Does CBD oil work for ADHD?

  • Research demonstrates that cannabidiol (CBD) may help reduce anxiety, a condition that is often seen in people with attention-deficit/hyperactivity disorder (ADHD).
  • Studies show that CBD helps regulate the “reward” pathway of the dopamine system, which may help improve attention, memory, and mood.
  • Researchers of a study reported that symptoms of hyperactivity and anxiety levels were reduced in most of the participants who took CBD.
  • However, most of the research on CBD and ADHD focuses on cannabis use and not CBD alone.
  • The side effects of CBD for ADHD symptoms may include drowsiness, upset stomach, or changes in weight or appetite.
  • Still, the results from studies on CBD use to manage ADHD symptoms are promising that mainstream medicine should be investigating CBD for ADHD further.

Best CBD Oils For ADHD

Jump to Section Jump to Section Jump to Section Jump to Section
750 mgShop 900mgShop 1000 mgShop 300 mg, 750 mg, 1500 mg, 3000 mg, 5000 mg and 7500 mgShop
Size 30ml 15ml 30 ml 30 ml and 60 ml
Perfect for... New CBD users Health-conscious persons Patients who are looking for serious CBD oil support CBD users with different needs
Spruce 750mg Lab Grade CBD Oil Shop Jump to Section
Size30ml
Perfect for...New CBD users
NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil Shop Jump to Section
Size15ml
Perfect for...Health-conscious persons
Sabaidee Super Good Vibes CBD Oil Shop Jump to Section
Size30 ml
Perfect for...Patients who are looking for serious CBD oil support
cbdMD CBD Oil Tinctures Shop Jump to Section
Size30 ml and 60 ml
Perfect for...CBD users with different needs

The following list is comprised of CBD oils, which could be used to help with the symptoms of ADHD.

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
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
  • 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
    •  Natural peppermint flavor
    •  Made from 100% organic and natural ingredients
    •  No other flavors
  • 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 900mg Full Spectrum Hemp CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
  • Summary

    Natural remedy for various illnesses. NuLeaf Naturals’ CBD oil is a whole-plant extract containing a full spectrum of naturally occurring synergistic cannabinoids and terpenes.

    Pro's
    Cons's
    •  Pure CBD hemp
    •  All natural
    •  Approximately 300 drops total
    •  No other flavors
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsFull Spectrum Hemp Extract, Organic Virgin Hemp Seed Oil
    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
    900mg per bottle
    Carrier OilOrganic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    60mg per dropper full (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursNatural
    Price Range$99 - $434
    $/mg CBD
    Price ($/mg)
    $0.08 - $0.13
    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 persons
    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, Paraguay, 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

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
  • Summary

    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.

    Pro's
    Cons's
    •  Extra strong
    •  Significant benefits with just a few drops
    •  100% Natural ingredients
    •  No other flavors
  • Features
    Discount pricing available?15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take itUsing 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier OilCoconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price RangeSingle Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsContaminant-free
    AllergensVegan and Gluten-free
    Refund policyWithin 30 days
    Recommended forPatients who are looking for serious CBD oil support
    Countries servedUSA only (all 50 states)
Check Latest Prices
Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
    •  Plenty of concentrations to choose from for all people with various kinds of needs
    •  Has vegan, organic, and gluten-free ingredients
    •  Affordable pricing
    •  Affordable pricing
    •  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
  • Features
    Discount pricing available?15% Off Coupon Code: cbdMD15
    Source
    Source of Hemp
    Kentucky, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier OilOrganic Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug TestContaining less than 0.3% THC, there are still trace amounts
    FlavoursNatural, Berry, Orange and Mint
    Price Range30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
    $/mg CBD
    Price ($/mg)
    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
    Shipping
    Shipping/Time to delivery
    2-5 Business days (via Fedex)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants100% organic, non-GMO, and vegan-certified
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forCBD users with different needs
    Countries servedUSA only (all 50 states)
Check Latest Prices

Why People Are Turning to CBD for ADHD

Although more medical research is needed to understand how CBD treatment could help with ADHD, anecdotal evidence has been influential in prompting people with ADHD to turn to hemp products to help their symptoms.

ADHD medications and treatment options typically used to manage symptoms include stimulants, non-stimulants, or anti-depressants.

However, these pharmaceuticals may be accompanied by adverse side effects, including sleeplessness, lack of appetite, and an increased risk of heart, psychiatric, or medication abuse problems.

At least 70 % of children diagnosed with ADHD are being treated with stimulants for their symptoms. However, many popular ADHD medications, like stimulants, have been in short supply, particularly the less-expensive generics.

Other drugs, such as Shire’s Adderall XR and its two authorized generics are in good supply, according to the U.S. Food and Drug Administration (FDA) and the American Society of Health-System Pharmacists.

Still, the drug shortages have affected the two main classes of ADHD drugs, methylphenidates and amphetamines, and left many of those with ADHD without medication.

This situation has caused parents to search for alternative methods for treating symptoms of ADHD, and CBD has emerged as one of these alternative products.

While stimulants work well for many people, if another treatment worked as well and induced no side effects, it would be more desirable.

Much of what experts know about CBD as an ADHD treatment comes from research on cannabis and not CBD as an isolated compound.

Researchers concluded in a report that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults.

Forest Tennant, MD, of Intractable Pain Management, in a report based on his research, suggests that there is a correlation between ADHD and chronic pain.

In a 2013 review conducted by the University at Albany Psychology Department, researchers found that those who used cannabis to manage ADHD symptoms reported symptoms of hyperactivity when not using the substance.

A 2016 study explored the relationship between ADHD, depression, and marijuana use. While the researchers established that some of the participants in the study used marijuana to manage depressive symptoms, its effect on these symptoms was unclear.

There have been no studies specifically investigating the effects of CBD on ADHD. Evidence of CBD’s effectiveness in treating symptoms of ADHD is mostly anecdotal, with people claiming that they feel more focused and less distracted with its use.

Meanwhile, some medical professionals believe in the therapeutic effects of CBD on ADHD.

Dr. David Berger, a pediatrician in Tampa, Florida, frequently suggests CBD to his young patients suffering from symptoms of ADHD. An advocate for the Autism Research Institute, he launched the Wholistic ReLeaf to help qualified patients use medical cannabis as a treatment option.

Berger has seen patients whose ADHD symptoms have improved after using CBD. He said that, although the results are partially a placebo effect, CBD is a much safer treatment than traditional pharmaceutical stimulants.

CBD treatment is also an attractive alternative because patients can stop using it any time without any complications, according to Berger.

He said that stimulant medications and CBD have similar pharmacodynamic properties.

Joy Neely, who runs a CBD brand in Kansas, also believes in CBD’s potential benefit for ADHD.

Neely found out about CBD while looking for another way for her nephew, who had been smoking marijuana, to treat his ADHD. She also uses CBD to treat her ADHD.

She says that CBD slows things down in hyperactive individuals so that they can focus better. Meanwhile, many of her customers use CBD to replace pharmaceuticals like Ritalin, saying that CBD helps them get off prescription drugs for ADHD.

However, all of these reports are without scientific evidence, and Neely recognizes the challenges caused by the lack of scientific research on CBD. Thus, she and her group continue to work to gain scientific backup for this claim.

To learn more about CBD and, at the same time, help her consumers understand it, she helps them monitor their progress and figure out the doses that work best for them.

Although clinical research surrounding the use of CBD oil to manage ADHD symptoms is far from comprehensive, results from small-scale studies and anecdotal use of CBD point to the fact that mainstream medicine should be investigating CBD for ADHD further.

How CBD Oil Works to Help with ADHD

ADHD does not lead to other psychological or developmental problems. However, according to Mayo Clinic, those with ADHD are more likely than others to also have medical conditions, such as anxiety disorders and mood disorders like depression.

CBD, or cannabidiol, is a nonpsychoactive constituent in the cannabis plant. It reacts to the endocannabinoid system that exists in the human body to help it utilize its naturally-occurring endocannabinoids more efficiently.

CBD oil engages with two receptors in the body. These cannabinoid receptors type 1 (CB1) and type 2 (CB2), have a direct effect on specific parts of the body.

CB1 is most abundant in the brain and is directly related to epilepsy, while CB2, which is more abundant in the immune system, is connected to pain and inflammation.

Brain receptors are not only responsive to neurotransmitters serotonin and dopamine but also chemical messengers outside the body, such as phytocannabinoids (plant cannabinoids) like tetrahydrocannabinol (THC) or CBD.

According to a study, individuals with ADHD often have lower than healthy levels of dopamine.

In a study, CBD has been shown to regulate the “reward” pathway of the dopamine system, which may enhance cognitive processes such as learning, attention, memory, and mood.

Research demonstrates that CBD possesses anxiety-reducing characteristics and may help those living with ADHD.

It has been hypothesized that CBD activates serotonin receptors in the body and causes the brain to release dopamine. This action is similar to the function of many medications for conditions like anxiety, depression, and ADHD.

Researchers studied the effects of CBD on animal models that were selected for their deficiency in the AMPAR, rendering them a suitable model for hyperactivity disorders such as ADHD.

AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) are abundant and widely distributed in the central nervous system, where they facilitate fast communication between neurons or nerve cells.

The researchers of the study found that when CBD is introduced into the hippocampus, the region of the brain in charge of spatial learning and adaptation, CBD reduced manifestations of hyperactivity. This finding suggests that CBD may inhibit hyperactive networks in the hippocampus and other parts of the brain.

Behaviors linked to autism spectrum disorder (ASD) can look a lot like ADHD. According to the Centers for Disease Control and Prevention (CDC), fourteen in 100 children with ADHD also have ASD.

Researchers of a study on children with ASD reported the experiences of parents who gave oral CBD oil to their children with ADHD.

Self-injury and rage improved in about 36 of the 53 children (ages 4 to 22) who received CBD for about 8 weeks. Symptoms of hyperactivity reduced in more than half of the participants, while anxiety levels lowered in almost half of them.

However, the other participants either did not experience any changes or had negative experiences. Adverse effects were sleeplessness and change in appetite, although they were mild.

In another review, the authors discussed CBD as a treatment for conditions associated with ASD, such as anxiety and behavioral problems. They noted that CBD could help normalize social deficits, improve cognition, and guard against hippocampal cell death.

The authors also emphasized that CBD reduced anxiety levels in both animal and human models when administered at moderate doses of 300 milligrams.

The Pros and Cons of CBD Oil for ADHD

Pros

  • In a review, CBD has been shown to be well-tolerated at doses of up to 1,500 mg per day.
  • The World Health Organization (WHO) says that “CBD is generally well-tolerated, with a good safety profile.”
  • Unlike other ADHD medications like stimulants and nonstimulants, which require a prescription, CBD oil may be purchased without a prescription in locations where they are legally available.

Cons

  • Due to several factors, it can take at least 20 minutes to two hours before the effects of CBD can be felt.
  • The side effects of CBD for ADHD symptoms may include drowsiness, upset stomach, or changes in weight or appetite.
  • In one study, CBD-rich cannabis extract was demonstrated to increase the risk of liver toxicity in mice that received high CBD doses.
  • CBD may interact with other supplements, prescription medications, or over-the-counter (OTC) drugs.

The CYP450 family of enzymes is responsible for metabolizing several cannabinoids. However, during this process, CBD also impacts how the CYP3A4 enzymes metabolize some medications, as one study shows.

If the drugs are metabolized too fast, there may not be enough of the medication in the system at one time to treat specific health issues or improve health conditions.

If the drugs are metabolized too slowly, there may be more medication in the system at one time than intended, resulting in unwanted or harmful side effects.

  • CBD has not been studied specifically to treat ADHD. Thus, it is best to talk to a doctor before starting a CBD regimen.
  • Due to findings by the Centers for Disease Control and Prevention (CDC) regarding vaping or other inhalation methods of CBD and related products, inhalation may not be the safest method to use.

How CBD Oil Compares to Alternative Treatments for ADHD

Proponents for CBD oil claim that its effects on the body are gentler and more effective than medications for ADHD because it is a natural product, made from a plant.

However, the CBD that is synthesized from a hemp plant must go through multiple mechanical and chemical processes to become usable and has little resemblance to the plant from which it started.

The purer the CBD product, the less natural it is. The end product does not exist in a natural form as one cannot chew on a cannabis leaf and receive any benefits from cannabidiol oil.

John Mitchell, Ph.D., researcher and assistant professor at the Duke ADHD Program, reminds CBD oil or cannabis products enthusiasts that there have been no studies showing the effectiveness or safety of CBD products in ADHD management.

On the other hand, Mitchell added, there are well-researched and beneficial non-medication treatment options, like lifestyle adjustments and parent training, that are shown to be effective in managing ADHD symptoms.

Also, CBD products are currently unregulated products, making it challenging for consumers to know whether or not they are actually getting what was being advertised.

Thus, unlike with other prescription pharmaceuticals, it is difficult to determine accurately the CBD dose that comes in every CBD product available in the market.

CBD may have the potential to treat other ailments and disorders, but CBD oil is getting misrepresented, Mitchell said. When people say CBD works for ADHD, this is going way beyond the data.

How to Choose the Right CBD for ADHD

Oral ingestion of CBD is less likely to induce side effects. This method allows CBD oil to be used sublingually, or by taking it in the form of capsules, gummies, or CBD-infused foods and beverages.

However, regardless of the form of CBD product one chooses, careful consideration must be exercised in choosing the best CBD oil for ADHD.

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 from legitimate and reliable big brands. Majority of companies that manufacture the best CBD oil products purchase their hemp from farms that are located in California, Texas, Europe, and Colorado.
  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. One important thing to look for in CBD products is certification codes. Several certification authorities approve certain products only after some thorough screening tests.
  5. Compare company claims about their products’ potency with that of the third-party lab reports.
  6. Consulting with a trusted medical professional who is experienced in CBD use is ideal before one purchases his or her first bottle of CBD.

CBD Dosage For ADHD

Although more research is needed, one study recommends that a single 300-mg dose of CBD may be enough to reduce anxiety, a condition that is often seen in people with ADHD.

Experts advise that if one is new to CBD, starting with the smallest dosage possible is the best course of action. Gradually increasing the dosage allows the body to get used to the oil and reduce the risk of side effects.

How to Take CBD Oil for ADHD

CBD oil for ADHD is typically taken via vaping or consuming through oral ingestion.

Oral ingestion of CBD is considered less likely to cause side effects. The user can put a few drops of the oil under the tongue, take CBD capsules, or consume CBD-infused edibles like gummies, brownies, and CBD-infused beverages like juices, coffee, and weight loss teas.

Meanwhile, inhaling CBD, through smoking or vaping, delivers the compound to the bloodstream more rapidly than other techniques.

However, medical experts are growing increasingly concerned about vaping and whether it is safe.

To date, there are no formal guidelines on how to use CBD oil to treat traditional ADHD symptoms, such as irritability, hyperactivity, and fidgeting.

Understanding CBD

Derived from the plant Cannabis sativa, medical marijuana is one of the longest-established and commonly-used drugs in the world. Of the more than 60 cannabinoids in marijuana, only THC has intoxicating effects.

The National Institute on Drug Abuse says that marijuana is the most commonly used psychotropic drug in the United States, after alcohol. Marijuana has both short-and long-term effects on the brain, and its use may have a wide range of effects on both physical and mental health.

Marijuana use disorders are often associated with dependence. However, results from a study on medical marijuana users engaged in substance abuse treatment indicate that medical marijuana may not adversely affect positive treatment outcomes.

CBD oil may be derived from either a hemp plant or marijuana plant, although most CBD oil products in the market are hemp-derived. CBD is nonpsychoactive, making it favorable to those who want to experience its health benefits without the ‘high’ induced by THC.

