plasma concentrations
occur within 3-9 days, then decrease slowly (Beresford & Ward 1987).

DISTRIBUTION

Haloperidol is about 92% bound to plasma proteins (Forsman & Ohman
1977b). It is widely distributed in the body, with an apparent volume
of distribution of 18 L/kg (Holley et al. 1983).

METABOLISM

Haloperidol decanoate undergoes hydrolysis by plasma and/or tissue
esterases to form haloperidol and decanoic acid (Beresford & Ward
1987).

Subsequently, haloperidol is metabolised in the liver, the main routes
of metabolism being oxidative N-dealkylation, and reduction of the
ketone group to form reduced haloperidol (Forsman & Larsson 1978).
Reduced haloperidol is much less active than haloperidol but undergoes
re-oxidation to haloperidol (Chakraborty et al. 1989, Cheng & Jusko
1993). The cytochrome P4502D6 has been shown to be involved in the
oxidative metabolic pathway (Llerena et al. 1992).

ELIMINATION

Haloperidol is excreted slowly in the urine and faeces. About 30% of a
dose is excreted in urine and about 20% of a dose in faeces via
biliary elimination (Beresford & Ward 1987). Only 1% of a dose is
excreted as unchanged drug in the urine (Forsman et al. 1977). There
is evidence of enterohepatic recycling (Chakraborty et al. 1989).

Half-life – substance

Haloperidol decanoate: 3 weeks

Half-life – metabolites

NA

Special populations

ELDERLY

Haloperidol plasma concentrations in the elderly tend to be higher
than in younger patients on equivalent doses but the difference is not
significant (Forsman & Ohman 1977a).

RENAL IMPAIRMENT

It is not anticipated that renal impairment would alter the
pharmacokinetic profile of haloperidol.

HEPATIC IMPAIRMENT

The clearance of haloperidol may be reduced in severe liver
impairment.

GENDER

Gender has been found not to influence haloperidol plasma
concentrations (Forsman & Ohman 1977a).

BREAST MILK

Haloperidol is excreted in breast milk.

Toxicokinetics

Absorption

Distribution

Metabolism

Elimination

Half-life – substance

Half-life – metabolites

Special populations

Breast milk

Summary

TYPE OF PRODUCT

Intramuscular antipsychotic depot injection.

INGREDIENTS

Haloperidol decanoate equivalent to 50mg/ml, or 100mg/ml of
haloperidol.
Formulated in benzyl alcohol and sesame oil.

NOTE: a separate entry exists for other haloperidol formulations – see
under ‘Haloperidol’.

SUMMARY OF TOXICITY

Plasma concentrations of haloperidol will be greatest during the first
week after injection. It will be during this period that there is the
greatest risk of acute toxicity. Any symptoms occurring may take
several weeks to resolve. Accidental injection or dose errors tend to
be in patients on long term therapy which carries a risk of
neuroleptic malignant syndrome and tardive dyskinesia in addition to
acute symptoms.

FEATURES

Rigidity, dystonic reactions, drowsiness, and tremor.

UNCOMMON FEATURES

Cardiac arrhythmias, neuroleptic malignant syndrome, tardive
dyskinesia.

SUMMARY OF MANAGEMENT: SUPPORTIVE

1. Check heart rhythm and blood pressure.

2. Acute dystonic reactions can be managed with IV procyclidine or
benztropine, followed by oral doses to prevent recurrence.

3. Other measures as required by the patients clinical condition.
Peak plasma concentrations occur within 3-9 days of
administration and it is during this time that symptoms are most
likely to occur.

Features – acute

Ingestion

Inhalation

Dermal

Ocular

Other routes

BY INJECTION:

Erythema, swelling, or tender lumps at the site of injection. Acute
dystonic reactions and other extrapyramidal signs (such as rigidity,
and tremor), drowsiness, hypotension (or rarely hypertension),
hypothermia, hypokalaemia, and cardiac arrhythmias particularly

prolongation of the QT interval and torsade de pointes (Aunsholt 1989,
Cummingham & Challapalli 1979, Henderson et al. 1991, Scialli &
Thornton 1978, Sinaniotis et al. 1978, Yoshida et al. 1993, Zee-Cheng
et al. 1985).

Features – chronic

Ingestion

Inhalation

Dermal

Ocular

Other routes

BY INJECTION: as for acute injection.

At risk groups

ELDERLY

Increased risk of toxic events.

PREGNANCY

The safety of haloperidol in human pregnancy has not been established.
There are two reports of limb defects in infants after first trimester
use of oral haloperidol given with other potentially teratogenic drugs
(AHFS 1998, Briggs 1994, Kopelman et al. 1975). Other investigators
have not found an association between haloperidol and birth defects.

CHILDREN

ENZYME DEFICIENCIES

The metabolism of haloperidol is subject to genetic polymorphism.
Subjects deficient in the isoenzyme P4502D6 are poor metabolisers of
haloperidol and will be at risk from high haloperidol plasma
concentrations due to a reduced metabolic capacity (Llerena et al.
1992). Approximately 7% of the caucasian population is deficient in
this enzyme.

ENZYME INDUCED

Reduced risk of toxicity from haloperidol.

Therapeutic administration with enzyme inducing drugs for a period of
1-3 weeks results in lower haloperidol plasma concentrations (Forsman
& Ohman 1977a, Jann et al. 1985).

Occupations

Others

RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of
toxicity.
HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired
metabolism.
CARDIAC DISEASE: increased risk of cardiotoxicity due to underlying
disease.
EPILEPSY: increased risk of seizures due to lowered seizure threshold.

Management

Decontamination

NA

Supportive care

MANAGEMENT OF THE SYMPTOMATIC PATIENT: SUPPORTIVE

1. ACUTE DYSTONIC AND OTHER EXTRAPYRAMIDAL REACTIONS

Severe dystonic reactions can be controlled within a few minutes by
giving procyclidine or benztropine by the intravenous (or
intramuscular) route. Subsequent oral doses may be required for 2-3
days to prevent recurrence. Less severe extrapyramidal symptoms can be
controlled by oral doses of procyclidine, benztropine, or other
similar anticholinergic drug (Corre et al. 1984, Guy’s, Lewisham & St.
Thomas Paediatric Formulary 1997, BNF 1996).

Procyclidine IV, IM:
Adult dose: 5-10 mg (use lower end of dose
range in elderly),
Child dose under 2 years: 500 micrograms-2 mg (unlicensed
indication)
Child dose 2-10 years: 2-5 mg (unlicensed indication).

Procyclidine oral:
Adult dose: 2.5-10mg three times a day
Child 7-14 years 1.25mg three times a day
(unlicensed indication)
Child over 14 years 2.5mg three times a day (unlicensed
indication)

Benztropine dose IV, IM, and oral:

Adult dose: 1-2 mg (use lower end of dose range in elderly),
Child dose: 20 micrograms/kg (unlicensed indication).

2. HYPOTENSION

Hypotension should be managed by the administration of intravenous
fluids and by physical means. Where these measures fail, consideration
may be given to the use of a direct acting sympathomimetic such as
noradrenaline with appropriate haemodynamic monitoring (e.g. insertion
of Swan-Ganz catheter).

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) in
dextrose 5% via a central venous catheter at an initial rate of 0.16
to 0.33 ml/minute adjusted according to response (BNF 1998).
CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
microgram/kg/minute of noradrenaline base) in glucose 5% or
glucose/saline via a central venous catheter (Guy’s, Lewisham & St
Thomas Paediatric Formulary 1997).

NOTE: sympathomimetics with mixed alpha and beta adrenergic effects
(e.g. adrenaline or dopamine) should not be used as they may aggravate
hypotension.