Hemp, which is legally defined as a cannabis plant that has less than 0.3 percent THC, is often referred to as a low THC variety.

Conclusion

The National Institute of Mental Health describes attention-deficit/hyperactivity disorder (ADHD) as a condition characterized by “an ongoing pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development.”

It is typical for people to exhibit some form of inattention, impulsivity, and unfocused motor activity, but for those with ADHD, these behaviors are more severe.

While there is no remedy for ADHD, available treatments can help reduce symptoms and improve functioning.

CBD use is becoming increasingly popular as more and more people try it for its health benefits. However, clinical research surrounding the use of CBD to manage ADHD symptoms is far from comprehensive.

Still, results from limited studies and anecdotal use of CBD look promising that mainstream medicine should be investigating CBD for ADHD further.

More Info

Less Info

Methylphenidate hydrochloride

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS numbers

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

   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

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological analyses 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 test(s)

         8.2.1.3 Simple qualitative method(s)

         8.2.1.4 Advanced quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple qualitative test(s)

         8.2.2.2 Advanced qualitative test(s)

         8.2.2.3 Simple qualitative method(s)

         8.2.2.4 Advanced quantitative Method(s)

         8.2.2.5 Other dedicated method(s)

      8.2.3 Interpretation of toxicological analyses

   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 analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

   8.6 References

  1. 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 (CNS)

         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 disturbance

         9.4.12.2 Fluid and electrolyte disturbance

         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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    Methylphenidate hydrochloride

 

    International Programme on Chemical Safety

    Poison Information Monograph 344

    Pharmaceutical

 

  1. NAME

 

        1.1  Substance

 

             Methylphenidate hydrochloride

 

        1.2  Group

 

             ATC Classification

 

             Psychostimulants (N06B)

             Phenylethylamine derivatives (N06B A)

 

        1.3  Synonyms

 

             Centedrin; Meridil;

             Ritalin hydrochloride

 

        1.4  Identification numbers

 

             1.4.1  CAS numbers

 

                    Methylphenidate hydrochloride  298-59-9

 

             1.4.2  Other numbers

 

                    Methylphenidate  CAS   113-45-1

 

                    Methylphenidate NIOSH/RTECS   TM3675000

                    Methylphenidate hydrochloride NIOSH/RTECS TM3850000

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             Acute central nervous system stimulation, cardiotoxicity

             causing tachycardia, arrhythmias, hypertension and

             cardiovascular collapse. High risk of dependency and abuse.

 

        2.2  Summary of clinical effects

 

             Cardiovascular – Palpitation, chest pain, tachycardia,

             arrhythmias and hypertension are common; cardiovascular

             collapse can occur in severe poisoning. Myocardial ischaemia,

             infarction and ventricular dysfunction are described.

    

 

             Central Nervous System (CNS) – Stimulation of CNS, tremor,

             restlessness, agitation, insomnia, increased motor activity,

             headache, convulsions, coma and hyperreflexia are described.

             Stroke and cerebral vasculitis have been observed.

    

             Gastrointestinal – Vomiting, diarrhoea and cramps may occur.

             Acute transient ischaemic colitis has occurred with chronic

             methamphetamine abuse.

    

             Genitourinary – Increased bladder sphincter tone may cause

             dysuria, hesitancy and acute urinary retention. Renal failure

             can occur secondary to dehydration or rhabdomyolysis. Renal

             ischaemia may be noted.

    

             Dermatologic – Skin is usually pale and diaphoretic, but

             mucous membranes appear dry.

    

             Endocrine – Transient hyperthyroxinaemia may be noted.

    

             Metabolism – Increased metabolic and muscular activity may

             result in hyperventilation and hyperthermia. Weight loss is

             common with chronic use.

    

             Fluid/Electrolyte – Hypo- and hyperkalaemia have been

             reported. Dehydration is common.

    

             Musculoskeletal – Fasciculations and rigidity may be noted.

             Rhabdomyolysis is an important consequence of severe

             amphetamine poisoning.

    

             Psychiatric – Agitation, confusion, mood elevation, increased

             wakefulness, talkativeness, irritability and panic attacks

             are typical. Chronic abuse can cause delusions and paranoia.

             A withdrawal syndrome occurs after abrupt cessation following

             chronic use.

 

        2.3  Diagnosis

 

             The diagnosis of acute amphetamine poisoning is made on

             the history of exposure or abuse, and the characteristic

             features of CNS and cardiovascular stimulation. The presence

             of amphetamines in urine or blood can support the diagnosis

             but is not helpful in management. Whilst some patients show

             signs of toxicity at blood concentrations of 20 µg/L, chronic

             abusers of amphetamine have been known to have blood

             concentration of up to 3000 µg/L.

 

        2.4  First aid measures and management principles

 

             Management of amphetamine and its complications is

             essentially supportive.

             The initial priority is stabilisation of the airway,

             breathing and circulation. Monitoring of pulse, blood

 

             pressure, oxygenation, core temperature and cardiac rhythm

             should instituted. Supplemental oxygen should be

             administered. Specific supportive care measures that may be

             necessary include:  maintenance of hydration, control of

             seizures, relief of agitation, control of hyperthermia,

             control of hypertension, management of rhabdomyolysis.

    

             Decontamination with oral activated charcoal is appropriate

             if the patient is conscious.

    

             There are no suitable methods of enhancing elimination of

             amphetamine and no specific antidotes.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Synthetic

 

        3.2  Chemical structure

 

             Methylphenidate hydrochloride

    

             Chemical Name:

             2-Piperidineacetic acid, alpha-phenyl-, methyl ester,

             hydrochloride

    

             Other chemical names:

             Methyl alpha-phenyl-2-piperidineacetate hydrochloride

    

             Molecular formula: C14H19NO2, HCL

             Molecular weight:   269.8

 

        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

 

                    Store in airtight containers. Refrigeration

                    unnecessary.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Psychostimulant

                    Phenylethylamine derivative; psychostimulant

 

             4.1.2  Description

 

                    Indications

    

                    Narcolepsy & Hyperkinetic states in children (as an

                    adjunct to psychological, educational and social

                    measures) for amphetamine, dextroamphetamine and

                    ethylphenidate.

    

                    Misuse:

    

                    Performance enhancement

                    Relief of fatigue

    

                    Abuse:

    

                    Abuse either orally or by injection is extremely

                    common.

    

                    (Dollery, 1991; Reynolds, 1996)

 

        4.2  Therapeutic dosage

 

             4.2.1  Adults

 

             4.2.2  Children

 

        4.3  Contraindications

 

             Anorexia, insomnia, psychopathic personality disorders,

             suicidal tendencies, Gilles de la Tourette syndrome and other

             disorders, hyperthyroidism, narrow angle glaucoma, diabetes

             mellitis and cardiovascular diseases such as angina,

             hypertension and arrythmias (Dollery, 1991; Reynolds, 1996).

    

             Amphetamine interacts with several other drugs (see 7.6).

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             Readily absorbed from the gastro-intestinal tract and 

             buccal mucosa. It Is resistant to metabolism by monoamine

             oxidase.

 

        5.2  Inhalation

 

             Amphetamine is rapidly absorbed by inhalation and is

             abused by this route (Brust, 1993).

 

        5.3  Dermal

 

             No data available.

 

        5.4  Eye

 

             No data available.

 

        5.5  Parenteral

 

             Frequent route of entry in abuse situations.

 

        5.6  Other

 

             No data available.

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             Amphetamine is rapidly absorbed after oral ingestion.

             Peak plasma levels occur within 1 to 3 hours, varying with

             the degree of physical activity and the amount of food in the

             stomach. Absorption is usually complete by 4 to 6 hours.

             Sustained release preparations are available as resin-bound,

             rather than soluble, salts. These compounds display reduced

             peak blood levels compared with standard amphetamine

             preparations, but total amount absorbed and time to peak

             levels remain similar (Dollery, 1991).

 

        6.2  Distribution by route of exposure

 

             Amphetamines are concentrated in the kidney, lungs,

             cerebrospinal fluid and brain. They are highly lipid soluble

             and readily cross the blood-brain barrier. Protein binding

             and volume of distribution varies widely, but the average

             volume of distribution is 5 L/kg body weight (Dollery, 1991).

 

        6.3  Biological half-life by route of exposure

 

             Under normal conditions, about 30% of amphetamine is

             excreted unchanged in the urine but this excretion is highly

             variable and is dependent on urinary pH. When the urinary pH

             is acidic (pH 5.5 to 6.0), elimination is predominantly by

             urinary excretion with approximately 60% of a dose of

             amphetamine being excreted unchanged by the kidney within 48

             hours. When the urinary pH is alkaline (pH 7.5 to 8.0),

             elimination is predominantly by deamination (less than 7%

 

             excreted unchanged in the urine); the half-life ranging from

             16 to 31 hours (Ellenhorn, 1997).

 

        6.4  Metabolism

 

             The major metabolic pathway for amphetamine involves

             deamination by cytochrome P450 to para-hydroxyamphetamine and

             phenylacetone; this latter compound is subsequently oxidised

             to benzoic acid and excreted as glucuronide or glycine

             (hippuric acid) conjugate. Smaller amounts of amphetamine are

             converted to norephedrine by oxidation. Hydroxylation

             produces an active metabolite, O-hyroxynorephedrine, which

             acts as a false neurotransmitter and may account for some

             drug effect, especially in chronic users (Dollery, 1991).

 

        6.5  Elimination and excretion

 

             Normally 5 to 30% of a therapeutic dose of amphetamine

             is excreted unchanged in the urine by 24 hours, but the

             actual amount of urinary excretion and metabolism is highly

             pH dependent (Dollery, 1991).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             Amphetamine appears to exert most or all of its effect

             in the CNS by causing release of biogenic amines, especialy

             norepinephrine and dopamine, from storage sites in nerve

             terminals. It may also slow down catecholamine metabolism by

             inhibiting monoamine oxidase (Hardman, et al., 1997).

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             The toxic dose varies considerably

                             due to individual variations and the

                             development of tolerance. Fatalities have

                             been reported following ingestion of doses as

                             low as 1.3 mg/kg, while tolerance has been

                             developed to 1,000 mg at a time and up to 5 g

                             in a day.

 

                    7.2.1.2  Children

 

                             Children appear to be more

                             susceptible than adults and are less likely

                             to have developed tolerance.

 

             7.2.2  Relevant animal data

 

                    Adult monkeys have an LD50 of 15 to 20 mg/kg,

                    whereas for young monkeys the LD50 is only 5 mg/kg.

 

             7.2.3  Relevant in vitro data

 

                    Not relevant

 

        7.3  Carcinogenicity

 

             To be completed

 

        7.4  Teratogenicity

 

             The use of amphetamine for medical indications does not

             pose a significant risk to the fetus for congenital anomalies

             (Briggs, 1990). Amphetamines generally do not appear to be

             human teratogens. Mild withdrawal symptoms may be observed in

             the newborn, but the few studies of infant follow-up have not

             shown long-term sequelae, although more studies of this

             nature are needed.

    

             Illicit maternal use or abuse of amphetamine presents a

             significant risk to the foetus and newborn, including

             intrauterine growth retardation, premature delivery and the

             potential for increased maternal, fetal and neonatal

             morbidity.

    

             These poor outcomes are probably multifactorial in origin,

             involving multiple drug use, life-styles and poor maternal

             health. However, cerebral injuries occurring in newborns

             exposed in utero appear to be directly related to the

             vasoconstrictive properties of amphetamines. Ericksson et al.

             (1989) followed 65 children whose mothers were addicted to

             amphetamine during pregnancy, at least during the first

             trimester. Intelligence, psychological function, growth, and

             physical health were all within the normal range at eight

             years, but those children exposed throughout pregnancy tended

             to be more aggressive.

 

        7.5  Mutagenicity

 

             No relevant data

 

        7.6  Interactions

 

             Acetazolamide – administration may increase serum

             concentration of amphetamine.

    

             Alcohol – may increase serum concentration of amphetamine.

    

 

             Ascorbic acid -lowering urinary pH, may enhance amphetamine

             excretion

    

             Furazolidone – amphetamines may induce a hypertensive

             response in patients taking furazolidone.

    

             Guanethidine – amphetamine inhibits the antihypertensive

             response to guanethidine.

    

             Haloperidol – limited evidence indicates that haloperidol may

             inhibit the effects of amphetamine but the clinical

             importance of this interaction is not established.

    

             Lithium carbonate – isolated case reports indicate that

             lithium may inhibit the effects of amphetamine.

    

             Monoamine oxidase inhibitor – severe hypertensive reactions

             have followed the administration of amphetamines to patients

             taking monoamine oxidase inhibitors.

    

             Noradrenaline – amphetamine abuse may enhance the pressor

             response to noradrenaline.

    

             Phenothiazines – amphetamine may inhibit the antipsychotic

             effect of phenothiazines, and phenothiazines may inhibit the

             anorectic effect of amphetamines.

    

             Sodium bicarbonate – large doses of sodium bicarbonate

             inhibit the elimination of amphetamine, thus increasing the

             amphetamine effect.

    

             Tobacco smoking – amphetamine appears to induce dose-related

             increases in cigarette smoking.

    

             Tricyclic antidepressants – theoretically increases the

             effect of amphetamine, but clinical evidence is lacking.

    

             (Stockley, 1994; Dollery, 1991)

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

 

             8.1.1  Sampling and specimen collection

 

                    8.1.1.1  Toxicological analyses

 

                    8.1.1.2  Biomedical analyses

 

                    8.1.1.3  Arterial blood gas analysis

 

                    8.1.1.4  Haematological analyses

 

                    8.1.1.5  Other (unspecified) analyses

 

             8.1.2  Storage of laboratory samples and specimens

 

                    8.1.2.1  Toxicological analyses

 

                    8.1.2.2  Biomedical analyses

 

                    8.1.2.3  Arterial blood gas analysis

 

                    8.1.2.4  Haematological analyses

 

                    8.1.2.5  Other (unspecified) analyses

 

             8.1.3  Transport of laboratory samples and specimens

 

                    8.1.3.1  Toxicological analyses

 

                    8.1.3.2  Biomedical analyses

 

                    8.1.3.3  Arterial blood gas analysis

 

                    8.1.3.4  Haematological analyses

 

                    8.1.3.5  Other (unspecified) analyses

 

        8.2  Toxicological analyses 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 test(s)

 

                    8.2.1.3  Simple qualitative method(s)

 

                    8.2.1.4  Advanced quantitative Method(s)

 

             8.2.2  Tests for biological specimens

 

                    8.2.2.1  Simple qualitative test(s)

 

                    8.2.2.2  Advanced qualitative test(s)

 

                    8.2.2.3  Simple qualitative method(s)

 

                    8.2.2.4  Advanced quantitative Method(s)

 

                    8.2.2.5  Other dedicated method(s)

 

             8.2.3  Interpretation of toxicological analyses

 

        8.3  Biomedical investigations and their interpretation

 

             8.3.1  Biochemical analysis

 

                    8.3.1.1  Blood, plasma or serum

 

                             8.3.1.1.1  Basic analyses

 

                             8.3.1.1.2  Dedicated analyses

 

                             8.3.1.1.3  Optional analyses

 

                    8.3.1.2  Urine

 

                             8.3.1.2.1  Basic analyses

 

                             8.3.1.2.2  Dedicated analyses

 

                             8.3.1.2.3  Optional analyses

 

                    8.3.1.3  Other fluids

 

             8.3.2  Arterial blood gas analyses

 

             8.3.3  Haematological analyses

 

                             8.3.3.1.1  Basic analyses

 

                             8.3.3.1.2  Dedicated analyses

 

                             8.3.3.1.3  Optional analyses

 

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and their 

             interpretation

 

        8.5  Overall interpretation of all toxicological analyses and 

             toxicological investigations

 

             Sample collection

    

             Creatinine, urea, and electrolyte measurement are important

             to establish whether renal impairment or hyperkalaemia is

             present. Measurements of serum creatine kinase, aspartate

             transaminase and myoglobin can help to establish if there is

             rhabdomyolysis, and myoglobin can be detected in urine.