3. CARDIAC ARRHYTHMIAS

The ventricular arrhythmia, torsade de pointes, may prove difficult to
manage. Treatment is aimed at shortening the QT interval by
accelerating the heart rate. The preferred method is by CARDIAC
OVERDRIVE PACING (Henderson et al. 1991).

Alternatively isoprenaline may be used to increase the heart rate, but
with caution, as the unopposed beta 2-adrenergic agonist effects will
exacerbate hypotension.
ADULT DOSE: intravenous isoprenaline infused at a starting dose
of 0.2 micrograms/minute and titrated to maintain a heart rate of 100
beats per minute (Kemper et al. 1983).

Intravenous magnesium sulphate has also been shown to be effective in
the management of torsade de pointes (Tzivoni et al. 1988).

ADULT DOSE; 8 mmol of magnesium sulphate (4 ml of 50% solution)
by intravenous injection over 10-15 minutes, repeated once if
necessary (BNF 1998). CHILD DOSE: clinical experience in children is
lacking, but based on the above recommendations for management in
adults, doses of 0.08-0.2 mmol/kg (0.04-0.1 ml/kg of 50% solution) may
be considered appropriate (based on Guy’s, Lewisham & St Thomas
Paediatric Formulary 1997).

4. TEMPERATURE DISTURBANCES

Where the patient is hypothermic the body temperature should be
allowed to recover naturally by wrapping the patient in blankets to
conserve body heat.

Conventional external cooling procedures should be used in patients
who are hyperthermic.

5. NEUROLEPTIC MALIGNANT SYNDROME

The development of NMS with a high central temperature (over 39°C) is
best treated by paralysing and mechanically ventilating the patient.
This usually controls the muscle spasm and allows the temperature to
fall. If the body temperature is 40°C or over, administer intravenous
dantrolene.

ADULT DOSE: dantrolene 1 mg/kg body weight by rapid IV injection
repeated as required to a cumulative maximum of 10 mg/kg (BNF 1998).

Monitoring

Check the heart rate and rhythm, blood pressure, and body temperature
during the first 7-10 days after administration. Correct any
electrolyte abnormalities.

Antidotes

None available.

Elimination techniques

None.

Investigations

Management controversies

Case data

Analysis

Agent/toxin/metabolite

The measurement of plasma haloperidol is of little benefit as no
correlation has been established between plasma haloperidol
concentration and therapeutic or toxic effect.

Sample container

NA

Storage conditions

NA

Transport

NA

Interpretation of data

It has been suggested that a plasma haloperidol concentration of
0.005-0.012 mg/L may be associated with a clinical response, but this
range should only be viewed as a rough guide (Van Putten et al. 1992).
Peak concentrations following depot injection have been in the range
0.001-0.050 mg/L with steady-state concentrations around 0.008 mg/L
(Nayak et al. 1987).

Conversion factors

Others

NA

Toxicological data

Carcinogenicity

An increase in mammary neoplasms has been observed in rodents
following long term administration of prolactin-stimulating
antipsychotic agents. Although no association between human breast
cancer and long term administration of these drugs has been shown,
current evidence is too limited to be conclusive (AHFS 1998).

Genotoxicity

Mutagenicity

Reprotoxicity

Hyperprolactinaemia resulting from haloperidol therapy may lead to
infertility in women and impotence in men.

Teratogenicity

Haloperidol has been shown to be teratogenic and fetotoxic in animals
at dosages 2-20 times the usual maximum human dosage (AHFS 1998).
In human pregnancy, haloperidol has not been associated with
teratogenic effects when used alone, but there are two reports of limb
defects following the first trimester administration of haloperidol
with other drugs (Briggs 1994, Kopelman et al. 1975).

Relevant animal data

Relevant in vitro data

Authors

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph was produced by the staff of the Leeds Centre of the
National Poisons Information Service in the United Kingdom. The work
was commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review was undertaken by the Directors of the UK National Poisons
Information Service.

Prepared October 1996
Updated May 1998

References

AHFS.
AHFS, (American Hospital Formulary Service), Drug Information.
Bethesda MD: American Society of Health-System Pharmacists, 1996.

Aunsholt NA.
Prolonged Q-T interval and hypokalemia caused by haloperidol. Acta
Psychiatr Scand 1989; 79: 411-412.

Beresford R, Ward A.
Haloperidol decanoate: a preliminary review of its pharmacodynamic and
pharmacokinetic properties and therapeutic use in psychosis. Drugs
1987; 33: 31-49.

BNF.
Joint Formulary Committee. British National Formulary, Number 35.
London: British Medical Association & Royal Pharmaceutical Society of
Great Britain, 1998.

Briggs GG, Freeman RK, Yaffe SJ.
Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams &
Wilkins, 1994: 409/h-410/h.

Chakraborty BS, Hubbard JW, Hawes EM, McKay G, Cooper JK, Gurnsey T,
Korchinski ED, Midha KK.
Interconversion between haloperidol and reduced haloperidol in healthy
volunteers. Eur J Clin Pharmacol 1989; 37: 45-48.

Cheng H, Jusko WJ.
Pharmacokinetics of reversible metabolic systems. Biopharm Drug Dispos
1993; 14: 721-766.

Cohen WJ, Cohen NH.
Lithium carbonate, haloperidol, and irreversible brain damage. J Am
Med Assoc 1974; 230: 1283-1287.

Corre KA, Niemann JT, Bessen HA.
Extended therapy for acute dystonic reactions. Ann Emerg Med 1984; 13:
194-197.

Cummingham DG, Challapalli M.
Hypertension in acute haloperidol poisoning. J Pediatr 1979; 95:
489-490.

Dollery C (Ed).
Therapeutic Drugs Volume 2. Edinburgh: Churchill Livingstone,
1991:H1-H4.

Forsman A, Folsch G, Larsson M, Ohman R.
On the metabolism of haloperidol in man. Curr Ther Res 1977; 21:
606-617.

Forsman A , Larsson M.
Metabolism of haloperidol. Curr Ther Res 1978; 24: 567-568.

Forsman A, Ohman R.
Applied pharmacokinetics of haloperidol in man. Curr Ther Res 1977a;
21: 396-411.

Forsman A, Ohman R.
Studies on serum protein binding of haloperidol. Curr Ther Res 1977b;
21: 245-255.

Guy’s, Lewisham and St. Thomas’ Paediatric Formulary.
4th edition. London: Guy’s and St. Thomas’ Hospitals Trust, 1997.

Henderson RA, Lane S, Henry JA.
Life-threatening ventricular arrhythmia (Torsade de Pointes) after
haloperidol overdose. Human Exper Toxicol 1991; 10: 59-62.

Holley FO, Magliozzi JR, Stanski DR, Lombrozo L, Hollister LE.
Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol
Ther 1983; 33: 477-484.

Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR,
Bowden CL.
Effects of carbamazepine on plasma haloperidol levels. J Clin
Psychopharmacol 1985; 5: 106-109.

Kemper AJ , Dunlap R, Pietro DA.
Thioridazine-induced torsade de pointes: successful therapy with
isoproterenol. J Am Med Assoc 1983; 249: 2931-2934.

Kopelman AE, McCullar FW, Heggeness L.
Limb malformations following maternal use of haloperidol. J Am Med
Assoc 1975; 231: 62-64.

Llerena A, Alm C, Dahl M-L, Ekqvist B, Bertilsson L.
Haloperidol disposition is dependent on debrisoquine hydoxylation
phenotype. Ther Drug Monit 1992; 14: 92-97.

Nayak RK, Doose DR, Nair NPV.
The bioavailability and pharmacokinetics of oral and depot
intramuscular haloperidol in schizophrenic patients. J Clin Pharmacol
1987; 27: 144-150.

Scialli JVK, Thornton WE.
Toxic reactions from a haloperidol overdose in two children: thermal
and cardiac manifestations. J Am Med Assoc 1978; 239: 48-49.

Sinaniotis CA, Spyrides P, Vlachos P, Papadatos C.
Acute haloperidol poisoning in children. J Pediatr 1978; 93:
1038-1039.

Stockley IH. Drug Interactions. 4th ed. London: The Pharmaceutical
Press, 1994

Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, Stern
S.
Treatment of torsade de pointes with magnesium sulfate. Circulation
1988; 77: 392-397.

Van Putten T, Marder SR, Mintz J, Poland RE.
Haloperidol plasma levels and clinical response: a therapeutic window
relationship. Am J Psychiatry 1992; 149: 500-505.

Yoshida I, Sakaguchi Y, Matsuishi T, Yano E, Yamashito Y, Hayata S,
Hitoshi T,
Yamashita F.
Acute accidental overdosage of haloperidol in children. Acta Paediatr
1993; 82 :877-880.

Zee-Cheng C-S, Mueller CE, Seifert CF, Gibbs HR.
Haloperidol and torsade de pointes. Ann Int Med 1985; 102: 418.

—————
INTOX Home Page

MONOGRAPH FOR UKPID

CHLORPROMAZINE HYDROCHLORIDE

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review group: Directors of the UK National Poisons Information
Service.

MONOGRAPH FOR UKPID

Drug name

Chlorpromazine hydrochloride

Chemical group

Phenothiazine

Origin

Synthetic

Name

UK Brand name(s)
Largactil(R), Chloractil(R)

Synonyms

Common names

Product licence number

Largactil(R) 10mg: 0012/5108R
Largactil(R) 25mg: 0012/5109R
Largactil(R) 50mg: 0012/5110R
Largactil(R) 100mg: 0012/5111R
Largactil(R) injection solution 2.5%: 0012/5308R
Largactil(R) syrup: 0012/5083R
Largactil(R) Forte Suspension: 0012/5001R

CAS number

69-09-0

Manufacturer

Rhône-Poulenc Rorer Ltd, RPR House, 50 Kings Hill Ave., Kings Hill,
West Malling, Kent, ME19 4AH.
Tel. no. 01732 584000
Fax. no. 01732 584086

Available as Largactil(R) from Rhône-Poulenc Rorer, and as generics or
branded generics from Antigen, APS, DDSA (Chloractil(R)), Hillcross,
Rosemont and Norton.

Form

Tablets
Oral liquids
Injection
Suppositories

Formulation details

Tablets of 10 mg, 25 mg, 50 mg, and 100 mg
Syrup containing 25 mg / 5 ml
Forte suspension equivalent to 100 mg/5 ml (as chlorpromazine
embonate)
Injection of 25 mg / ml.
Suppositories of 100 mg (unlicensed product)

Pack size

Largactil tabs 10 mg, 25 mg, 50 mg, and 100 mg – blister packs of 56
Largactil syrup – 100ml pack
Largactil forte suspension – 100ml pack
Largactil injection – ampoules of 1 ml and 2 ml

Pack sizes may differ for generics and branded generics.

Packaging

Largactil(R) tabs 10mg – white tablets marked LG10
Largactil(R) tabs 25mg – white tablets marked LG25
Largactil(R) tabs 50mg – white tablets marked LG50
Largactil(R) tabs 100mg – white tablets marked LG100

Chemical structure

C17H19ClN2S.HCl

Chemical name

3-(2-Chlorophenothiazin-10-yl)propyldimethylamine hydrochloride

Indication

Schizophrenia and other psychoses, (especially paranoid and
hypomania); short-term adjunctive management of anxiety, psychomotor
agitation, excitement, and violent or dangerously impulsive behaviour;
intractable hiccup; nausea and vomiting of terminal illness (where
other drugs have failed or are not available); induction of
hypothermia; childhood schizophrenia and autism.

Therapeutic dosage – adults

BY MOUTH: 75-300 mg daily in divided doses (doses up to 1 g used in
psychoses).
BY DEEP IM INJECTION: 25-50 mg every 6-8 hours.
BY RECTUM (unlicensed route): 100 mg every 6-8 hours.

For equivalent therapeutic effect:

100 mg by rectum ° 20-25 mg by IM injection ° 40-50 mg by mouth

Therapeutic dosage – children

BY MOUTH: 1-5 years: 500 micrograms/kg 4-6 hourly (maximum 40 mg
daily).
6-12 years: _ to ´ adult dose (maximum 75 mg daily).

BY DEEP IM INJECTION:
500 micrograms/kg 6-8 hourly with maximum daily dose as for
oral dose.

BY RECTUM (unlicensed route):
1-4 years: 12.5 mg 3-4 hourly.
5-12 years: 25 mg 3-4 hourly.
over 12 years: 50-100 mg 3-4 hourly.

Contra-indications

Coma caused by CNS depressants, bone marrow depression,
phaeochromocytoma.

Abuses

Epidemiology

Although the phenothiazines show similar toxic properties to the
tricyclic antidepressants, overdoses tend to be less serious, with
severe hypotension and cardiotoxicity being less common. (Ellenhorn
1997).

ADVERSE EFFECTS

There are a large number of adverse effects associated with
therapeutic use including changes in hepatic, cardiovascular,
respiratory, haematologic, ocular and endocrine functions, besides
extrapyramidal reactions and the risk of neuroleptic malignant
syndrome.
Postural hypotension commonly occurs, especially after intramuscular
administration.

INTERACTIONS

PHARMACODYNAMIC

1. Chlorpromazine enhances the central nervous system depression
produced by other CNS DEPRESSANT drugs.

2. The hypotensive effect of ANTIHYPERTENSIVE AGENTS is likely to be
enhanced, the exception being GUANETHIDINE where chlorpromazine
may antagonise its hypotensive effect (Fruncillo 1985, Janowsky
1973).
3. There is an increased risk of ventricular arrhythmias when
chlorpromazine is taken with drugs that increase the QT interval
e.g. ASTEMIZOLE, TERFENADINE, or ANTI-ARRHYTHMIC AGENTS.

4. Combination with other antidopaminergic agents such as
METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of
extrapyramidal effects.

PHARMACOKINETIC

1. The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by
chlorpromazine, increasing the risk of toxicity (Balant-Gorgia &
Balant 1987).

OTHER

An interaction between phenothiazine drugs and ‘caffeinated’ beverages
has been reported. A precipitation occurs when these drugs are diluted
in tea or coffee (including decaffeinated varieties) which is
considered to be a nonspecific reaction between the
nitrogen-containing organic bases and tannic acid. The reaction is
reversible in the acid environment of the stomach (Curry et al. 1991).

ETHANOL

The administration of ethanol with chlorpromazine results in
potentiated sedative effects and impaired co-ordination (Lieber 1994,
Milner & Landauer 1971, Zirkle 1959).

MECHANISM OF ACTION

Chlorpromazine blocks post-synaptic D2 dopamine receptors. It is
considered that dopamine receptor blockade in the mesolimbic area
accounts for the antipsychotic effect, whilst blockade in the
nigrostriatal system produces the extrapyramidal effects associated
with chlorpromazine use. The anti-emetic effect results from dopamine
antagonism in the chemoreceptor trigger zone. Chlorpromazine also
possesses antimuscarinic properties. It is an antagonist at histamine
(H1), serotonin and alpha-1-adrenergic receptors (Dollery 1991).