    

             Liver function tests are relevant, since hepatitis can occur.

    

             A full blood count and coagulation studies can be helpful,

             with measurement of fibrinogen and of fibrin degradation

             products, in establishing a diagnosis of disseminated

             intravascular coagulation.

    

 

             Biomedical analysis

    

             Temperature, blood pressure, and pulse rate should be

             monitored frequently. A temperature above 40°C, and marked

             hypertension and tachycardia are seen in severe poisoning.

    

             An electrocardiogram can be useful in detecting myocardial

             ischaemia or arrhythmia. Electrocardiographic monitoring can

             be helpful in patients with arrhythmia.

    

             Toxicological analysis

    

             Urine or serum analysis for amphetamine can help to confirm

             exposure, but cannot be used to establish poisoning, because

             of difference in individual tolerance to amphetamines.

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    Effects are most marked on the central nervous

                    system, cardiovascular system, and muscles. The triad

                    of hyperactivity, hyperpyrexia, and hypertension is

                    characteristic of acute amphetamine overdosage.

    

                    Agitation, confusion, headache, delirium, and

                    hallucination, can be followed by coma, intracranial

                    haemorrhage, stroke, and death.

    

                    Chest pain, palpitation, hypertension, tachycardia,

                    atrial and ventricular arrhythmia, and myocardial

                    infarction can occur.

    

                    Muscle contraction, bruxism (jaw-grinding), trismus

                    (jaw clenching), fasciculation, rhabdomyolysis, are

                    seen leading to renal failure; and flushing, sweating,

                    and hyperpyrexia can all occur. Hyperpyrexia can cause

                    disseminated intravascular coagulation.

    

                    (Brust, 1993; Derlet et al., 1989)

 

             9.1.2  Inhalation

 

                    The clinical effects are similar to those after

                    ingestion, but occur more rapidly (Brust, 1993).

 

             9.1.3  Skin exposure

 

                    No data available

 

             9.1.4  Eye contact

 

                    No data available

 

             9.1.5  Parenteral exposure

 

                    Intravenous injection is a common mode of

                    administration of amphetamine by abusers. The euphoria

                    produced is more intense, leading to a “rush” or 

                    “flash” which is compared to sexual orgasm  (Brust,

                    1993). Other clinical effects are similar to those

                    observed after ingestion, but occur more rapidly.

 

             9.1.6  Other

 

                    No data available

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Tolerance to the euphoric effects and CNS

                    stimulation induced by amphetamine develops rapidly,

                    leading abusers to use larger and larger amounts to

                    attain and sustain the desired affect.

    

                    Habitual use or chronic abuse usually results in toxic

                    psychosis classically characterised by paranoia,

                    delusions and hallucinations, which are usually

                    visual, tactile or olfactory in nature, in contrast to

                    the typical auditory hallucinations of schizophrenia.

                    The individual may act on the delusions, resulting in

                    bizarre violent behaviour, hostility and aggression,

                    sometimes leading to suicidal or homicidal actions.

                    Dyskinesia, compulsive behaviour and impaired

                    performance are common in chronic abusers. The chronic

                    abuser presents as a restless, garrulous, tremulous

                    individual who is suspicious and anxious.

 

             9.2.2  Inhalation

 

                    As for 9.2.1.

 

             9.2.3  Skin exposure

 

                    No relevant data.

 

             9.2.4  Eye contact

 

                    No relevant data.

 

             9.2.5  Parenteral exposure

 

                    As for 9.2.1.

 

             9.2.6  Other

 

                    Vaginal exposure, as for 9.2.1.

 

        9.3  Course, prognosis, cause of death

 

             Symptoms and signs give a clinical guide to the severity

             of intoxication as follows (Espelin and Done, 1968):

    

             Mild toxicity – restlessness, irritability, insomnia, tremor,

             hyperreflexia, sweating, dilated pupils, flushing;

    

             Moderate toxicity – hyperactivity, confusion, hypertension,

             tachypnoea, tachycardia, mild fever, sweating;

    

             Severe toxicity – delirium, mania, self-injury, marked

             hypertension, tachycardia, arrhythmia, hyperpyrexia,

             convulsion, coma, circulatory collapse.

    

             Death can be due to intracranial haemorrhage, acute heart

             failure or arrhythmia, hyperpyrexia, rhabdomyolysis and

             consequent hyperkalaemia or renal failure, and to violence

             related to the psychiatric effects (Kalant & Kalant,

             1975).

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Cardiovascular symptoms of acute poisoning

                    include palpitation and chest pain. Tachycardia and

                    hypertension are common. One third of patients

                    reported by Derlet et al. (1989) had a blood pressure

                    greater than 140/90 mmHg, and nearly two-thirds had a

                    pulse rate above 100 beats per minute.

    

                    Severe poisoning can cause acute myocardial ischaemia,

                    myocardial infarction (Carson et al., 1987; Packe et

                    al., 1990), and left ventricular failure (Kalant &

                    Kalant, 1975). These probably result from vasospasm,

                    perhaps at sites of existing atherosclerosis. In at

                    least one case, thrombus was demonstrated initially

                    (Bashour, 1994).

    

 

                    Chronic oral amphetamine abuse can cause a chronic

                    cardiomyopathy; an acute cardiomyopathy has also been

                    described (Call et al., 1982).

    

                    Hypertensive stroke is a well-recognised complication

                    of amphetamine poisoning (see 9.4.3).

    

                    Intra-arterial injection of amphetamine can cause

                    severe burning pain, vasospasm, and gangrene (Birkhahn

                    & Heifetz, 1973).

 

             9.4.2  Respiratory

 

                    Pulmonary fibrosis, right ventricular

                    hypertrophy and pulmonary hypertension are frequently

                    found at post-mortem examination.

    

                    Pulmonary function tests usually are normal except for

                    the carbon monoxide diffusing capacity. Respiratory

                    complications are sometimes caused by fillers or

                    adulterants used in injections by chronic users. These

                    can cause multiple microemboli to the lung, which can

                    lead to restrictive lung disease.

    

                    Pneumomediastinum has been reported after amphetamine

                    inhalation (Brust, 1993).

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             Main symptoms include agitation,

                             confusion, delirium, hallucinations,

                             dizziness, dyskinesia, hyperactivity, muscle

                             fasciculation and rigidity, rigors, tics, 

                             tremors, seizures and coma.

    

                             Both occlusive and haemorrhagic strokes have

                             been reported after abuse of amphetamines.

                             Twenty-one of  73 drug-using young persons

                             with stroke had taken amphetamine (Kaku &

                             Lowenstein, 1990), of whom six had documented

                             intracerebral haemorrhage and two had

                             subarachnoid haemorrhage. Patients with

                             underlying arteriovenous malformations may be

                             at particular risk (Selmi et al., 1995).

    

                             Stroke can occur after oral, intravenous, or

                             nasal administration. Severe headache

                             beginning within minutes of ingestion of

                             amphetamine is usually the first symptom. In

                             more than half the cases, hypertension which

 

                             is sometimes extreme, accompanies other

                             symptoms. A Cerebral vasculitis has also been

                             observed (Brust, 1993).

    

                             Dystonia and dyskinesia can occur, even with

                             therapeutic dosages (Mattson & Calverley,

                             1968).

    

                             Psychiatric effects, particularly euphoria

                             and excitement, are the motives for abuse.

                             Paranoia and a psychiatric syndrome

                             indistinguishable from schizophrenia are

                             sequelae of chronic use ( Hall et al., 1988;

                             Flaum & Schultz, 1996; Johnson & Milner,

                             1966).

 

                    9.4.3.2  Peripheral nervous system

 

                             No relevant data

 

                    9.4.3.3  Autonomic nervous system

 

                             Stimulation of alpha-adrenergic

                             receptors produces mydriasis, increased

                             metabolic rate, diaphoresis, increased

                             sphincter tone, peripheral vasoconstriction

                             and decreased gastrointestinal motility.

    

                             Stimulation of ß-adrenergic receptors

                             produces increased heart rate and

                             contractility, increased automaticity and

                             dilatation of bronchioles.

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             Myalgia, muscle tenderness, muscle

                             contractions, and rhabdomyolysis, leading to

                             fever, circulatory collapse, and

                             myoglobinuric renal failure, can occur with

                             amphetamines (Kendrick et al., 1977).

 

             9.4.4  Gastrointestinal

 

                    Most common symptoms are nausea, vomiting,

                    diarrhoea, and abdominal cramps. Anorexia may be

                    severe. Epigastric pain and haematemesis have been

                    described after intravenous amphetamine use. A case of

                    ischaemic colitis with normal mesenteric arteriography

                    in a patient taking dexamphetamine has been described

                    (Beyer et al., 1991).

 

             9.4.5  Hepatic

 

                    Hepatitis and fatal acute hepatic necrosis have

                    been described (Kalant & Kalant, 1975).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Renal failure, secondary to dehydration 

                             or rhabdomyolysis may be observed.

 

                    9.4.6.2  Other

 

                             Increased bladder sphincter tone may

                             cause dysuria, hesitancy and acute urinary

                             retention. This effect may be a direct result

                             of peripheral alpha-agonist activity.

    

                             Spontaneous rupture of the bladder has been

                             described in a young woman who took alcohol

                             and an amphetamine-containing diet tablet

                             (Schwartz, 1981).

 

             9.4.7  Endocrine and reproductive systems

 

                    Transient hyperthyroxinaemia may result from

                    heavy amphetamine use (Morley et al., 1980).

 

             9.4.8  Dermatological

 

                    Skin is usually pale and diaphoretic, but

                    mucous membranes appear dry. Chronic users may display

                    skin lesion, abscesses, ulcers, cellulitis or

                    necrotising angiitis due to physical insult to skin,

                    or dermatologic signs of dietary deficiencies, e.g.

                    cheilosis, purpura.

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    Mydriasis may be noted.

                    Diffuse hair loss may be noted.

                    Chronic users may display signs of dietary

                    deficiencies.

 

             9.4.10 Haematological

 

                    Disseminated intravascular coagulation is an

                    important consequence of severe poisoning ( Kendrick

                    et al., 1980).

                    Idiopathic thrombocytopenic purpura may occur.

 

             9.4.11 Immunological

 

                    No relevant data.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbance

 

                             No relevant data

 

                    9.4.12.2 Fluid and electrolyte disturbance

 

                             Increase metabolic and muscular activity 

                             may result in dehydration.

 

                    9.4.12.3 Others

 

                             No data available

 

             9.4.13 Allergic reactions

 

                    No relevant data

 

             9.4.14 Other clinical effects

 

                    No relevant data

 

             9.4.15 Special risks

 

                    Pregnancy:  Eriksson et al. (1989) followed 65

                    children whose mother were addicted to amphetamine

                    during pregnancy, at least during the first trimester.

                    Intelligence, psychological function, growth, and

                    physical health were all within the normal range at

                    eight years, but those exposed throughout pregnancy

                    tended to be more aggressive.

    

                    A case report describes a normal female infant born to

                    mother who took up to 180 mg/day of dexamphetamine for

                    narcolepsy throughout pregnancy (Briggs et al., 1975).

    

                    Breast-feeding:  Amphetamine is passed into breast

                    milk and measurable amounts can be detected in

                    breast-fed infant’s urine. Therefore lactating mothers

                    are advised not to take or use amphetamine.

 

        9.5  Other

 

             Amphetamine withdrawal syndrome:  Abrupt discontinuance

             following chronic use is characterised by apathy, depression,

             lethargy, anxiety and sleep disturbances. Myalgias, abdominal

             pain, voracious appetite and a profound depression with

             suicidal tendencies may complicate the immediate

 

             post-withdrawal period and peak in 2 to 3 days. To relieve

             these symptoms, the user will often return to use more

             amphetamine, often at increasing doses due to the tolerance

             which is readily established. Thus a cycle of

             use-withdrawal-use is established (Kramer et al., 1967; Hart

             & Wallace, 1975). Physical effects are not life threatening

             but can lead to a stuporose state (Tuma, 1993); the

             associated depression can lead to suicide. It may take up to

             eight weeks for suppressed REM (rapid eye movement) sleep to

             return to normal (Brust 1993).

    

             “Overamped”:  When the intravenous dosage is increased too

             rapidly the individual develops a peculiar condition referred

             to as “overamped: in which he or she is conscious but unable

             to speak or move. Elevated blood pressure, temperature and

             pulse as well as chest distress occurs in this setting. Death

             from overdose in tolerant individuals is infrequent.

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             General supportive measures should be used. These

             should include stabilisation of the airway, breathing, and

             circulation; relief of agitation, adequate hydration, and

             control of core temperature. Convulsions, hyperthermia, and

             rhabdomyolysis may require specific treatment. Activated

             charcoal may be helpful for decontamination after oral

             ingestion. Ipecacuanha is contra-indicated because of its

             stimulant properties. There are no effective methods of

             enhancing elimination and no antidote.

    

             Agitation and convulsion can be treated with diazepam. If

             agitation is severe, then chlorpromazine may have specific

             advantages over other major tranquillisers ( Espelin & Done,

             1968; Klawans, 1968). Parenteral dosages of 0.5 to 2

             milligrams per kilogram have been used in Infants (Espelin &

             Done, 1968).

    

             Severe hyperthermia (core temperature greater than 40°C)

             requires forced cooling by fans, tepid sponging or other

             means, and may also require the administration of diazepam or

             dantrolene or both agents in order to eliminate muscle

             activity.

    

             Rhabdomyolysis associated with muscle overactivity can cause

             hyperkalaemia or renal failure, and should be treated

             conventionally. Dialysis may be needed if renal failure

             supervenes.

    

 

             Acute severe hypertension (diastolic blood pressure greater

             than 100 mmHg) can be controlled by infusion of sodium

             nitroprusside by continuous intravenous infusion at an

             initial rate of 3 mcg/kg/min, titrated to achieve the desired

             response.

    

             Patients who are addicted to amphetamines may develop the

             withdrawal syndrome described in 9.5.

 

        10.2 Life supportive procedures and symptomatic/specific

             treatment

 

             Treatment is supportive. Administration of 

             supplemental oxygen, establishment of intravenous access and

             monitoring of vital signs including core temperature, and

             cardiac rhythm are recommended. The following may be

             necessary according to clinical indication:

    

             -Maintenance adequate airway and ventilation

             -Rehydration with intravenous fluids

             -Control of seizures

             -Control of agitation with benzodiazepines

             -Control of severe hypertension (diastolic blood pressure

             greater than 110 mmHg)

             -Control of hyperthermia

             -Treatment of hyperkalaemia

             -Cardiac intensive care for ischaemia or arrhythmia

 

        10.3 Decontamination

 

             No regime of oral decontamination has been demonstrated

             to improve outcome. Ipecacuanha is contra-indicated. Oral

             activated charcoal may be helpful following oral overdosage.

 

        10.4 Enhanced elimination

 

             No regime of decontamination has been demonstrated to

             improve outcome. Forced acid diuresis has been abandoned as a

             decontamination procedure. Neither haemodialysis nor charcoal

             haemoperfusion is likely to be of benefit.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    There is no antidote to amphetamine poisoning.