MECHANISM OF TOXICITY

The extrapyramidal, anticholinergic, sedative, and hypotensive
features of toxicity result from the blockade of dopaminergic,
muscarinic, histaminic, and alpha adrenergic receptors respectively.
The cardiotoxic effects of phenothiazines in overdose are similar to
that of the tricyclic antidepressants. (Ellenhorn 1997). Cardiac
arrhythmia and apparent ‘sudden death’ have been associated with
therapeutic doses of chlorpromazine, the sudden cardiovascular
collapse being attributed to ventricular dysrhythmia (Fowler et al.
1976, Hollister & Kosec 1965).

Pharmacokinetics

ABSORPTION

Peak plasma concentrations occur on average 2-3 hours (range 1.5-8
hours) after an oral dose (Midha et al. 1989, Yeung et al. 1993).
After intramuscular injection chlorpromazine is slowly absorbed from
the injection site, with the peak plasma concentration occurring 6-24
hours after administration (Dahl & Strandjord 1977).
The oral bioavailability of chlorpromazine is about 30% that of
intramuscular doses (Dahl & Strandjord 1977) and about 10% that of
intravenous doses (Yeung et al. 1993) as a result of pre-systemic
metabolism.

DISTRIBUTION

Chlorpromazine is highly lipid soluble and is 98% bound to plasma
proteins (Dollery 1991). It is extensively distributed throughout the
body and has a mean volume of distribution of 17 L/kg (Yeung et al.
1993).

METABOLISM

Chlorpromazine is subject to significant pre-systemic metabolism
attributed to first passage through the gut wall, liver and lung
(Yeung et al. 1993).
It is extensively metabolised involving cytochrome P450 microsomal
pathways (Lieber 1994) with more than 100 metabolites being
theoretically possible (Javaid 1994). The major routes of metabolism
include hydroxylation, N-oxidation, sulphoxidation, demethylation,
deamination and conjugation (Dollery 1991). A number of the
metabolites may contribute to the pharmacological effects of
chlorpromazine including 7-hydroxychlorpromazine,
chlorpromazine-N-oxide, 3-hydroxychlorpromazine and
desmethylchlorpromazine (Chetty et al. 1994). Although the metabolite
chlorpromazine-N-oxide does not possess activity in vitro, it exerts
an indirect pharmacological effect in vivo by reverting to
chlorpromazine (Cheng & Jusko 1993). It is considered that one of the
metabolites produced (chlorpromazine-sulphoxide) may oppose the
alpha-adrenergic blocking action of chlorpromazine (Chetty et al.
1994).
There is limited evidence to suggest that following multiple doses,
the metabolism of chlorpromazine may be increased due to induction of
microsomal liver enzymes (Dahl & Strandjord 1977).

ELIMINATION

Excretion is primarily via the kidneys with less than 1% of a dose
excreted as unchanged drug in the urine, and 20-70% as conjugated or
unconjugated metabolites (Dollery 1991). 5-6% of a dose is excreted in
faeces via biliary elimination (Dollery 1991).
Some metabolites can still be detected up to 18 months after
discontinuation of long-term therapy (Dollery 1991).

HALF-LIFE

The half-life of chlorpromazine is usually within the range 8-35 hours
(Dollery 1991), although it is as short as 2 hours or as long as 60
hours in some individuals (Midha et al. 1989). The half-lives of the
primary metabolites are generally within the same range (Yeung et al.
1993).

Special populations

ELDERLY: it has been suggested that the elderly metabolise
antipsychotic drugs more slowly than do the non-elderly adult
population (Balant-Gorgia & Balant 1987).

RENAL IMPAIRMENT: the effects of renal disease on chlorpromazine
pharmacokinetics are not known, but since it is extensively
metabolised in the liver, they are not anticipated to be great.

HEPATIC IMPAIRMENT: it is considered that hepatic dysfunction will
increase the bioavailability of chlorpromazine and delay its
elimination (Dollery 1991).

GENDER:

Breast milk

Chlorpromazine has been identified in the milk of nursing mothers
receiving the drug.
In one study (Blacker et al. 1962) the peak milk concentration of
chlorpromazine (0.29 mg/L) occurred 2 hours after a single oral dose
of 1200 mg, although in this report the assay design was relatively
nonspecific and no account was taken of active metabolites.
In a later study chlorpromazine and several metabolites were
identified in the breast milk of four nursing mothers receiving the
drug (doses not specified). The milk concentrations ranged from
0.007-0.098 mg/L, with maternal serum levels ranging from 0.016-0.052
mg/L. In two of the four patients the milk concentrations of
chlorpromazine were higher than the maternal plasma concentrations.
One of the babies was reported to be drowsy and lethargic (the milk
chlorpromazine level in this case was 0.092 mg/L) (Wiles et al. 1978).

Toxicokinetics

Absorption

Distribution

Metabolism

Elimination

HALF-LIFE

HALF-LIFE – METABOLITES

Special populations

ELDERLY:

RENAL IMPAIRMENT:

HEPATIC IMPAIRMENT:

GENDER:

Breast milk

Summary

TYPE OF PRODUCT

A phenothiazine antipsychotic.

INGREDIENTS

Tablets of 10 mg, 25 mg, 50 mg, and 100 mg.
Oral liquids containing 25 mg / 5 ml, and 100 mg / 5 ml.
Injection of 25 mg / ml.
Suppositories of 100 mg (unlicensed product).

SUMMARY OF TOXICITY

Central nervous system depression is the most common feature of
toxicity and usually begins 1-2 hours after ingestion. Hypotension and
anticholinergic symptoms are also common. Acute dystonic reactions and
cardiac arrhythmias may occur. Chlorpromazine lowers the seizure
threshold (a dose-related effect) so convulsions may occur in patients
not previously known to be epileptic.

Individual response to chlorpromazine overdose is variable – an
ingestion of 20 g has been survived, whilst 2 g has proved fatal.

In children, hypotension and drowsiness can follow doses ranging from
100-375 mg, with severe central nervous system depression resulting
from higher doses. Fatalities have been reported in children, the
doses ingested ranging from 20-74 mg/kg.

In mixed drug ingestions chlorpromazine enhances the sedation produced
by other central nervous system depressants including ethanol.

FEATURES

Drowsiness, hypotension, anticholinergic symptoms (e.g. dry mouth,
dilated pupils, urinary retention, visual disturbances), acute
dystonic reactions, and cardiac arrhythmias.

UNCOMMON FEATURES

Acute pulmonary oedema, and neuroleptic malignant syndrome.

SUMMARY OF MANAGEMENT

1. Maintain a clear airway and adequate ventilation if consciousness
is impaired.

2. If within 1 hour of the ingestion and more than 500mg has been
ingested by an adult, or more than 4mg/kg by a child, give oral
activated charcoal.

3. Monitor the cardiac rhythm.

4. Manage hypotension with IV fluids.

5. Treat acute dystonic reactions with IV procyclidine or
benztropine.

Clinical Features

Features – acute

Ingestion

Hypotension, sinus tachycardia, varying degrees of CNS depression,
blurred vision, dry mouth, urinary retention, acute dystonic
reactions, akathisia, parkinsonism, ECG changes including prolonged PR
and QT intervals, ventricular tachyarrhythmias, convulsions,
hypothermia (or occasionally hyperthermia), pulmonary oedema, and
respiratory depression (Allen et al. 1980, Barry et al. 1973,
Ellenhorn 1997, Li & Gefter 1992, Reid & Harrower 1984).

Inhalation

Dermal

Contact dermatitis.

Ocular

Other routes

BY INJECTION: as for acute ingestion.

Features – chronic

Ingestion

As for acute ingestion, but with the additional risks of the
development of neuroleptic malignant syndrome (characterised by muscle
rigidity, hyperthermia, altered consciousness, and autonomic
instability), and tardive dyskinesia (involuntary movements of the
tongue, face, jaw, or mouth) (Rosenberg & Green 1989).

Inhalation

Dermal

Contact dermatitis.

Ocular

Other routes

BY INJECTION: as for chronic ingestion.

At risk groups

ELDERLY

Elderly and volume depleted subjects are particularly susceptible to
postural hypotension.

PREGNANCY

The administration of chlorpromazine near term has been associated
with unpredictable falls in maternal blood pressure which could be
dangerous to the mother and the foetus. Administration near term has
also resulted in an extrapyramidal syndrome in some infants,
characterised by tremors, increased muscle tone, and hyperactive deep
tendon reflexes persisting some months (Briggs 1994).

One psychiatric patient who ingested 8 g of chlorpromazine in the last
ten days of pregnancy, delivered a hypotonic, lethargic infant with
depressed reflexes and jaundice (Hammond & Toseland 1970).

CHILDREN

ENZYME DEFICIENCIES

ENZYME INDUCED

Occupations

Pharmacists, nurses, and other health workers should avoid direct
contact with chlorpromazine due to a risk of contact sensitisation.
Tablets should not be crushed and solutions handled with care (BNF
1998).

Others

RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of
toxicity.
HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired
metabolism and hepatotoxic potential.
CARDIAC DISEASE: increased risk of cardiotoxicity due to underlying
disease.
EPILEPSY: increased risk of seizures due to lowered seizure threshold.

Management

Decontamination

If within one hour of the ingestion, and more than 500mg has been
ingested by an adult, or 100mg by a child, oral activated charcoal may
be given to reduce drug absorption.
ADULT DOSE: 50g; CHILD DOSE; 1g/kg.
If the patient is drowsy this should be administered via a nasogastric
tube, and if there is no gag reflex present, using an endotracheal
tube to protect the airway.

Supportive care

GENERAL MANAGEMENT OF THE SYMPTOMATIC PATIENT

Clear and maintain airway, and give cardiopulmonary resuscitation if
necessary.
Evaluate the patient’s condition and provide support for vital
functions. The aim is to maintain vital bodily functions with minimal
intervention whilst the elimination of chlorpromazine takes place.
Particular care should be given to the prevention of hypoxia and
acidosis, and the correction of any electrolyte imbalance.

SPECIFIC MANAGEMENT OF THE SYMPTOMATIC PATIENT

1. HYPOTENSION

Hypotension should be managed by the administration of intravenous
fluids and by physical means. Where these measures fail, consideration
may be given to the use of a direct acting sympathomimetic such as
noradrenaline with appropriate haemodynamic monitoring (e.g. insertion
of Swan-Ganz catheter).

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via
a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute
adjusted according to response (BNF 1998).
CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
microgram/kg/minute of noradrenaline base) in glucose 5% or
glucose/saline via a central venous catheter (Guy’s, Lewisham & St
Thomas Paediatric Formulary, 1997).

NOTE: vasopressors with mixed alpha and beta adrenergic effects (e.g.
adrenaline, dopamine) should not be used as hypotension may be
exacerbated.

2. COMA
Good supportive care is essential.

3. CARDIOTOXICITY

In practice it is seldom necessary or advisable to use specific drug
treatment for arrhythmias. If hypoxia and acidosis are reversed, and
adequate serum potassium levels maintained, then the majority of
patients will show improvement with supportive measures. Where these
measures fail and life-threatening arrhythmias persist, intravenous
sodium bicarbonate should be given (even in the absence of acidosis)
before considering antiarrhythmic drug therapy.
Where an antiarrhythmic is considered necessary, lignocaine is the
preferred drug.
ADULT DOSE: 50-100 mg lignocaine by IV bolus given over a few
minutes, followed by an infusion of 4 mg/minute for 30 minutes, 2
mg/minute for 2 hours, then 1 mg/minute (BNF 1998).
NOTE: the use of quinidine, procainamide, flecainide, or disopyramide,
is contraindicated as these agents further depress cardiac conduction
and contractility. The use of beta-blockers and calcium channel
blockers should also be avoided as they decrease cardiac output and
exacerbate hypotension.

The ventricular arrhythmia, TORSADE DE POINTES, may prove difficult to
manage. The preferred treatment is cardiac overdrive pacing, but in
cases where cardiac pacemaker insertion is not readily available,
intravenous magnesium sulphate has been shown to be effective (Tzivoni
et al. 1988).
ADULT DOSE: 8 mmol of magnesium sulphate (4 ml of 50% solution)
by intravenous injection over 10-15 minutes, repeated once if
necessary (BNF 1998).
CHILD DOSE: clinical experience in children is lacking, but based
on the above recommendations for management in adults, doses of 0.08-
0.2 mmol/kg (0.04-0.1 ml/kg of 50% solution) may be considered
appropriate (based on Guy’s, Lewisham & St Thomas Paediatric
Formulary, 1997).
Torsade de pointes has also been successfully managed in adults by the
intravenous administration of isoprenaline (infused at a starting dose
of 0.2 micrograms/minute and titrated to maintain a heart rate of 100
beats per minute) (Kemper et al. 1983). However it should be used with
caution as its beta-2-adrenergic agonist effects exacerbate
hypotension.

4. ACUTE DYSTONIC AND OTHER EXTRAPYRAMIDAL REACTIONS

Severe dystonic reactions can be controlled within a few minutes by
giving procyclidine or benztropine by the intravenous (or
intramuscular) route. Subsequent oral doses may be required for 2-3

days to prevent recurrence. Less severe extrapyramidal symptoms can be
controlled by oral doses of procyclidine, benztropine, or other
similar anticholinergic drug (Corre et al. 1984, Guy’s, Lewisham & St.
Thomas Paediatric Formulary, 1997, BNF 1998).
Procyclidine IV, IM, and oral:
ADULT DOSE: 5-10 mg (use lower end of dose range in elderly),
CHILD DOSE under 2 years: 500 micrograms-2 mg (unlicensed
indication)
2-10 years: 2-5 mg (unlicensed indication).
Benztropine dose IV, IM, and oral:
ADULT DOSE: 1-2 mg (use lower end of dose range in elderly),
CHILD DOSE: 20 micrograms/kg (unlicensed indication).

5. SEIZURES/MUSCLE SPASMS

Diazepam by slow intravenous injection preferably in emulsion form,
may be given to control muscle spasms and convulsions not remitting
spontaneously.
ADULT DOSE: 10 mg repeated as required depending upon clinical
condition;
CHILD DOSE: 200 – 300 micrograms/kg.

6. TEMPERATURE DISTURBANCES

Where the patient is hypothermic the body temperature should be
allowed to recover naturally by wrapping the patient in blankets to
conserve body heat.
Conventional external cooling procedures should be used in patients
who are hyperthermic.

7. NEUROLEPTIC MALIGNANT SYNDROME

The development of neuroleptic malignant syndrome with a high central
temperature (over 39°C) is best treated by paralysing and mechanically
ventilating the patient. This usually controls the muscle spasm and
allows the temperature to fall. If the body temperature is 40°C or
over, administer intravenous dantrolene.
ADULT DOSE: 1 mg/kg body weight by rapid IV injection repeated as
required to a cumulative maximum of 10 mg/kg (BNF 1998).

8. OTHER MEASURES

Pulmonary oedema typically resolves with conventional supportive
management within 18-40 hours of ingestion (Li & Gefter 1992).

Monitoring

Monitor the heart rate and rhythm, blood pressure, arterial blood
gases, serum electrolytes, body temperature, respiratory rate and
depth, and urinary output.

Observe for a minimum of 4 hours post-ingestion where:
i) more than 4 mg/kg has been ingested by a child (or more than
the child’s normal therapeutic dose, if this is greater),
ii) more than 500 mg is known to have been ingested by an adult
(or more than the patients’s normal therapeutic dose, if this is
greater),
iii) the patient is symptomatic.
Where symptoms develop following overdose, they may persist for 24
hours. Complications following severe toxicity may require the patient
to be hospitalised for several days.