 

             10.5.2 Children

 

                    There is no antidote to amphetamine poisoning.

 

        10.6 Management discussion

 

             There are differences between dexamphetamine and

             related compounds such as 3,4-methylenedeoxymetamphetamine

             (“ecstacy”); for example, hyperthermia appears to be more of

             a problem with the latter, and this may be because of the

             association between use and frenetic physical activity

             (“rave” dancing) (Henry et al., 1992).

    

             In the past, energetic gastric decontamination procedures

             were suggested (Espelin & Done, 1968). There is no evidence

             that such procedures improve outcome in amphetamine

             poisoning, and they are potentially hazardous.

    

             Oral activated charcoal is probably the safest option for

             decontamination, but is only likely to bind drug in the

             stomach if a substantial oral dose of amphetamine has been

             taken, and the charcoal is given within an hour or two of

             ingestion. If should only administered to patients in whom

             swallowing and gag reflexes are intact. In drug smugglers who

             have swallowed supposedly inert packages of amphetamines

             (“stuffers” or  “packers”), and who develop symptoms because

             of leakage from the packages, then repeated doses of oral

             activated charcoal with a cathartic are likely to be

             worthwhile.

    

             Forced acid diuresis has now been abandoned as an elimination

             treatment, because it is intrinsically difficult and

             potentially dangerous.

    

             Treatment of agitation in amphetamine poisoning is required

             when a patient is a danger to himself or herself, or to

             others. Because poisoning is associated with sympathetic

             overactivity, and chlorpromazine has alpha-adrenoreceptor

             antagonist actions, chlorpromazine has been recommended as

             the sedative treatment of choice (see 10.1). There is no

             study to demonstrate that chlorpromazine is in fact superior

             to benzodiazepine.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             Ingestion of 2.2g (28mg/kg) in a 21 year old man

             resulted in severe toxicity (Ginsberg et.al., 1970).

    

             An 18 month old male infant ingested an unknown amount of

             amphetamine, subsequently detected in the urine. He had a

             history of restlessness and vomiting for 10 hours and was

             admitted to hospital with mild fever (38°C), pulse rate of

             140 per minute and respiratory rate of 34 per minute. He

             looked acutely unwell, hyperactive and combative and had

             normal pupils with a bi-lateral light reflex. Some irregular

 

             flushing was found over the skin of the trunk. He was given

             diazepam 10mg intravenously, 10% chloral hydrate 10ml

             rectally and haloperidol 20mg intravenously. After a sleep of

             20 hours normal activity resumed and the patient was

             clinically well and discharged (Soong et.al., 1991).

    

             A 20-month-old male infant was admitted to hospital with a

             history of being too restless, hyperactive and agitated to be

             manageable for several hours, and had not responded to 10mg

             diazepam given intravenously in a local medical clinic. He

             had dilated pupils, doll’s eyes and normal discs. Generalised

             hypperreflexia and a mild clonus were noted, but no focal

             neurological abnormalities could be found. His vital signs

             were – blood pressure 130/90 mmHg, pulse rate 150/min,

             respiratory rate 46/min and normal temperature. The clinical

             status remained unchanged for a further 18 hours and the

             patient then calmed down to sleep for 20 hours. Subsequently

             the parents found amphetamine powder spread near the infant’s

             bed (Soong, et.al., 1991).

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventive measures

 

             When prescribing amphetamines, due regard must be given

             to its potential for misuse and addiction.

 

        12.2 Other

 

             No data available.

 

  1. REFERENCES

 

        Bashour TT (1994) Acute myocardial infarction resulting from

        amphetamine abuse: a spasm-thrombus interplay?  Am Heart J, 128:

        1237-1239.

    

        Beyer K., Bickel JT & Butt JH (1991) Ischemic colitis associated

        with dextroamphetamine use. J Clin Gastroenterol, 13: 198-201.

    

        Birkhahn HJ & Heifetz M (1973) Accidental intra-arterial injection

        of amphetamine: an unusual hazard of drug addiction. Brit. J

        Anaesthesia, 45: 761-763.

    

        Briggs GG, Samson JH & Crawford DJ (1975) Lack of abnormalities in

        a newborn exposed to amphetamine during gestation. Am J Dis Child,

        129: 249-250.

    

        Briggs G, Freeman J & Yaffe S (1990) Drugs in pregnancy and

        lactation: a reference guide to fetal and neonatal risk, ed 3.

        Baltimore, Williams & Wilkins.

    

 

        Brust JCM (1993) Neurological aspects of substance abuse.

        Stoneham, Butterworth-Heineman.

    

        Budavari S ed. (1996) The Merck Index: an encyclopedia of

        chemical, drugs, and biological, 12th ed. Rahway, New Jersey, Merck

        and Co., Inc.

    

        Call TD, Hartneck J, Dickinson WW, Hartman CW & Bartel AG (1982) 

        Acute cardiomyopathy secondary to amphetamine abuse. Ann Int Med,

        97: 559-560.

    

        Carson P, Oldroyd K & Phadkle K (1987) Myocardial infarction due

        to amphetamine. Brit Med J, 294: 1525-1526.

    

        Derlet RW, Price P, Horowitz BZ & Lord RV (1989) Amphetamine

        toxicity: experience with 127 cases. J Emerg Med, 7: 157-161.

    

        Dollery CT (1991) Therapeutic drugs. Edinburgh Churchill,

        Livingstone.

    

        Ellenhorn, M.J. (1997) Ellenhorn’s Medical Toxicology, 2nd edition.

        Baltimore, Williams and Wilkins.

    

        Eriksson M, Billing L, Steneroth G & Zetterstrom R (1989)  Health

        and development of 8-year-old children whose mothers abused

        amphetamine during pregnancy. Acta Paediatrica Scandinavica, 78:

        944-949.

    

        Espelin DE, Done AK (1968) Amphetamine poisoning. Effectiveness of

        chlorpromazine. New Eng J Med, 278:1361-1365.

    

        Flaum M & Schultz SK (1996) When does amphetamine-induced

        psychosis become schizophrenia?  Am J Psych, 153: 812-815.

    

        Ginsberg MD Hertzman M & Schmidt-Nowara WW (1970) Amphetamine

        intoxication with coagulopathy, hyperthermia and reversible renal

        failure. A syndrome resembling heatstroke. Ann Intern Med, 73:

        81-85.

    

        Hall RCW, Popkin MK, Beresford TP & Hall AK (1988) Amphetamine

        psychosis: clinical presentation and differential diagnosis.

        Psychiatric Med, 6: 73-79.

    

        Hardman JG, Limbird LE, Molinoff  PB, Ruddon RW & Goodman Gilman A

        (1996) Goodman & Gilman’s the pharmacological basis of

        therapeutics, 9th ed. New York, McGraw Hill.

    

        Hart JB & Wallace J (1975)  The adverse effects of amphetamines.

        Clin Toxicol, 8: 179-190.

    

        Henry JA, Jeffreys KS & Dawling S (1992) Toxicity and deaths from

        3,4-methylenedeoxymetamphetamine (“ecstasy”). Lancet, 340:

        384-387.

    

 

        Johnson J & Milner G (1966)  Psychiatric complications of

        amphetamine abuse. Acta Psychiatrica Scandinavica, 42:

        252-263.

    

        Kalant H & Kalant OJ (1975) Death in amphetamine users: causes and

        rates. Canad Med Assoc J, 112: 299-304.

    

        Kaku DA & Lowenstein DH (1990) Emergence of recreational drug

        abuse as a major risk factor for stroke in young adults. Ann Int

        Med, 113: 821-827.

    

        Kendrick WC, Hull AR & Knochel JP (1977)  Rhabdomyolysis and shock

        after intravenous amphetamine administration. Ann Int Med, 86:

        381-387.

    

        Klawans HL (1968) Chlorpromazine vs. amphetamine. New Engl J Med,

        279:329.

    

        Kramer JC, Fischman VS & Littlefield DC (1967) Amphetamine abuse.

        Pattern and effects of high doses taken intravenously. JAMA, 201:

        305-304.

    

        Mattson RH & Calverly JR (1968) Dextroamphetamine-sulphate-induced

        dyskinesias. JAMA, 204: 400-402.

    

        Morley JE, Schafer RB, Elson MK, Slag MF, Raleigh MJ, Brammer GL,

        Yuwiler A & Herschman JM  (1980) Amphetamine-induced

        hyperthyroxinemia. Ann Int Med,  93: 707-709.

    

        Packe GE, Garton MJ & Jenning K (1990) Acute myocardial infarction

        caused by intravenous amphetamine abuse. Brit Med J, 64:

        23-24.

    

        Reynolds JEF (1996) Martindale; The extra pharmacopoeia, 31st ed.

        London, Pharmaceutical Press.

    

        Schwartz DT (1981) Idiopathic rupture of the bladder. J Urol, 125:

        602.

    

        Selmi F, Davies KG, Sharma RR & Neal JW (1995) Intracerebral

        haemorrhage due to amphetamine abuse; report of two cases with

        underlying arteriovenous malformation. Brit J Neruosurg,  9:

        93-96.

    

        Soong WJ, Hwang BT, Tsai WJ & Deng JF (1991)  [Amphetamine

        poisoning in infants: report of 2 cases]. Chung-Hua-I-Hsueh-Tsa-

        Chih, 48: 228-231.

    

        Stockley IH (1994)  Drug interactions, 3rd ed. Oxford, Blackwell

        Science.

    

 

        Tuma TA (1993) Depressive stupor following amphetamine withdrawal.

        Brit J Hosp Med, 49: 361-363.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Authors:    Miss Glady Heedes

                    Senior Pharmacist-in-Charge

    

                    Mr John Ailakis

                    Clinical Pharmacist

    

                    Western Australian Poisons Information Centre

                    Princess Margaret Hospital for Children

                    GPO Box D184

                    Perth, WA 6001

                    Australia

    

                    June 1992

    

        Revised by: Dr Robin Ferner

                    West Midlands Centre for Adverse Drug Reaction

                    Reporting

                    City Hospital

                    Birmingham B18 7Q

                    United Kingdom

    

                    August 1997

    

        Peer Review:         INTOX 5 Meeting, September 1992: J-F Deng, R

                             Ferner, Landoni, Maramba, E Wickstrom

    

                             INTOX 10 Meeting, Rio, Brazil, September

                             1997: N Ben-Salah, A Borges, M Mathieu-Nolf,

                             L Murray, M-O Rambourg, R Ferner

    

        Editor:     Michael Ruse, IPCS (June, 1998)

    

 

    

Amphetamines

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS numbers

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological analyses 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 test(s)

         8.2.1.3 Simple qualitative method(s)

         8.2.1.4 Advanced quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple qualitative test(s)

         8.2.2.2 Advanced qualitative test(s)

         8.2.2.3 Simple qualitative method(s)

         8.2.2.4 Advanced quantitative Method(s)

         8.2.2.5 Other dedicated method(s)

      8.2.3 Interpretation of toxicological analyses

   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 analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

   8.6 References

  1. 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 (CNS)

         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 disturbance

         9.4.12.2 Fluid and electrolyte disturbance

         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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    AMPHETAMINES

 

    International Programme on Chemical Safety

    Poison Information Monograph(Group PIM) G009

    Pharmaceutical

 

  1. NAME

 

        1.1  Substance

 

             Amphetamines

 

        1.2  Group

 

             The members of this group include:

 

             Amphetamine

             Benzphetamine

             Chlorphentermine

             Clortermine

             Dexamphetamine

             Dexfenfluramine

             Diethylpropion

             Fenfluramine

             Methamphetamine

             Methylphenidate

             Pemoline

             Phendimetrazine

             Phenmetrazine

             Phentermine

 

        1.3  Synonyms

 

             Amfetamines

 

        1.4  Identification numbers

 

             1.4.1  CAS numbers

 

                    Amphetamine  300-62-9

                    Amphetamine phosphate  139-10-6

                    Amphetamine sulfate  60-13-9

                    Benzphetamine 156-08-1

                    Benzphetamine hydrochloride 5411-22-3

                    Chlorphentermine 461-78-9

                    Chorphentermine hydrochloride 151-06-4

                    Clortermine 10389-73-8

                    Clortermine hydrochloride 10389-72-7

                    Dexamphetamine 51-64-9

                    Dexamphetamine phosphate 7528-00-9

                    Dexamphetamine sulphate 51-63-8

                    Dexfenfluramine 3239-44-9

                    Dexfenfluramine hydrochloride 3239-45-0

                    Diethylpropion 90-84-6

                    Diethylpropion hydrochloride  134-80-5

                    Fenfluramine 458-24-2

 

                    Fenfluramine hydrochloride 404-82-0

                    Methamphetamine (methylamphetamine)  537-46-2

                    Methamphetamine 

                    (methylamphetamine hydrochloride) 51-57-0

                    Methylphenidate 113-45-1

                    Methylphenidate hydrochloride  298-59-9

                    Pemoline  2152-34-3

                    Pemoline hydrochloride  68942-31-4

                    Pemoline magnesium (magnesium pemoline) 18968-99-5

                    Phendimetrazine 634-03-7

                    Phendimetrazine hydrochloride  7635-51-0

                    Phendimetrazine tartrate 50-58-8

                    Phenmetrazine  134-49-6

                    Phenmetrazine hydrochloride  1707-14-8

                    Phenmetrazine theoclate 13931-75-4

                    Phentermine 122-09-8

                    Phentermine hydrochloride 1197-21-3

 

             1.4.2  Other numbers

 

                    Amphetamine NIOSH/RTECS        SH 9000000

                    Benzphetamine NIOSH/RTECS      SG9602000

                    Chlorphentermine NIOSH/RTECS   SH1050000

                    Dexamphetamine NIOSH/RTECS     SH9100000

                    Dexfenfluramine NIOSH/RTECS    SH6822000

                    Diethylpropion NIOSH/RTECS     UG9450000

                    Fenfluramine NIOSH/RTECS       SH6820000

                    Methamphetamine NIOSH/RTECS    SH4910000

                    Methylphenidate NIOSH/RTECS    TM3675000

                    Pemoline NIOSH/RTECS           RQ2975000

                    Phendimetrazine NIOSH/RTECS    QE2300000

                    Phenmetrazine NIOSH/RTECS      QE6475000

                    Phentermine NIOSH/RTECS        SH4025000

 

                    ATC Classification:

 

                    Antiobesity preparations, excl., diet products (A08A)

                    Centrally acting antiobesity products (A08A A)

                    or

                    Psychostimulants (N06B)

                    Phenylethylamine derivatives (N06B A)

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             Acute central nervous system stimulation, cardiotoxicity

             causing tachycardia, arrhythmias, hypertension and

             cardiovascular collapse. High risk of dependency and abuse.

 

        2.2  Summary of clinical effects

 

             Cardiovascular – Palpitation, chest pain, tachycardia,

             arrhythmias and hypertension are common; cardiovascular

             collapse can occur in severe poisoning. Myocardial ischaemia,

             infarction and ventricular dysfunction are described.

    

             Central Nervous System (CNS) – Stimulation of CNS, tremor,

             restlessness, agitation, insomnia, increased motor activity,

             headache, convulsions, coma and hyperreflexia are described.

             Stroke and cerebral vasculitis have been observed.

    

             Gastrointestinal – Vomiting, diarrhoea and cramps may occur.

             Acute transient ischaemic colitis has occurred with chronic

             methamphetamine abuse.

    

             Genitourinary – Increased bladder sphincter tone may cause

             dysuria, hesitancy and acute urinary retention. Renal failure

             can occur secondary to dehydration or rhabdomyolysis. Renal

             ischaemia may be noted.