Antidotes

None available.

Elimination techniques

Haemodialysis and diuresis are ineffective as ways of increasing drug
elimination due to the large volume of distribution and high lipid
solubility of chlorpromazine. It is not considered that haemoperfusion
will be of benefit (Ellenhorn 1997).

Investigations

Where there is evidence of severe toxicity a chest radiograph should
be performed within 24 hours of the ingestion to exclude pulmonary
complications.

Management controversies

GASTRIC LAVAGE is not recommended as the procedure may be associated
with significant morbidity, and there is no evidence that it is of any
greater benefit than activated charcoal used alone.
If the procedure is used (i.e. in cases where activated charcoal
cannot be administered), a cuffed endotracheal tube should be used to
protect the airway if the patient is drowsy, and activated charcoal
left in the stomach following the lavage.

Case data

CASE REPORT 1

A 27 year old woman was admitted 12 hours after ingesting 8 g
chlorpromazine and 150 mg flurazepam. After 18 hours she was fully
alert and normotensive. Six hours later she sustained a cardiac arrest
and was successfully resuscitated. Subsequent ventricular tachycardia
responded to intravenous lignocaine, and a prolonged QT interval
shortened progressively to normal over the next three days (Reid &
Harrower 1984).

Analysis

Agent/toxin/metabolite

Several studies to determine the relationship between plasma
concentration and therapeutic response have been performed. The
majority of studies showed large individual variations in
chlorpromazine concentration relative to dose, and no clear
association between plasma concentration and therapeutic response has
been made (Dahl & Strandjord 1977).
As a consequence the measurement of plasma chlorpromazine
concentrations following overdose is not routinely advised.

Sample container

Storage conditions

Transport

Interpretation of data

Although no clear relationship exists between plasma concentration and
therapeutic effect,
it has been suggested that therapeutic response may be associated with
the plasma concentration range 0.05-0.30 mg/L (Rivera-Calimlim et al.
1976).
In a study of unexplained deaths in patients receiving multiple
antipsychotic therapy, five cases had concentrations of antipsychotic
drugs which were considered ‘probably’ toxic and were implicated in
the development of ventricular fibrillation. The plasma chlorpromazine
concentrations in these cases were in the range 0.5-7.0 mg/L (Jusic &
Lader 1994).

Conversion factors

1 mg/L = 2.817 micromoles/L
1 micromole/L = 0.355 mg/L

The molecular weight of chlorpromazine hydrochloride is 355.3

Others

Toxicological data

Carcinogenicity

Genotoxicity

Mutagenicity

Reprotoxicity

Teratogenicity

Chlorpromazine readily crosses the placenta. Although one study found
an increased incidence of malformations in first trimester
phenothiazine-exposed infants compared to non-exposed controls
(3.5%compared to 1.6%), most reports describing the use of
phenothiazines in pregnancy (during all stages of gestation) conclude
that they do not adversely affect the foetus or newborn (Briggs 1994).

Relevant animal data

Relevant in vitro data

Authors

HY Allen
ZM Everitt
AT Judd

National Poisons Information Service (Leeds Centre)
Leeds Poisons Information Centre
Leeds General Infirmary
Leeds
LS1 3EX
UK

This monograph was produced by the staff of the Leeds Centre of the
National Poisons Information Service in the United Kingdom. The work
was commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.

Peer review was undertaken by the Directors of the UK National Poisons
Information Service.

Prepared November 1996
Updated May 1998

References

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Balant-Gorgia AE, Balant L.
Antipsychotic drugs – clinical pharmacokinetics of potential
candidates for plasma concentration monitoring. Clin Pharmacokinet
1987; 13: 65-90.

Barry D, Meyskens FL, Becker CE.
Phenothiazine poisoning – a review of 48 cases. Calif Med 1973; 118:
1-5.

Blacker KH, Weinstein BJ, Ellman GL.
Mother’s milk and chlorpromazine. Am J Psychiatry 1962; 119: 178-179.

BNF 1998.
Joint Formulary Committee. British National Formulary, Number 35.
London: British Medical Association & Royal Pharmaceutical Society of
Great Britain, 1998.

Briggs GG, Freeman RK, Yaffe SJ.
Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams &
Wilkins, 1994: 166c-168c.

Cheng H, Jusko WJ.
Pharmacokinetics of reversible metabolic systems. Biopharm Drug Dispos
1993; 14: 721-766.

Chetty M, Moodley SV, Miller R.
Important metabolites to measure in pharmacodynamic studies of
chlorpromazine. The Drug Monit 1994; 16: 30-36.

Corre KA, Niemann JT, Bessen HA.
Extended therapy for acute dystonic reactions. Ann Emerg Med 1984; 13:
194-197.

Curry ML, Curry SH, Marroum PJ.
Interaction of phenothiazine and related drugs and caffeinated
beverages (letter). Ann Pharmacother 1991; 25: 437.

Dahl SG, Strandjord RE.
Pharmacokinetics of chlorpromazine after single and chronic dosage.
Clin Pharmacol The 1977; 21: 437-448.

Dollery C (Ed).
Therapeutic Drugs Volume 1. Edinburgh: Churchill Livingstone, 1991:
C201-C206.

Donlon PT, Tupin JP.
Successful suicides with thioridazine and mesoridazine. Arch Gen
Psychiatry 1977; 34: 955-957.

Ellenhorn MJ
Ellenhorn,s Medical Toxicology: diagnosis and treatment of human
poisoning. 2nd ed. Baltimore: Williams and Wilkins, 1997.

Fowler NO, McCall D, Chou T-C, Holmes JC, Hanenson IB.
Electrocardiographic changes and cardiac arrhythmias in patients
receiving psychotropic drugs. Am J Cardiol 1976; 37: 223-230.

Fruncillo RJ, Gibbons WJ, Vlasses PH, Ferguson RK.
Severe hypotension associated with concurrent clonidine and
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Guy’s, Lewisham & St. Thomas’ Hospitals Paediatric Formulary, 4th
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Hammond JE, Toseland PA.
Placental transfer of chlorpromazine. Arch Dis Child 1970; 45:
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Hollister LE, Kosek JC.
Sudden death during treatment with phenothiazine derivatives. J Am Med
Assoc 1965; 192: 1035-1038.

Janowsky DS, El-Yousef MK, Davis JM, Fann WE.
Antagonism of guanethidine by chlorpromazine. Am J Psychiatry 1973;
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Javaid JI.
Clinical pharmacokinetics of antipsychotics. J Clin Pharmacol 1994;
34: 286-295.

Jusic N, Lader M.
Post-mortem antipsychotic drug concentrations and unexplained deaths.
Br J Psychiatry 1994; 165: 787-791.

Kemper AJ , Dunlap R, Pietro DA.
Thioridazine-induced torsade de pointes: successful therapy with
isoproterenol. J Am Med Assoc 1983; 249: 2931-2934.

Li C, Gefter WB.
Acute pulmonary edema induced by overdosage of phenothiazines. Chest
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Lieber CS.
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Overdosage effects and danger from tranquillizing drugs. J Am Med
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Midha KK, Hawes EM, Hubbard JW, Korchinski ED, McKay G.
Intersubject variation in the pharmacokinetics of chlorpromazine in
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Cardiac arrest after apparent recovery from an overdose of
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See Also:
Chlorpromazine (PIM 125)

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As CBD goes into the body, it moves along the endocannabinoid system. This system is set up to hold the different CB receptors in the body and to receive messages that the body sends. 

Unfortunately, in many instances, when someone faces anxiety issues, those receptors are not working correctly. The receptors forget to open or do not open in time to receive a message. 

CBD helps to naturally remind those receptors to open and take in the messages being sent around. From there, the receptor can decipher what was the message and reply in a way that makes sense. 

Medication forces the body to act in some specific way, but CBD allows the body to respond naturally. This helps the body relearn how to move in ways it once forgot, or learn how to act in ways it never knew. 

When someone has anxiety, those messages only sometimes get opened. Many times, when the signals of worry or concern are opened, sometimes the receptors send back inadequate responses, such as not being able to breathe correctly or tensing up the muscles. 

CBD allows the body and the central nervous system a chance to synchronize backup and work together as they should. 

This is not an instant fix, nor does it work for everyone, but in many cases, CBD may help alleviate anxiety symptoms and put the person back in control. 

There are other effects that those taking CBD also feel, including: 

  • Anti-inflammatory effects 
  • Relief from chronic pain 
  • Relaxation and a sense of calm 
  • Tired when appropriate, allowing the person to sleep at bedtime 
  • Relief from nausea
  • An increased feeling of control in overwhelming situations 
  • Reduction in the effects and inflammation of diabetes 

Causes of Anxiety Disorders

Many different things can lead to an anxiety issue. Some things are controllable, such as situations in life, while others are not. The most common causes of anxiety include: 

  • A person’s genetics plays a role in how anxious someone is. For example, if a person’s mother had anxiety, it makes him or her more likely to develop it as well.
  • Brain chemistry also plays a role in how much anxiety someone experiences. Those who struggle with mental health issues that alter brain chemistry are more likely to develop anxiety.
  • The situation of someone’s life also plays a role in anxiety. People who have been the victim of crimes or suffered abuse are more likely to feel anxious than those who have not. 
  • Whether someone has an outgoing or introverted personality also plays a role in how much anxiety someone feels. 

Which Forms of Anxiety Are Most Present in the Population?

People all around the United States struggle with anxiety, but the specific type of stress varies. Here are some of the most common forms of anxiety that people are trying to manage.

  • Generalized Anxiety Disorder: This form of anxiety affects approximately 7 million adults in the U.S. 
  • Panic Disorder: This form of anxiety affects approximately 6 million adults in the U.S.
  • Social Anxiety Disorder: This form of anxiety affects approximately 15 million adults in the U.S. 
  • Post-Traumatic Stress Disorder: This form of anxiety affects approximately 8 million adults in the U.S. 
  • Several Phobias, Such as Social Phobia: Phobias affect approximately 19 million adults in the U.S. 
  • OCD, or Obsessive-Compulsive Disorder: This form of anxiety affects more than 2 million adults in the U.S. 
  • Major Depressive Disorder: This form of anxiety affects over 16 million adults in the U.S. 

Most Common Treatments for Anxiety

By far, the most common way of treating anxiety is medication, at least out of the people who seek treatment. However, most people do not try to receive treatment. 

The classifications of medication often used to treat anxiety include: 

  • Selective Serotonin Reuptake Inhibitors, or SSRIs, often help with obsessive-compulsive disorder. 
  • Tricyclic antidepressants are used to help with the treatment of anxiety or depression, but they tend to be difficult for most people to take due to the effects they cause. 
  • Serotonin-Norepinephrine Reuptake Inhibitors, or SNRIs, are often used to treat anxiety or depression. 
  • Benzodiazepines are used to treat any physical manifestation of anxiety, such as the inability to sleep or muscles that stay tense, since they are sedatives. 
  • Beta-blockers are most commonly used for those with heart issues or high blood pressure, but they can also help those struggling with anxiety. 
  • Monoamine Oxidase Inhibitors, or MAOIs, are used for those struggling with panic disorders and social forms of phobia. 

Another treatment option that is coming to light is CBD oil. The properties of CBD allow it to be an excellent way for many people to relax. 

Plus, cannabinoids are natural, therefore causing fewer adverse effects to the people taking them. Instead of racing heart rates, the inability to focus, or being so sedated that it can be challenging to function, many people want to get similar results without those negative feelings that come with it. 

People have been noticing the benefits of CBD a lot, and people are not the only ones taking notice. 

The FDA has been running clinical trials and approved at least one medication that contains CBD for use in the U.S. so far, and more are on the horizon. 

Plus, several animal studies are going on testing several cannabis products, since the bodies of animals are so similar to human bodies in how they react to many substances. 

Can CBD Products Be Used as Any Other Potential Treatment Option?

Using CBD for medical ailments aside from anxiety is also possible. 

It is already used medicinally to treat seizures and some forms of epilepsy, but there are other ailments that it could help with, too. Some of those ailments include: 

    • MS or Multiple Sclerosis: Studies have found it effective at reducing pain, improving the relaxation of muscles, and allowing patients to have to urinate less frequently. 
    • Schizophrenia: Studies have shown that the psychotic symptoms of those with schizophrenia have declined when CBD is taken for four weeks. 
    • Dystonia: Studies are showing an improvement in dystonia symptoms by as much as 50 percent in people taking CBD for six weeks. 
    • Parkinson’s Disease: Studies are showing significant improvement in the psychotic symptoms of those struggling with Parkinson’s disease. 

Graft-Versus-Host Disease (GVHD): Studies have shown that taking CBD before a bone marrow transplant and continuing to take it for at least one month after can slow the development of GVHD. 

  • Social Anxiety: Studies have shown that people with different types of social anxiety can have markedly better relationships and much less anxiety when taking CBD. 

Those who have a fear of public speaking often need higher doses of CBD to feel the effects. Those who struggle with other social fears can often have doses as low as 300 mg per day to feel more in control. 

  • Insomnia: Studies had shown that people taking at least 160 mg of CBD each night before bed slept better and struggled less with insomnia than those who took smaller doses. 

Health Benefits and Risks That Come From Cannabinoids

Aside from a reduction of anxiety, there are other benefits that products containing CBD can provide. Here are some of the most common: 

  • Reducing or stopping inflammation all over the body 
  • Cutting down on the frequency of kidney stones
  • Relieving pain all over the body 
  • Reducing or stopping nausea, especially when it comes from chemo 
  • Slowing the growth of cancerous tumors 
  • Killing off cancerous cells floating around the body 
  • Helping prevent obesity
  • Calming tight muscles 
  • Stimulating the appetite in higher doses
  • Improving the ability to gain weight in patients that have cancer or AIDS 
  • Stops many of the symptoms of depression 
  • Reducing appearance and inflammation of acne in some concentrations 
  • Improving overall heart health 
  • Strengthening the circulatory system as a whole 
  • Reducing dependence on drugs and alcohol for those going through withdrawals 
  • Preventing the spread of tumors to other parts of the body, especially cancerous tumors 

There is constant testing happening on all types of products that contain CBD because of the promising effects of cannabidiol. 

There are very few risks that come with using CBD in any form. They include: 

  • Feeling tired some of the time after taking the CBD. This usually passes after a short time and stops once the body adjusts to the new chemical. 
  • Diarrhea sometimes happens when the doses of CBD are too high. To remove this effect, all people have to do is decrease the dose they are taking. 
  • The use of CBD is often associated with dry mouth. This can be easily combated by adding more water into the diet daily. 
  • Occasionally people taking CBD feel dizzy. This is due to lower blood pressure and will pass as the body gets used to the change in nearly all instances. 

How Can CBD Products Be Taken?

There are many ways to use CBD. It all depends on what the results are that the person wants and how quickly he or she wants those results. 

Various methods provide different results in how immediately the effects are felt and in terms of how long the effects last. 