    

             Dermatologic – Skin is usually pale and diaphoretic, but

             mucous membranes appear dry.

    

             Endocrine – Transient hyperthyroxinaemia may be noted.

    

             Metabolism – Increased metabolic and muscular activity may

             result in hyperventilation and hyperthermia. Weight loss is

             common with chronic use.

    

             Fluid/Electrolyte – Hypo- and hyperkalaemia have been

             reported. Dehydration is common.

    

             Musculoskeletal – Fasciculations and rigidity may be noted.

             Rhabdomyolysis is an important consequence of severe

             amphetamine poisoning.

    

             Psychiatric – Agitation, confusion, mood elevation, increased

             wakefulness, talkativeness, irritability and panic attacks

             are typical. Chronic abuse can cause delusions and paranoia.

             A withdrawal syndrome occurs after abrupt cessation following

             chronic use.

 

        2.3  Diagnosis

 

             The diagnosis of acute amphetamine poisoning is made on

             the history of exposure or abuse, and the characteristic

             features of CNS and cardiovascular stimulation. The presence

             of amphetamines in urine or blood can support the diagnosis

             but is not helpful in management. Whilst some patients show

             signs of toxicity at blood concentrations of 20 µg/L, chronic

             abusers of amphetamine have been known to have blood

             concentration of up to 3000 µg/L.

 

        2.4  First aid measures and management principles

 

             Management of amphetamine and its complications is

             essentially supportive.

             The initial priority is stabilisation of the airway,

             breathing and circulation. Monitoring of pulse, blood

             pressure, oxygenation, core temperature and cardiac rhythm

             should instituted. Supplemental oxygen should be

             administered. Specific supportive care measures that may be

             necessary include:  maintenance of hydration, control of

             seizures, relief of agitation, control of hyperthermia,

             control of hypertension, management of rhabdomyolysis.

    

             Decontamination with oral activated charcoal is appropriate

             if the patient is conscious.

    

             There are no suitable methods of enhancing elimination of

             amphetamine and no specific antidotes.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Synthetic

 

        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

 

                    Store in airtight containers. Refrigeration

                    unnecessary.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Psychostimulant

                    Antiobesity preparation (not diet product)

                    Centrally acting antiobesity product

 

             4.1.2  Description

 

                    Indications

    

                    Narcolepsy & Hyperkinetic states in children (as an

                    adjunct to psychological, educational and social

                    measures) for amphetamine, dextroamphetamine and

                    ethylphenidate.

    

                    Appetite suppressant (anorectic) for benzphetamine,

                    diethypropion, phendimetrazine, phenmetrazine and

                    phenteramine.

    

                    Veterinary indications:

    

                    CNS stimulant in narcotic poisoning, anaesthetic

                    collapse or encephalitis.

    

                    Misuse:

    

                    Performance enhancement

                    Relief of fatigue

    

                    Abuse:

    

                    Abuse either orally or by injection is extremely

                    common.

    

                    (Dollery, 1991; Reynolds, 1996)

 

        4.2  Therapeutic dosage

 

             4.2.1  Adults

 

                    Narcolepsy – Usual starting dose is 5 to 10 mg

                    daily in divided doses, increased if necessary at

                    weekly intervals to a maximum of 60 mg daily.

 

             4.2.2  Children

 

                    Hyperkinetic states – Individualisation of

                    treatment is especially important. Children aged 6

                    years and over usually start with a dose of 5 mg once

                    or twice daily, increased if necessary by 5 mg at

                    weekly intervals to an upper limit of 20 mg daily,

                    though older children might require up to 40 mg daily.

 

        4.3  Contraindications

 

             Anorexia, insomnia, psychopathic personality disorders,

             suicidal tendencies, Gilles de la Tourette syndrome and other

             disorders, hyperthyroidism, narrow angle glaucoma, diabetes

             mellitis and cardiovascular diseases such as angina,

             hypertension and arrythmias (Dollery, 1991; Reynolds, 1996).

    

 

             Amphetamine interacts with several other drugs (see 7.6).

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             Readily absorbed from the gastro-intestinal tract and

             buccal mucosa. It Is resistant to metabolism by monoamine

             oxidase.

 

        5.2  Inhalation

 

             Amphetamine is rapidly absorbed by inhalation and is

             abused by this route (Brust, 1993).

 

        5.3  Dermal

 

             No data available.

 

        5.4  Eye

 

             No data available.

 

        5.5  Parenteral

 

             Frequent route of entry in abuse situations.

 

        5.6  Other

 

             No data available.

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             Amphetamine is rapidly absorbed after oral ingestion.

             Peak plasma levels occur within 1 to 3 hours, varying with

             the degree of physical activity and the amount of food in the

             stomach. Absorption is usually complete by 4 to 6 hours.

             Sustained release preparations are available as resin-bound,

             rather than soluble, salts. These compounds display reduced

             peak blood levels compared with standard amphetamine

             preparations, but total amount absorbed and time to peak

             levels remain similar (Dollery, 1991).

 

        6.2  Distribution by route of exposure

 

             Amphetamines are concentrated in the kidney, lungs,

             cerebrospinal fluid and brain. They are highly lipid soluble

             and readily cross the blood-brain barrier. Protein binding

             and volume of distribution varies widely, but the average

             volume of distribution is 5 L/kg body weight (Dollery, 1991).

 

        6.3  Biological half-life by route of exposure

 

             Under normal conditions, about 30% of amphetamine is

             excreted unchanged in the urine but this excretion is highly

             variable and is dependent on urinary pH. When the urinary pH

             is acidic (pH 5.5 to 6.0), elimination is predominantly by

             urinary excretion with approximately 60% of a dose of

             amphetamine being excreted unchanged by the kidney within 48

             hours. When the urinary pH is alkaline (pH 7.5 to 8.0),

             elimination is predominantly by deamination (less than 7%

             excreted unchanged in the urine); the half-life ranging from

             16 to 31 hours (Ellenhorn, 1997).

 

        6.4  Metabolism

 

             The major metabolic pathway for amphetamine involves

             deamination by cytochrome P450 to para-hydroxyamphetamine and

             phenylacetone; this latter compound is subsequently oxidised

             to benzoic acid and excreted as glucuronide or glycine

             (hippuric acid) conjugate. Smaller amounts of amphetamine are

             converted to norephedrine by oxidation. Hydroxylation

             produces an active metabolite, O-hyroxynorephedrine, which

             acts as a false neurotransmitter and may account for some

             drug effect, especially in chronic users (Dollery, 1991).

 

        6.5  Elimination and excretion

 

             Normally 5 to 30% of a therapeutic dose of amphetamine

             is excreted unchanged in the urine by 24 hours, but the

             actual amount of urinary excretion and metabolism is highly

             pH dependent (Dollery, 1991).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             7.1.1  Toxicodynamics

 

                    Amphetamine appears to exert most or all of its

                    effect in the CNS by causing release of biogenic

                    amines, especialy norepinephrine and dopamine, from

                    storage sites in nerve terminals. It may also slow

                    down catecholamine metabolism by inhibiting monoamine

                    oxidase (Hardman et al., 1997).

 

             7.1.2  Pharmacodynamics

 

                    See section 7.1.1

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             The toxic dose varies considerably

                             due to individual variations and the

                             development of tolerance. Fatalities have

                             been reported following ingestion of doses as

                             low as 1.3 mg/kg, while tolerance has been

                             developed to 1,000 mg at a time and up to 5 g

                             in a day.

 

                    7.2.1.2  Children

 

                             Children appear to be more

                             susceptible than adults and are less likely

                             to have developed tolerance.

 

             7.2.2  Relevant animal data

 

                    Adult monkeys have an LD50 of 15 to 20 mg/kg,

                    whereas for young monkeys the LD50 is only 5 mg/kg.

 

             7.2.3  Relevant in vitro data

 

                    Not relevant

 

        7.3  Carcinogenicity

 

             To be completed

 

        7.4  Teratogenicity

 

             The use of amphetamine for medical indications does not

             pose a significant risk to the fetus for congenital anomalies

             (Briggs, 1990). Amphetamines generally do not appear to be

             human teratogens. Mild withdrawal symptoms may be observed in

             the newborn, but the few studies of infant follow-up have not

             shown long-term sequelae, although more studies of this

             nature are needed.

    

             Illicit maternal use or abuse of amphetamine presents a

             significant risk to the foetus and newborn, including

             intrauterine growth retardation, premature delivery and the

             potential for increased maternal, fetal and neonatal

             morbidity.

    

             These poor outcomes are probably multifactorial in origin,

             involving multiple drug use, life-styles and poor maternal

             health. However, cerebral injuries occurring in newborns

             exposed in utero appear to be directly related to the

 

             vasoconstrictive properties of amphetamines. Ericksson et al.

             (1989) followed 65 children whose mothers were addicted to

             amphetamine during pregnancy, at least during the first

             trimester. Intelligence, psychological function, growth, and

             physical health were all within the normal range at eight

             years, but those children exposed throughout pregnancy tended

             to be more aggressive.

 

        7.5  Mutagenicity

 

             No relevant data

 

        7.6  Interactions

 

             Acetazolamide – administration may increase serum

             concentration of amphetamine.

    

             Alcohol – may increase serum concentration of amphetamine.

    

             Ascorbic acid – lowering urinary pH, may enhance amphetamine

             excretion

    

             Furazolidone – amphetamines may induce a hypertensive

             response in patients taking furazolidone.

    

             Guanethidine – amphetamine inhibits the antihypertensive

             response to guanethidine.

    

             Haloperidol – limited evidence indicates that haloperidol may

             inhibit the effects of amphetamine but the clinical

             importance of this interaction is not established.

    

             Lithium carbonate – isolated case reports indicate that

             lithium may inhibit the effects of amphetamine.

    

             Monoamine oxidase inhibitor – severe hypertensive reactions

             have followed the administration of amphetamines to patients

             taking monoamine oxidase inhibitors.

    

             Noradrenaline – amphetamine abuse may enhance the pressor

             response to noradrenaline.

    

             Phenothiazines – amphetamine may inhibit the antipsychotic

             effect of phenothiazines, and phenothiazines may inhibit the

             anorectic effect of amphetamines.

    

             Sodium bicarbonate – large doses of sodium bicarbonate

             inhibit the elimination of amphetamine, thus increasing the

             amphetamine effect.

    

             Tobacco smoking – amphetamine appears to induce dose-related

             increases in cigarette smoking.

    

 

             Tricyclic antidepressants – theoretically increases the

             effect of amphetamine, but clinical evidence is lacking.

    

             (Stockley, 1994; Dollery, 1991)

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

 

             8.1.1  Sampling and specimen collection

 

                    8.1.1.1  Toxicological analyses

 

                    8.1.1.2  Biomedical analyses

 

                    8.1.1.3  Arterial blood gas analysis

 

                    8.1.1.4  Haematological analyses

 

                    8.1.1.5  Other (unspecified) analyses

 

             8.1.2  Storage of laboratory samples and specimens

 

                    8.1.2.1  Toxicological analyses

 

                    8.1.2.2  Biomedical analyses

 

                    8.1.2.3  Arterial blood gas analysis

 

                    8.1.2.4  Haematological analyses

 

                    8.1.2.5  Other (unspecified) analyses

 

             8.1.3  Transport of laboratory samples and specimens

 

                    8.1.3.1  Toxicological analyses

 

                    8.1.3.2  Biomedical analyses

 

                    8.1.3.3  Arterial blood gas analysis

 

                    8.1.3.4  Haematological analyses

 

                    8.1.3.5  Other (unspecified) analyses

 

        8.2  Toxicological analyses 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 test(s)

 

                    8.2.1.3  Simple qualitative method(s)

 

                    8.2.1.4  Advanced quantitative Method(s)

 

             8.2.2  Tests for biological specimens

 

                    8.2.2.1  Simple qualitative test(s)

 

                    8.2.2.2  Advanced qualitative test(s)

 

                    8.2.2.3  Simple qualitative method(s)

 

                    8.2.2.4  Advanced quantitative Method(s)

 

                    8.2.2.5  Other dedicated method(s)

 

             8.2.3  Interpretation of toxicological analyses

 

        8.3  Biomedical investigations and their interpretation

 

             8.3.1  Biochemical analysis

 

                    8.3.1.1  Blood, plasma or serum

 

                             8.3.1.1.1  Basic analyses

 

                             8.3.1.1.2  Dedicated analyses

 

                             8.3.1.1.3  Optional analyses

 

                    8.3.1.2  Urine

 

                             8.3.1.2.1  Basic analyses

 

                             8.3.1.2.2  Dedicated analyses

 

                             8.3.1.2.3  Optional analyses

 

                    8.3.1.3  Other fluids

 

             8.3.2  Arterial blood gas analyses

 

             8.3.3  Haematological analyses

 

                             8.3.3.1.1  Basic analyses

 

                             8.3.3.1.2  Dedicated analyses

 

                             8.3.3.1.3  Optional analyses

 

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and their 

             interpretation

 

        8.5  Overall interpretation of all toxicological analyses and 

             toxicological investigations

 

             Sample collection

    

             Creatinine, urea, and electrolyte measurement are important

             to establish whether renal impairment or hyperkalaemia is

             present. Measurements of serum creatine kinase, aspartate

             transaminase and myoglobin can help to establish if there is

             rhabdomyolysis, and myoglobin can be detected in urine.

    

             Liver function tests are relevant, since hepatitis can occur.

    

             A full blood count and coagulation studies can be helpful,

             with measurement of fibrinogen and of fibrin degradation

             products, in establishing a diagnosis of disseminated

             intravascular coagulation.

    

             Biomedical analysis

    

             Temperature, blood pressure, and pulse rate should be

             monitored frequently. A temperature above 40°C, and marked

             hypertension and tachycardia are seen in severe poisoning.

    

             An electrocardiogram can be useful in detecting myocardial

             ischaemia or arrhythmia. Electrocardiographic monitoring can

             be helpful in patients with arrhythmia.

    

             Toxicological analysis

    

             Urine or serum analysis for amphetamine can help to confirm

             exposure, but cannot be used to establish poisoning, because

             of difference in individual tolerance to amphetamines.

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    Effects are most marked on the central nervous

                    system, cardiovascular system, and muscles. The triad

                    of hyperactivity, hyperpyrexia, and hypertension is

                    characteristic of acute amphetamine overdosage.

    

                    Agitation, confusion, headache, delirium, and

                    hallucination, can be followed by coma, intracranial

                    haemorrhage, stroke, and death.

    

 

                    Chest pain, palpitation, hypertension, tachycardia,

                    atrial and ventricular arrhythmia, and myocardial

                    infarction can occur.

    

                    Muscle contraction, bruxism (jaw-grinding), trismus

                    (jaw clenching), fasciculation, rhabdomyolysis, are

                    seen leading to renal failure; and flushing, sweating,

                    and hyperpyrexia can all occur. Hyperpyrexia can cause

                    disseminated intravascular coagulation.

    

                    (Brust, 1993; Derlet et al., 1989)

 

             9.1.2  Inhalation

 

                    The clinical effects are similar to those after

                    ingestion, but occur more rapidly (Brust, 1993).

 

             9.1.3  Skin exposure

 

                    No data available

 

             9.1.4  Eye contact

 

                    No data available

 

             9.1.5  Parenteral exposure

 

                    Intravenous injection is a common mode of

                    administration of amphetamine by abusers. The euphoria

                    produced is more intense, leading to a “rush” or 

                    “flash” which is compared to sexual orgasm  (Brust,

                    1993). Other clinical effects are similar to those

                    observed after ingestion, but occur more rapidly.

 

             9.1.6  Other

 

                    No data available

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Tolerance to the euphoric effects and CNS

                    stimulation induced by amphetamine develops rapidly,

                    leading abusers to use larger and larger amounts to

                    attain and sustain the desired affect.

    

                    Habitual use or chronic abuse usually results in toxic

                    psychosis classically characterised by paranoia,

                    delusions and hallucinations, which are usually

                    visual, tactile or olfactory in nature, in contrast to

                    the typical auditory hallucinations of schizophrenia.

                    The individual may act on the delusions, resulting in

 

                    bizarre violent behaviour, hostility and aggression,

                    sometimes leading to suicidal or homicidal actions.

                    Dyskinesia, compulsive behaviour and impaired

                    performance are common in chronic abusers. The chronic

                    abuser presents as a restless, garrulous, tremulous

                    individual who is suspicious and anxious.

 

             9.2.2  Inhalation

 

                    As for 9.2.1.

 

             9.2.3  Skin exposure

 

                    No relevant data.

 

             9.2.4  Eye contact

 

                    No relevant data.

 

             9.2.5  Parenteral exposure

 

                    As for 9.2.1.

 

             9.2.6  Other

 

                    Vaginal exposure, as for 9.2.1.

 

        9.3  Course, prognosis, cause of death

 

             Symptoms and signs give a clinical guide to the severity

             of intoxication as follows (Espelin and Done, 1968):

    

             Mild toxicity – restlessness, irritability, insomnia, tremor,

             hyperreflexia, sweating, dilated pupils, flushing;

    

             Moderate toxicity – hyperactivity, confusion, hypertension,

             tachypnoea, tachycardia, mild fever, sweating;

    

             Severe toxicity – delirium, mania, self-injury, marked

             hypertension, tachycardia, arrhythmia, hyperpyrexia,

             convulsion, coma, circulatory collapse.

    

             Death can be due to intracranial haemorrhage, acute heart

             failure or arrhythmia, hyperpyrexia, rhabdomyolysis and

             consequent hyperkalaemia or renal failure, and to violence

             related to the psychiatric effects (Kalant & Kalant, 1975).

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Cardiovascular symptoms of acute poisoning

                    include palpitation and chest pain. Tachycardia and

                    hypertension are common. One third of patients

 

                    reported by Derlet et al. (1989) had a blood pressure

                    greater than 140/90 mmHg, and nearly two-thirds had a

                    pulse rate above 100 beats per minute.

    

                    Severe poisoning can cause acute myocardial ischaemia,

                    myocardial infarction (Carson et al., 1987; Packe et

                    al., 1990), and left ventricular failure (Kalant &

                    Kalant, 1975). These probably result from vasospasm,

                    perhaps at sites of existing atherosclerosis. In at

                    least one case, thrombus was demonstrated initially

                    (Bashour, 1994).

    

                    Chronic oral amphetamine abuse can cause a chronic

                    cardiomyopathy; an acute cardiomyopathy has also been

                    described (Call et al., 1982).

    

                    Hypertensive stroke is a well-recognised complication

                    of amphetamine poisoning (see 9.4.3).

    

                    Intra-arterial injection of amphetamine can cause

                    severe burning pain, vasospasm, and gangrene (Birkhahn

                    & Heifetz, 1973).

 

             9.4.2  Respiratory

 

                    Pulmonary fibrosis, right ventricular

                    hypertrophy and pulmonary hypertension are frequently

                    found at post-mortem examination.

    

                    Pulmonary function tests usually are normal except for

                    the carbon monoxide diffusing capacity. Respiratory

                    complications are sometimes caused by fillers or

                    adulterants used in injections by chronic users. These

                    can cause multiple microemboli to the lung, which can

                    lead to restrictive lung disease.

    

                    Pneumomediastinum has been reported after amphetamine

                    inhalation (Brust, 1993).

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             Main symptoms include agitation,

                             confusion, delirium, hallucinations,

                             dizziness, dyskinesia, hyperactivity, muscle

                             fasciculation and rigidity, rigors, tics, 

                             tremors, seizures and coma.

    

                             Both occlusive and haemorrhagic strokes have

                             been reported after abuse of amphetamines.

                             Twenty-one of 73 drug-using young persons

                             with stroke had taken amphetamine (Kaku &

 

                             Lowenstein, 1990), of whom six had documented

                             intracerebral haemorrhage and two had

                             subarachnoid haemorrhage. Patients with

                             underlying arteriovenous malformations may be

                             at particular risk (Selmi et al., 1995).

    

                             Stroke can occur after oral, intravenous, or

                             nasal administration. Severe headache

                             beginning within minutes of ingestion of

                             amphetamine is usually the first symptom. In

                             more than half the cases, hypertension which

                             is sometimes extreme, accompanies other

                             symptoms. A Cerebral vasculitis has also been

                             observed (Brust, 1993).

    

                             Dystonia and dyskinesia can occur, even with

                             therapeutic dosages (Mattson & Calverley,

                             1968).

    

                             Psychiatric effects, particularly euphoria

                             and excitement, are the motives for abuse.

                             Paranoia and a psychiatric syndrome

                             indistinguishable from schizophrenia are

                             sequelae of chronic use (Hall et al., 1988;

                             Flaum & Schultz, 1996; Johnson & Milner,

                             1966).

 

                    9.4.3.2  Peripheral nervous system

 

                             No relevant data

 

                    9.4.3.3  Autonomic nervous system

 

                             Stimulation of alpha-adrenergic

                             receptors produces mydriasis, increased

                             metabolic rate, diaphoresis, increased

                             sphincter tone, peripheral vasoconstriction

                             and decreased gastrointestinal motility.

    

                             Stimulation of ß-adrenergic receptors

                             produces increased heart rate and

                             contractility, increased automaticity and

                             dilatation of bronchioles.

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             Myalgia, muscle tenderness, muscle

                             contractions, and rhabdomyolysis, leading to

                             fever, circulatory collapse, and

                             myoglobinuric renal failure, can occur with

                             amphetamines (Kendrick et al., 1977).

 

             9.4.4  Gastrointestinal

 

                    Most common symptoms are nausea, vomiting,

                    diarrhoea, and abdominal cramps. Anorexia may be

                    severe. Epigastric pain and haematemesis have been

                    described after intravenous amphetamine use. A case of

                    ischaemic colitis with normal mesenteric arteriography

                    in a patient taking dexamphetamine has been described

                    (Beyer et al., 1991).

 

             9.4.5  Hepatic

 

                    Hepatitis and fatal acute hepatic necrosis have

                    been described

                    (Kalant & Kalant, 1975).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Renal failure, secondary to dehydration 

                             or rhabdomyolysis may be observed.

 

                    9.4.6.2  Other

 

                             Increased bladder sphincter tone may

                             cause dysuria, hesitancy and acute urinary

                             retention. This effect may be a direct result

                             of peripheral alpha-agonist activity.

    

                             Spontaneous rupture of the bladder has been

                             described in a young woman who took alcohol

                             and an amphetamine-containing diet tablet

                             (Schwartz, 1981).

 

             9.4.7  Endocrine and reproductive systems

 

                    Transient hyperthyroxinaemia may result from

                    heavy amphetamine use (Morley et al., 1980).

 

             9.4.8  Dermatological

 

                    Skin is usually pale and diaphoretic, but

                    mucous membranes appear dry. Chronic users may display

                    skin lesion, abscesses, ulcers, cellulitis or

                    necrotising angiitis due to physical insult to skin,

                    or dermatologic signs of dietary deficiencies, e.g.

                    cheilosis, purpura.

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    Mydriasis may be noted.

                    Diffuse hair loss may be noted.

                    Chronic users may display signs of dietary

                    deficiencies.

 

             9.4.10 Haematological

 

                    Disseminated intravascular coagulation is an

                    important consequence of severe poisoning (Kendrick et

                    al., 1980).

                    Idiopathic thrombocytopenic purpura may occur.

 

             9.4.11 Immunological

 

                    No relevant data.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbance

 

                             No relevant data

 

                    9.4.12.2 Fluid and electrolyte disturbance

 

                             Increase metabolic and muscular activity 

                             may result in dehydration.

 

                    9.4.12.3 Others

 

                             No data available

 

             9.4.13 Allergic reactions

 

                    No relevant data

 

             9.4.14 Other clinical effects

 

                    No relevant data

 

             9.4.15 Special risks

 

                    Pregnancy:  Eriksson et al. (1989) followed 65

                    children whose mother were addicted to amphetamine

                    during pregnancy, at least during the first trimester.

                    Intelligence, psychological function, growth, and

                    physical health were all within the normal range at

                    eight years, but those exposed throughout pregnancy

                    tended to be more aggressive.

    

 

                    A case report describes a normal female infant born to

                    mother who took up to 180 mg/day of dexamphetamine for

                    narcolepsy throughout pregnancy (Briggs et al., 1975).

    

                    Breast-feeding:  Amphetamine is passed into breast

                    milk and measurable amounts can be detected in

                    breast-fed infant’s urine. Therefore lactating mothers

                    are advised not to take or use amphetamine.

 

        9.5  Other

 

             Amphetamine withdrawal syndrome:  Abrupt discontinuance

             following chronic use is characterised by apathy, depression,

             lethargy, anxiety and sleep disturbances. Myalgias, abdominal

             pain, voracious appetite and a profound depression with

             suicidal tendencies may complicate the immediate

             post-withdrawal period and peak in 2 to 3 days. To relieve

             these symptoms, the user will often return to use more

             amphetamine, often at increasing doses due to the tolerance

             which is readily established. Thus a cycle of

             use-withdrawal-use is established (Kramer et al., 1967; Hart

             & Wallace, 1975). Physical effects are not life threatening

             but can lead to a stuporose state (Tuma, 1993); the

             associated depression can lead to suicide. It may take up to

             eight weeks for suppressed REM (rapid eye movement) sleep to

             return to normal (Brust 1993).

    

             “Overamped”:  When the intravenous dosage is increased too

             rapidly the individual develops a peculiar condition referred

             to as “overamped: in which he or she is conscious but unable

             to speak or move. Elevated blood pressure, temperature and

             pulse as well as chest distress occurs in this setting. Death

             from overdose in tolerant individuals is infrequent.

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             General supportive measures should be used. These

             should include stabilisation of the airway, breathing, and

             circulation; relief of agitation, adequate hydration, and

             control of core temperature. Convulsions, hyperthermia, and

             rhabdomyolysis may require specific treatment. Activated

             charcoal may be helpful for decontamination after oral

             ingestion. Ipecacuanha is contra-indicated because of its

             stimulant properties. There are no effective methods of

             enhancing elimination and no antidote.

    

 

             Agitation and convulsion can be treated with diazepam. If

             agitation is severe, then chlorpromazine may have specific

             advantages over other major tranquillisers (Espelin & Done,

             1968; Klawans, 1968). Parenteral dosages of 0.5 to 2

             milligrams per kilogram have been used in Infants (Espelin &

             Done, 1968).

    

             Severe hyperthermia (core temperature greater than 40°C)

             requires forced cooling by fans, tepid sponging or other

             means, and may also require the administration of diazepam or

             dantrolene or both agents in order to eliminate muscle

             activity.

    

             Rhabdomyolysis associated with muscle overactivity can cause

             hyperkalaemia or renal failure, and should be treated

             conventionally. Dialysis may be needed if renal failure

             supervenes.

    

             Acute severe hypertension (diastolic blood pressure greater

             than 100 mmHg) can be controlled by infusion of sodium

             nitroprusside by continuous intravenous infusion at an

             initial rate of 3 mcg/kg/min, titrated to achieve the desired

             response.

    

             Patients who are addicted to amphetamines may develop the

             withdrawal syndrome described in 9.5.

 

        10.2 Life supportive procedures and symptomatic/specific 

             treatment

 

             Treatment is supportive. Administration of 

             supplemental oxygen, establishment of intravenous access and

             monitoring of vital signs including core temperature, and

             cardiac rhythm are recommended. The following may be

             necessary according to clinical indication:

    

             -Maintenance adequate airway and ventilation

             -Rehydration with intravenous fluids

             -Control of seizures

             -Control of agitation with benzodiazepines

             -Control of severe hypertension (diastolic blood pressure

             greater than 110 mmHg)

             -Control of hyperthermia

             -Treatment of hyperkalaemia

             -Cardiac intensive care for ischaemia or arrhythmia

 

        10.3 Decontamination

 

             No regime of oral decontamination has been demonstrated

             to improve outcome. Ipecacuanha is contra-indicated. Oral

             activated charcoal may be helpful following oral overdosage.

 

        10.4 Enhanced elimination

 

             No regime of decontamination has been demonstrated to

             improve outcome. Forced acid diuresis has been abandoned as a

             decontamination procedure. Neither haemodialysis nor charcoal

             haemoperfusion is likely to be of benefit.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    There is no antidote to amphetamine poisoning.

 

             10.5.2 Children

 

                    There is no antidote to amphetamine poisoning.

 

        10.6 Management discussion

 

             There are differences between dexamphetamine and

             related compounds such as 3,4-methylenedeoxymetamphetamine

             (“ecstacy”); for example, hyperthermia appears to be more of

             a problem with the latter, and this may be because of the

             association between use and frenetic physical activity

             (“rave” dancing) (Henry et al., 1992).

    

             In the past, energetic gastric decontamination procedures

             were suggested (Espelin & Done, 1968). There is no evidence

             that such procedures improve outcome in amphetamine

             poisoning, and they are potentially hazardous.

    

             Oral activated charcoal is probably the safest option for

             decontamination, but is only likely to bind drug in the

             stomach if a substantial oral dose of amphetamine has been

             taken, and the charcoal is given within an hour or two of

             ingestion. If should only administered to patients in whom

             swallowing and gag reflexes are intact. In drug smugglers who

             have swallowed supposedly inert packages of amphetamines

             (“stuffers” or “packers”), and who develop symptoms because

             of leakage from the packages, then repeated doses of oral

             activated charcoal with a cathartic are likely to be

             worthwhile.

    

             Forced acid diuresis has now been abandoned as an elimination

             treatment, because it is intrinsically difficult and

             potentially dangerous.

    

             Treatment of agitation in amphetamine poisoning is required

             when a patient is a danger to himself or herself, or to

             others. Because poisoning is associated with sympathetic

             overactivity, and chlorpromazine has alpha-adrenoreceptor

             antagonist actions, chlorpromazine has been recommended as

             the sedative treatment of choice (see 10.1). There is no

 

             study to demonstrate that chlorpromazine is in fact superior

             to benzodiazepine.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             Ingestion of 2.2g (28mg/kg) in a 21 year old man

             resulted in severe toxicity (Ginsberg et.al., 1970).

    

             An 18 month old male infant ingested an unknown amount of

             amphetamine, subsequently detected in the urine. He had a

             history of restlessness and vomiting for 10 hours and was

             admitted to hospital with mild fever (38°C), pulse rate of

             140 per minute and respiratory rate of 34 per minute. He

             looked acutely unwell, hyperactive and combative and had

             normal pupils with a bi-lateral light reflex. Some irregular

             flushing was found over the skin of the trunk. He was given

             diazepam 10mg intravenously, 10% chloral hydrate 10ml

             rectally and haloperidol 20mg intravenously. After a sleep of

             20 hours normal activity resumed and the patient was

             clinically well and discharged (Soong et.al., 1991).