Here are the most common methods of ingestion for products containing CBD: 

  • Edibles: This is one method of getting the CBD into the body. Edibles come in the form of gummies, lollipops, candy, desserts, popcorn, and honey. 
  • Tincture: This is another method of getting CBD into the body, but this uses CBD oil that is placed under the tongue. This product can come in many flavors like vanilla, mint, coffee, watermelon, and strawberry banana. 
  • Inhalation: Pure CBD can be inhaled through a vape pen or a smoking rig, allowing the CBD to enter the lungs and hit the bloodstream almost instantly. 
  • Skin: CBD can also be absorbed through the skin. This can be done by using CBD lotion, massage oils, ointments for pain relief, rollers with oil on them, and balms. There are even products for the skin to improve how the skin looks or feels, such as facial creams and lip balm. 

Items taken under the tongue or through inhalation hit the system much more quickly than those that have to be absorbed or ingested. 

However, they also tend to wear off more quickly. Those that are eaten or absorbed take a little longer to start working, but they also last longer. 

Some products need to be taken every few hours, others need to be taken when symptoms arise, and others need to be taken on a schedule, such as twice per day. It all depends on what method of ingestion is used and what the goal results are. 

Anxiety is more common than most people realize. Unfortunately, it is treated far less often than it should be. 

There are ways of being able to combat anxiety naturally, and CBD is one of the most promising methods around. 

Testing is being done on many products that contain CBD to see not only how effectively it can treat issues like depression and anxiety, but also what other benefits come with it. 

People can face situations they never could before while on CBD, including simulated public speaking and talking with people who once made the users afraid. 

If CBD can provide these effects currently, imagine what it could do in the near future for extensive medical and mental health issues.

Having anxiety during pregnancy is a real mental health condition. It is not a sign of weakness, but rather a sign that a woman’s body needs help. 

A pregnant woman who suspects she has anxiety or experiences panic attacks should get help right away for the health of her baby.

What Is Normal?

Pregnancy can be a stressful time. If a woman is experiencing normal anxiety, she will find that it comes and goes. Often it is triggered by a stressful experience, such as a fight with a loved one or problems with other children. 

While some stress during pregnancy is normal, if it is beginning to bother the mother or impact her daily life, she should consult her doctor.

Antenatal Anxiety

A pregnant woman experiencing antenatal anxiety, or anxiety during pregnancy, may feel intense and excessive anxiety. 

Often, she cannot be able to pinpoint the reason for her anxiety. Even small tasks like paying the bills may make her feel anxious.

An expectant mother also experiences other symptoms in antenatal anxiety. Anxiety is one of the most common mental disorders, affecting one in four people, and the risk of anxiety is thought to increase during pregnancy.

Symptoms

Each case of antenatal anxiety is different for each patient. However, there are some common symptoms pregnant women can look out for. 

While having one or two of these symptoms does not necessarily indicate anxiety, having several of these symptoms may mean an expectant mother should see her doctor.

  • Persistent worry – While some worry is normal during pregnancy, worry that do not go away is not normal. Often, this worry is focused on the health or well-being of the baby.
  • Panic attacks – These are characterized by heart palpitations and an intense feeling of terror.
  • Finding it difficult to focus – Sometimes, this feeling is described as “brain fog.”
  • Becoming easily annoyed – Pregnant women with antenatal anxiety often find themselves getting irritated at family and friends easily.
  • Odd behavior changes – Pregnant women with antenatal anxiety often develop obsessive or compulsive behaviors.
  • Unexplainable sadness – Mothers with depression-like symptoms, such as crying for no reason and feeling consistently low, may be suffering from antenatal anxiety, especially if these symptoms persist for two weeks or more.

Because anxiety and depression go together during pregnancy, having anxiety may be a symptom of depression.

Causes

Women are more at risk for anxiety and depression during pregnancy because hormone changes can affect hormones in the brain that are related to depression and anxiety. Difficult life situations can also lead to feelings of depression and anxiety.

Depression

Depression and anxiety during pregnancy often go hand in hand. Moreover, in some cases, it can be a vicious cycle. 

Feeling depressed can lead to anxiety about why one is feeling depressed. The American College of Obstetricians and Gynecologists estimates that between 14 percent and 23 percent of women experience depression during pregnancy.

Like clinical depression, depression during pregnancy is a mental disorder.

Panic Attacks

 

Anxiety can lead to panic attacks. These attacks can come quickly, seemingly without a cause. 

There are many symptoms of a panic attack, some of which a woman might experience all at once. 

Women experiencing panic attacks can have a racing heartbeat, dizziness, sweating, shaky limbs, tingling, shortness of breath, and a severe feeling of dread.

These attacks can last anywhere from five minutes to 20 minutes. While they can be terrifying, they are generally not dangerous for the mother or baby.

Effect on the Baby

 

Left untreated, anxiety during pregnancy can harm the baby. One study found that when a woman experiences anxiety during her pregnancy, the child’s neurodevelopment is at risk, and the baby is more likely to be born preterm.

After birth, any anxiety or depression a mother still has makes it harder for her to bond with her baby. Bonding with the baby right away is important for the baby’s development.

If a woman has lingering depression after her baby’s birth, she may not have the desire or strength to care for her baby. These babies may be less active and show higher levels of agitation.

Risk Factors

Anyone can experience anxiety during pregnancy. However, there are a few risk factors which can make a woman more likely to develop anxiety in pregnancy.

  • Family history – Genetics play a role. If a woman’s family members have had anxiety or panic attacks in the past, she is more likely to experience them as well.
  • Personal history – If a woman has had panic disorders or anxiety in the past, pregnancy generally makes them worse.
  • Too much stress – In women who experience excessive stress in their everyday life, panic attacks, and anxiety can be triggered.
  • Previous difficult birth – If a woman had a difficult birth or pregnancy in the past, she is more likely to experience anxiety in her next pregnancy.

While researchers do not know every risk factor that can result in anxiety, they believe that factors such as environment, physical well-being, and emotional well-being all play into a woman’s risk of having anxiety during pregnancy.

Treatment

The good news is, there are many treatments for anxiety that can help an expectant mother feel better and calmer about her pregnancy. 

A pregnant woman’s doctor may suggest she use coping mechanisms. These include cognitive behavioral therapy, self-help resources, activity for emotional release, or medication.

Cognitive Behavioral Therapy

Cognitive behavioral therapy teaches skills to cope with different problems such as anxiety. 

The idea behind cognitive behavioral therapy is that people’s feelings and behavior tend to reflect how they think about different situations. 

If they think about situations negatively, their feelings imitate that. In cognitive behavioral therapy, an individual suffering from anxiety works with a therapist to identify negative thinking patterns that may be causing anxiety.

Self-help Resources

Self-help resources can also help anxiety. A woman with anxiety may work through these resources by herself or with another individual who has suffered from similar problems.

Finding Release

It can help pregnant women with anxiety to find a release for their emotions. It can help them take their minds off their problems. 

Engaging in physical activity, such as walking, swimming, or yoga, can help the brain release endorphins. 

Endorphins kill pain, boost happiness, and relieve stress. Physical activity for as little as five minutes can help release endorphins from the brain.

For pregnant women where physical activity is not an option, mind-body wellness strategies can work. 

An expectant mother might try meditation, deep breathing exercises, journaling, or even acupuncture.

Medication

If these anxiety treatments are not working, or a pregnant woman’s anxiety is severe, her doctor may prescribe medication to ease her anxiety. 

A woman’s doctor may recommend antidepressants, such as selective serotonin reuptake inhibitors, which are fairly safe to take during pregnancy.

Anxiety in pregnancy is a very common thing. Having it does not mean a woman will be a bad mother. 

There are several ways to treat it, and expectant mothers should remember there is no “one size fits all” approach. 

What works for one woman may not work for another. Trying different techniques, such as stress management, self-help, and cognitive behavioral therapy, helps a woman get the peace of mind which is essential for her health and her baby.

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