    

             A 20-month-old male infant was admitted to hospital with a

             history of being too restless, hyperactive and agitated to be

             manageable for several hours, and had not responded to 10mg

             diazepam given intravenously in a local medical clinic. He

             had dilated pupils, doll’s eyes and normal discs. Generalised

             hypperreflexia and a mild clonus were noted, but no focal

             neurological abnormalities could be found. His vital signs

             were – blood pressure 130/90 mmHg, pulse rate 150/min,

             respiratory rate 46/min and normal temperature. The clinical

             status remained unchanged for a further 18 hours and the

             patient then calmed down to sleep for 20 hours. Subsequently

             the parents found amphetamine powder spread near the infant’s

             bed (Soong, et.al., 1991).

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventive measures

 

             When prescribing amphetamines, due regard must be given

             to its potential for misuse and addiction.

 

        12.2 Other

 

             No data available.

 

  1. REFERENCES

 

        Bashour TT (1994) Acute myocardial infarction resulting from

        amphetamine abuse: a spasm-thrombus interplay?  Am Heart J, 128:

        1237-1239.

    

        Beyer K., Bickel JT & Butt JH (1991) Ischemic colitis associated

        with dextroamphetamine use. J Clin Gastroenterol, 13: 198-201.

    

        Birkhahn HJ & Heifetz M (1973) Accidental intra-arterial injection

        of amphetamine: an unusual hazard of drug addiction. Brit. J

        Anaesthesia, 45: 761-763.

    

        Briggs GG, Samson JH & Crawford DJ (1975) Lack of abnormalities in

        a newborn exposed to amphetamine during gestation. Am J Dis Child,

        129: 249-250.

    

        Briggs G, Freeman J & Yaffe S (1990) Drugs in pregnancy and

        lactation: a reference guide to fetal and neonatal risk, ed 3.

        Baltimore, Williams & Wilkins.

    

        Brust JCM (1993) Neurological aspects of substance abuse.

        Stoneham, Butterworth-Heineman.

    

        Budavari S ed. (1996) The Merck Index: an encyclopedia of

        chemical, drugs, and biological, 12th ed. Rahway, New Jersey, Merck

        and Co., Inc.

    

        Call TD, Hartneck J, Dickinson WW, Hartman CW & Bartel AG (1982) 

        Acute cardiomyopathy secondary to amphetamine abuse. Ann Int Med,

        97: 559-560.

    

        Carson P, Oldroyd K & Phadkle K (1987) Myocardial infarction due

        to amphetamine. Brit Med J, 294: 1525-1526.

    

        Derlet RW, Price P, Horowitz BZ & Lord RV (1989) Amphetamine

        toxicity: experience with 127 cases. J Emerg Med, 7: 157-161.

    

        Dollery CT (1991) Therapeutic drugs. Edinburgh Churchill,

        Livingstone.

    

        Ellenhorn, M.J. (1997) Ellenhorn’s Medical Toxicology, 2nd edition.

        Baltimore, Williams and Wilkins.

    

        Eriksson M, Billing L, Steneroth G & Zetterstrom R (1989)  Health

        and development of 8-year-old children whose mothers abused

        amphetamine during pregnancy. Acta Paediatrica Scandinavica, 78:

        944-949.

    

        Espelin DE, Done AK (1968) Amphetamine poisoning. Effectiveness of

        chlorpromazine. New Eng J Med, 278:1361-1365.

    

 

        Flaum M & Schultz SK (1996) When does amphetamine-induced

        psychosis become schizophrenia?  Am J Psych, 153: 812-815.

    

        Ginsberg MD Hertzman M & Schmidt-Nowara WW (1970) Amphetamine

        intoxication with coagulopathy, hyperthermia and reversible renal

        failure. A syndrome resembling heatstroke. Ann Intern Med, 73:

        81-85.

    

        Hall RCW, Popkin MK, Beresford TP & Hall AK (1988) Amphetamine

        psychosis: clinical presentation and differential diagnosis.

        Psychiatric Med, 6: 73-79.

    

        Hardman JG, Limbird LE, Molinoff  PB, Ruddon RW & Goodman Gilman A

        (1996) Goodman & Gilman’s the pharmacological basis of

        therapeutics, 9th ed. New York, McGraw Hill.

    

        Hart JB & Wallace J (1975)  The adverse effects of amphetamines.

        Clin Toxicol, 8: 179-190.

    

        Henry JA, Jeffreys KS & Dawling S (1992) Toxicity and deaths from

        3,4-methylenedeoxymetamphetamine (“ecstasy”). Lancet, 340:

        384-387.

    

        Johnson J & Milner G (1966)  Psychiatric complications of

        amphetamine abuse. Acta Psychiatrica Scandinavica, 42:

        252-263.

    

        Kalant H & Kalant OJ (1975) Death in amphetamine users: causes and

        rates. Canad Med Assoc J, 112: 299-304.

    

        Kaku DA & Lowenstein DH (1990) Emergence of recreational drug

        abuse as a major risk factor for stroke in young adults. Ann Int

        Med, 113: 821-827.

    

        Kendrick WC, Hull AR & Knochel JP (1977)  Rhabdomyolysis and shock

        after intravenous amphetamine administration. Ann Int Med, 86:

        381-387.

    

        Klawans HL (1968) Chlorpromazine vs. amphetamine. New Engl J Med,

        279:329.

    

        Kramer JC, Fischman VS & Littlefield DC (1967) Amphetamine abuse.

        Pattern and effects of high doses taken intravenously. JAMA, 201:

        305-304.

    

        Mattson RH & Calverly JR (1968) Dextroamphetamine-sulphate-induced

        dyskinesias. JAMA, 204: 400-402.

    

        Morley JE, Schafer RB, Elson MK, Slag MF, Raleigh MJ, Brammer GL,

        Yuwiler A & Herschman JM  (1980) Amphetamine-induced

        hyperthyroxinemia. Ann Int Med,  93: 707-709.

    

 

        Packe GE, Garton MJ & Jenning K (1990) Acute myocardial infarction

        caused by intravenous amphetamine abuse. Brit Med J, 64:

        23-24.

    

        Reynolds JEF (1996) Martindale; The extra pharmacopoeia, 31st ed.

        London, Pharmaceutical Press.

    

        Schwartz DT (1981) Idiopathic rupture of the bladder. J Urol, 125:

        602.

    

        Selmi F, Davies KG, Sharma RR & Neal JW (1995) Intracerebral

        haemorrhage due to amphetamine abuse; report of two cases with

        underlying arteriovenous malformation. Brit J Neruosurg,  9:

        93-96.

    

        Soong WJ, Hwang BT, Tsai WJ & Deng JF (1991)  [Amphetamine

        poisoning in infants: report of 2 cases]. Chung-Hua-I-Hsueh-Tsa-

        Chih, 48: 228-231.

    

        Stockley IH (1994)  Drug interactions, 3rd ed. Oxford, Blackwell

        Science.

    

        Tuma TA (1993) Depressive stupor following amphetamine withdrawal.

        Brit J Hosp Med, 49: 361-363.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

        ADDRESS(ES)

 

        Authors:  Miss Glady Heedes

                    Senior Pharmacist-in-Charge

    

                    Mr John Ailakis

                    Clinical Pharmacist

    

                    Western Australian Poisons Information Centre

                    Princess Margaret Hospital for Children

                    GPO Box D184

                    Perth, WA 6001

                    Australia

    

                    June 1992

    

        Revised by: Dr Robin Ferner

                    West Midlands Centre for Adverse Drug Reaction

                    Reporting

                    City Hospital

                    Birmingham B18 7Q

                    United Kingdom

    

                    August 1997

    

 

        Peer Review:         INTOX 5 Meeting, September 1992: J-F Deng, R

                             Ferner, Landoni, Maramba, E Wickstrom

    

                             INTOX 10 Meeting, Rio, Brazil, September

                             1997: N Ben-Salah, A Borges, M Mathieu-Nolf,

                             L Murray, M-O Rambourg, R Ferner

    

        Editor:     Michael Ruse, IPCS (June, 1998)

    

 

Pemoline

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS numbers

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. 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

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Physical properties

      3.2.1 Colour

      3.2.2 State/Form

      3.2.3 Description

   3.3 Other characteristics

      3.3.1 Shelf-life of the substance

      3.3.2 Storage conditions

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

   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

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological analyses 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 test(s)

         8.2.1.3 Simple qualitative method(s)

         8.2.1.4 Advanced quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple qualitative test(s)

         8.2.2.2 Advanced qualitative test(s)

         8.2.2.3 Simple qualitative method(s)

         8.2.2.4 Advanced quantitative Method(s)

         8.2.2.5 Other dedicated method(s)

      8.2.3 Interpretation of toxicological analyses

   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 analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

   8.6 References

  1. 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 (CNS)

         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 disturbance

         9.4.12.2 Fluid and electrolyte disturbance

         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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    Pemoline

 

    International Programme on Chemical Safety

    Poison Information Monograph 940

    Pharmaceutical

 

  1. NAME

 

        1.1  Substance

 

             Pemoline

 

        1.2  Group

 

             ATC Classifcation

 

             Psychostimulants (N06B)

             Phenylethylamine derivatives (N06B A)

 

        1.3  Synonyms

 

             A 13397;  Azoksodon;

             Azoxodone; Centramin;

             CS 293; Dantromin;

             Deltamine; Endolin;

             Fenoxazol; FWH-352; H 3104;

             Hyton;  Juston-wirkstoff;

             Kethamed; LA 956; Nitan;

             Notair; Okodon; Pemolina;

             Phenoxazole; Phenylisohydantoin;

             Phenylpseudohydantoin; PIO;

             Pioxol; PN/135; Pondex;

             PT 360; Ronyl; Sigmadyn;

             Sistra; Stimul; Tradon;

             Tradone; Yh 1

 

        1.4  Identification numbers

 

             1.4.1  CAS numbers

 

                    2152-34-3

 

             1.4.2  Other numbers

 

                    NIOSH/RTECS hRQ2975000

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             Acute central nervous system stimulation, cardiotoxicity

             causing tachycardia, arrhythmias, hypertension and

             cardiovascular collapse. High risk of dependency and abuse.

 

        2.2  Summary of clinical effects

 

             Cardiovascular – Palpitation, chest pain, tachycardia,

             arrhythmias and hypertension are common; cardiovascular

             collapse can occur in severe poisoning. Myocardial ischaemia,

             infarction and ventricular dysfunction are described.

    

             Central Nervous System (CNS) – Stimulation of CNS, tremor,

             restlessness, agitation, insomnia, increased motor activity,

             headache, convulsions, coma and hyperreflexia are described.

             Stroke and cerebral vasculitis have been observed.

    

             Gastrointestinal – Vomiting, diarrhoea and cramps may occur.

             Acute transient ischaemic colitis has occurred with chronic

             methamphetamine abuse.

    

             Genitourinary – Increased bladder sphincter tone may cause

             dysuria, hesitancy and acute urinary retention. Renal failure

             can occur secondary to dehydration or rhabdomyolysis. Renal

             ischaemia may be noted.

    

             Dermatologic – Skin is usually pale and diaphoretic, but

             mucous membranes appear dry.

    

             Endocrine – Transient hyperthyroxinaemia may be noted.

    

             Metabolism – Increased metabolic and muscular activity may

             result in hyperventilation and hyperthermia. Weight loss is

             common with chronic use.

    

             Fluid/Electrolyte – Hypo- and hyperkalaemia have been

             reported. Dehydration is common.

    

             Musculoskeletal – Fasciculations and rigidity may be noted.

             Rhabdomyolysis is an important consequence of severe

             amphetamine poisoning.

    

             Psychiatric – Agitation, confusion, mood elevation, increased

             wakefulness, talkativeness, irritability and panic attacks

             are typical. Chronic abuse can cause delusions and paranoia.

             A withdrawal syndrome occurs after abrupt cessation following

             chronic use.

 

        2.3  Diagnosis

 

             The diagnosis of acute amphetamine poisoning is made on

             the history of exposure or abuse, and the characteristic

             features of CNS and cardiovascular stimulation. The presence

             of amphetamines in urine or blood can support the diagnosis

             but is not helpful in management. Whilst some patients show

             signs of toxicity at blood concentrations of 20 µg/L, chronic

             abusers of amphetamine have been known to have blood

             concentration of up to 3000 µg/L.

 

        2.4  First aid measures and management principles

 

             Management of amphetamine and its complications is

             essentially supportive.

             The initial priority is stabilisation of the airway,

             breathing and circulation. Monitoring of pulse, blood

             pressure, oxygenation, core temperature and cardiac rhythm

             should instituted. Supplemental oxygen should be

             administered. Specific supportive care measures that may be

             necessary include:  maintenance of hydration, control of

             seizures, relief of agitation, control of hyperthermia,

             control of hypertension, management of rhabdomyolysis.

    

             Decontamination with oral activated charcoal is appropriate

             if the patient is conscious.

    

             There are no suitable methods of enhancing elimination of

             amphetamine and no specific antidotes.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Synthetic

    

             Chemical name

    

             2-Imino-5-phenyl-4-oxazolidinone

    

             Other chemical names

    

             2-Amino-5-phenyl-4(5H)-oxazolone

             2-Imino-4-keto-5-phenyltetrahydrooxazole

             5-Phenyl-2-imino-4-oxazolidinone

    

             Molecular formula: C9H8N2O2

             Molecular weight:  176.2

 

        3.2  Physical properties

 

             3.2.1  Colour

 

             3.2.2  State/Form

 

             3.2.3  Description

 

        3.3  Other characteristics

 

             3.3.1  Shelf-life of the substance

 

             3.3.2  Storage conditions

 

                    Store in airtight containers.

                    Refrigeration unnecessary.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Psychostimulant

                    Phenylethylamine derivative; psychostimulant

 

             4.1.2  Description

 

                    Indications

    

                    Narcolepsy & Hyperkinetic states in children (as an

                    adjunct to psychological, educational and social

                    measures) for amphetamine, dextroamphetamine and

                    ethylphenidate.

    

                    Misuse:

    

                    Performance enhancement

                    Relief of fatigue

    

                    Abuse:

    

                    Abuse either orally or by injection is extremely

                    common.

    

                    (Dollery, 1991; Reynolds, 1996)

 

        4.2  Therapeutic dosage

 

             4.2.1  Adults

 

             4.2.2  Children

 

        4.3  Contraindications

 

             Anorexia, insomnia, psychopathic personality disorders,

             suicidal tendencies, Gilles de la Tourette syndrome and other

             disorders, hyperthyroidism, narrow angle glaucoma, diabetes

             mellitis and cardiovascular diseases such as angina,

             hypertension and arrythmias (Dollery, 1991; Reynolds, 1996).

    

             Amphetamine interacts with several other drugs (see 7.6).

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             Readily absorbed from the gastro-intestinal tract and

             buccal mucosa. It Is resistant to metabolism by monoamine

             oxidase.

 

        5.2  Inhalation

 

             Amphetamine is rapidly absorbed by inhalation and is

             abused by this route (Brust, 1993).

 

        5.3  Dermal

 

             No data available.

 

        5.4  Eye

 

             No data available.

 

        5.5  Parenteral

 

             Frequent route of entry in abuse situations.

 

        5.6  Other

 

             No data available.

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             Amphetamine is rapidly absorbed after oral ingestion.

             Peak plasma levels occur within 1 to 3 hours, varying with

             the degree of physical activity and the amount of food in the

             stomach. Absorption is usually complete by 4 to 6 hours.

             Sustained release preparations are available as resin-bound,

             rather than soluble, salts. These compounds display reduced

             peak blood levels compared with standard amphetamine

             preparations, but total amount absorbed and time to peak

             levels remain similar (Dollery, 1991).

 

        6.2  Distribution by route of exposure

 

             Amphetamines are concentrated in the kidney, lungs,

             cerebrospinal fluid and brain. They are highly lipid soluble

             and readily cross the blood-brain barrier. Protein binding

             and volume of distribution varies widely, but the average

             volume of distribution is 5 L/kg body weight (Dollery, 1991).

 

        6.3  Biological half-life by route of exposure

 

             Under normal conditions, about 30% of amphetamine is

             excreted unchanged in the urine but this excretion is highly

             variable and is dependent on urinary pH. When the urinary pH

             is acidic (pH 5.5 to 6.0), elimination is predominantly by

             urinary excretion with approximately 60% of a dose of

             amphetamine being excreted unchanged by the kidney within 48

             hours. When the urinary pH is alkaline (pH 7.5 to 8.0),

             elimination is predominantly by deamination (less than 7%

             excreted unchanged in the urine); the half-life ranging from

             16 to 31 hours (Ellenhorn, 1997).

 

        6.4  Metabolism

 

             The major metabolic pathway for amphetamine involves

             deamination by cytochrome P450 to para-hydroxyamphetamine and

             phenylacetone; this latter compound is subsequently oxidised

             to benzoic acid and excreted as glucuronide or glycine

             (hippuric acid) conjugate. Smaller amounts of amphetamine are

             converted to norephedrine by oxidation. Hydroxylation

             produces an active metabolite, O-hyroxynorephedrine, which

             acts as a false neurotransmitter and may account for some

             drug effect, especially in chronic users (Dollery, 1991).

 

        6.5  Elimination and excretion

 

             Normally 5 to 30% of a therapeutic dose of amphetamine

             is excreted unchanged in the urine by 24 hours, but the

             actual amount of urinary excretion and metabolism is highly

             pH dependent (Dollery, 1991).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             Amphetamine appears to exert most or all of its effect

             in the CNS by causing release of biogenic amines, especialy

             norepinephrine and dopamine, from storage sites in nerve

             terminals. It may also slow down catecholamine metabolism by

             inhibiting monoamine oxidase (Hardman, et al., 1997).

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             The toxic dose varies considerably

                             due to individual variations and the

                             development of tolerance. Fatalities have

                             been reported following ingestion of doses as

                             low as 1.3 mg/kg, while tolerance has been

 

                             developed to 1,000 mg at a time and up to 5 g

                             in a day.

 

                    7.2.1.2  Children

 

                             Children appear to be more

                             susceptible than adults and are less likely

                             to have developed tolerance.

 

             7.2.2  Relevant animal data

 

                    Adult monkeys have an LD50 of 15 to 20 mg/kg, whereas

                    for young monkeys the LD50 is only 5 mg/kg.

 

             7.2.3  Relevant in vitro data

 

                    Not relevant

 

        7.3  Carcinogenicity

 

             To be completed

 

        7.4  Teratogenicity

 

             The use of amphetamine for medical indications does not

             pose a significant risk to the fetus for congenital anomalies

             (Briggs, 1990). Amphetamines generally do not appear to be

             human teratogens. Mild withdrawal symptoms may be observed in

             the newborn, but the few studies of infant follow-up have not

             shown long-term sequelae, although more studies of this

             nature are needed.

    

             Illicit maternal use or abuse of amphetamine presents a

             significant risk to the foetus and newborn, including

             intrauterine growth retardation, premature delivery and the

             potential for increased maternal, fetal and neonatal

             morbidity.

    

             These poor outcomes are probably multifactorial in origin,

             involving multiple drug use, life-styles and poor maternal

             health. However, cerebral injuries occurring in newborns

             exposed in utero appear to be directly related to the

             vasoconstrictive properties of amphetamines. Ericksson et al.

             (1989) followed 65 children whose mothers were addicted to

             amphetamine during pregnancy, at least during the first

             trimester. Intelligence, psychological function, growth, and

             physical health were all within the normal range at eight

             years, but those children exposed throughout pregnancy tended

             to be more aggressive.

 

        7.5  Mutagenicity

 

             No relevant data

 

        7.6  Interactions

 

             Acetazolamide – administration may increase serum

             concentration of amphetamine.

    

             Alcohol – may increase serum concentration of

             amphetamine.

    

             Ascorbic acid -lowering urinary pH, may enhance amphetamine

             excretion

    

             Furazolidone – amphetamines may induce a hypertensive

             response in patients taking furazolidone.

    

             Guanethidine – amphetamine inhibits the antihypertensive

             response to guanethidine.

    

             Haloperidol – limited evidence indicates that haloperidol may

             inhibit the effects of amphetamine but the clinical

             importance of this interaction is not established.

    

             Lithium carbonate – isolated case reports indicate that

             lithium may inhibit the effects of amphetamine.

    

             Monoamine oxidase inhibitor – severe hypertensive reactions

             have followed the administration of amphetamines to patients

             taking monoamine oxidase inhibitors.

    

             Noradrenaline – amphetamine abuse may enhance the pressor

             response to noradrenaline.

    

             Phenothiazines – amphetamine may inhibit the antipsychotic

             effect of phenothiazines, and phenothiazines may inhibit the

             anorectic effect of amphetamines.

    

             Sodium bicarbonate – large doses of sodium bicarbonate

             inhibit the elimination of amphetamine, thus increasing the

             amphetamine effect.

    

             Tobacco smoking – amphetamine appears to induce dose-related

             increases in cigarette smoking.

    

             Tricyclic antidepressants – theoretically increases the

             effect of amphetamine, but clinical evidence is lacking.

    

             (Stockley, 1994; Dollery, 1991)

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

 

             8.1.1  Sampling and specimen collection

 

                    8.1.1.1  Toxicological analyses

 

                    8.1.1.2  Biomedical analyses

 

                    8.1.1.3  Arterial blood gas analysis

 

                    8.1.1.4  Haematological analyses

 

                    8.1.1.5  Other (unspecified) analyses

 

             8.1.2  Storage of laboratory samples and specimens

 

                    8.1.2.1  Toxicological analyses

 

                    8.1.2.2  Biomedical analyses

 

                    8.1.2.3  Arterial blood gas analysis

 

                    8.1.2.4  Haematological analyses

 

                    8.1.2.5  Other (unspecified) analyses

 

             8.1.3  Transport of laboratory samples and specimens

 

                    8.1.3.1  Toxicological analyses

 

                    8.1.3.2  Biomedical analyses

 

                    8.1.3.3  Arterial blood gas analysis

 

                    8.1.3.4  Haematological analyses

 

                    8.1.3.5  Other (unspecified) analyses

 

        8.2  Toxicological analyses 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 test(s)

 

                    8.2.1.3  Simple qualitative method(s)

 

                    8.2.1.4  Advanced quantitative Method(s)

 

             8.2.2  Tests for biological specimens

 

                    8.2.2.1  Simple qualitative test(s)

 

                    8.2.2.2  Advanced qualitative test(s)

 

                    8.2.2.3  Simple qualitative method(s)

 

                    8.2.2.4  Advanced quantitative Method(s)

 

                    8.2.2.5  Other dedicated method(s)

 

             8.2.3  Interpretation of toxicological analyses

 

        8.3  Biomedical investigations and their interpretation

 

             8.3.1  Biochemical analysis

 

                    8.3.1.1  Blood, plasma or serum

 

                             8.3.1.1.1  Basic analyses

 

                             8.3.1.1.2  Dedicated analyses

 

                             8.3.1.1.3  Optional analyses

 

                    8.3.1.2  Urine

 

                             8.3.1.2.1  Basic analyses

 

                             8.3.1.2.2  Dedicated analyses

 

                             8.3.1.2.3  Optional analyses

 

                    8.3.1.3  Other fluids

 

             8.3.2  Arterial blood gas analyses

 

             8.3.3  Haematological analyses

 

                             8.3.3.1.1  Basic analyses

 

                             8.3.3.1.2  Dedicated analyses

 

                             8.3.3.1.3  Optional analyses

 

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and their 

             interpretation

 

        8.5  Overall interpretation of all toxicological analyses and 

             toxicological investigations

 

             Sample collection

    

             Creatinine, urea, and electrolyte measurement are important

             to establish whether renal impairment or hyperkalaemia is

             present. Measurements of serum creatine kinase, aspartate

             transaminase and myoglobin can help to establish if there is

             rhabdomyolysis, and myoglobin can be detected in urine.

    

             Liver function tests are relevant, since hepatitis can occur.

    

             A full blood count and coagulation studies can be helpful,

             with measurement of fibrinogen and of fibrin degradation

             products, in establishing a diagnosis of disseminated

             intravascular coagulation.

    

             Biomedical analysis

    

             Temperature, blood pressure, and pulse rate should be

             monitored frequently. A temperature above 40°C, and marked

             hypertension and tachycardia are seen in severe poisoning.

    

             An electrocardiogram can be useful in detecting myocardial

             ischaemia or arrhythmia. Electrocardiographic monitoring can

             be helpful in patients with arrhythmia.

    

             Toxicological analysis

    

             Urine or serum analysis for amphetamine can help to confirm

             exposure, but cannot be used to establish poisoning, because

             of difference in individual tolerance to amphetamines.

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    Effects are most marked on the central nervous

                    system, cardiovascular system, and muscles. The triad

                    of hyperactivity, hyperpyrexia, and hypertension is

                    characteristic of acute amphetamine overdosage.

    

                    Agitation, confusion, headache, delirium, and

                    hallucination, can be followed by coma, intracranial

                    haemorrhage, stroke, and death.

    

 

                    Chest pain, palpitation, hypertension, tachycardia,

                    atrial and ventricular arrhythmia, and myocardial

                    infarction can occur.

    

                    Muscle contraction, bruxism (jaw-grinding), trismus

                    (jaw clenching), fasciculation, rhabdomyolysis, are

                    seen leading to renal failure; and flushing, sweating,

                    and hyperpyrexia can all occur. Hyperpyrexia can cause

                    disseminated intravascular coagulation.

    

                    (Brust, 1993; Derlet et al., 1989)

 

             9.1.2  Inhalation

 

                    The clinical effects are similar to those after

                    ingestion, but occur more rapidly (Brust,

                    1993).

 

             9.1.3  Skin exposure

 

                    No data available

 

             9.1.4  Eye contact

 

                    No data available

 

             9.1.5  Parenteral exposure

 

                    Intravenous injection is a common mode of

                    administration of amphetamine by abusers. The euphoria

                    produced is more intense, leading to a “rush” or 

                    “flash” which is compared to sexual orgasm  (Brust,

                    1993). Other clinical effects are similar to those

                    observed after ingestion, but occur more rapidly.

 

             9.1.6  Other

 

                    No data available

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Tolerance to the euphoric effects and CNS

                    stimulation induced by amphetamine develops rapidly,

                    leading abusers to use larger and larger amounts to

                    attain and sustain the desired affect.

    

                    Habitual use or chronic abuse usually results in toxic

                    psychosis classically characterised by paranoia,

                    delusions and hallucinations, which are usually

                    visual, tactile or olfactory in nature, in contrast to

                    the typical auditory hallucinations of schizophrenia.

 

                    The individual may act on the delusions, resulting in

                    bizarre violent behaviour, hostility and aggression,

                    sometimes leading to suicidal or homicidal actions.

                    Dyskinesia, compulsive behaviour and impaired

                    performance are common in chronic abusers. The chronic

                    abuser presents as a restless, garrulous, tremulous

                    individual who is suspicious and anxious.

 

             9.2.2  Inhalation

 

                    As for 9.2.1.

 

             9.2.3  Skin exposure

 

                    No relevant data.

 

             9.2.4  Eye contact

 

                    No relevant data.

 

             9.2.5  Parenteral exposure

 

                    As for 9.2.1.

 

             9.2.6  Other

 

                    Vaginal exposure, as for 9.2.1.

 

        9.3  Course, prognosis, cause of death

 

             Symptoms and signs give a clinical guide to the severity

             of intoxication as follows (Espelin and Done, 1968):

    

             Mild toxicity – restlessness, irritability, insomnia, tremor,

             hyperreflexia, sweating, dilated pupils, flushing;

    

             Moderate toxicity – hyperactivity, confusion, hypertension,

             tachypnoea, tachycardia, mild fever, sweating;

    

             Severe toxicity – delirium, mania, self-injury, marked

             hypertension, tachycardia, arrhythmia, hyperpyrexia,

             convulsion, coma, circulatory collapse.

    

             Death can be due to intracranial haemorrhage, acute heart

             failure or arrhythmia, hyperpyrexia, rhabdomyolysis and

             consequent hyperkalaemia or renal failure, and to violence

             related to the psychiatric effects (Kalant & Kalant, 1975).

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Cardiovascular symptoms of acute poisoning

                    include palpitation and chest pain. Tachycardia and

                    hypertension are common. One third of patients

                    reported by Derlet et al. (1989) had a blood pressure

                    greater than 140/90 mmHg, and nearly two-thirds had a

                    pulse rate above 100 beats per minute.

    

                    Severe poisoning can cause acute myocardial ischaemia,

                    myocardial infarction (Carson et al., 1987; Packe et

                    al., 1990), and left ventricular failure (Kalant &

                    Kalant, 1975). These probably result from vasospasm,

                    perhaps at sites of existing atherosclerosis. In at

                    least one case, thrombus was demonstrated initially

                    (Bashour, 1994).

    

                    Chronic oral amphetamine abuse can cause a chronic

                    cardiomyopathy; an acute cardiomyopathy has also been

                    described (Call et al., 1982).

    

                    Hypertensive stroke is a well-recognised complication

                    of amphetamine poisoning (see 9.4.3).

    

                    Intra-arterial injection of amphetamine can cause

                    severe burning pain, vasospasm, and gangrene (Birkhahn

                    & Heifetz, 1973).

 

             9.4.2  Respiratory

 

                    Pulmonary fibrosis, right ventricular

                    hypertrophy and pulmonary hypertension are frequently

                    found at post-mortem examination.

    

                    Pulmonary function tests usually are normal except for

                    the carbon monoxide diffusing capacity. Respiratory

                    complications are sometimes caused by fillers or

                    adulterants used in injections by chronic users. These

                    can cause multiple microemboli to the lung, which can

                    lead to restrictive lung disease.

    

                    Pneumomediastinum has been reported after amphetamine

                    inhalation (Brust, 1993).

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             Main symptoms include agitation,

                             confusion, delirium, hallucinations,

                             dizziness, dyskinesia, hyperactivity, muscle

 

                             fasciculation and rigidity, rigors, tics, 

                             tremors, seizures and coma.

    

                             Both occlusive and haemorrhagic strokes have

                             been reported after abuse of amphetamines.

                             Twenty-one of  73 drug-using young persons

                             with stroke had taken amphetamine (Kaku &

                             Lowenstein, 1990), of whom six had documented

                             intracerebral haemorrhage and two had

                             subarachnoid haemorrhage. Patients with

                             underlying arteriovenous malformations may be

                             at particular risk (Selmi et al., 1995).

    

                             Stroke can occur after oral, intravenous, or

                             nasal administration. Severe headache

                             beginning within minutes of ingestion of

                             amphetamine is usually the first symptom. In

                             more than half the cases, hypertension which

                             is sometimes extreme, accompanies other

                             symptoms. A Cerebral vasculitis has also been

                             observed (Brust, 1993).

    

                             Dystonia and dyskinesia can occur, even with

                             therapeutic dosages (Mattson & Calverley,

                             1968).

    

                             Psychiatric effects, particularly euphoria

                             and excitement, are the motives for abuse.

                             Paranoia and a psychiatric syndrome

                             indistinguishable from schizophrenia are

                             sequelae of chronic use (Hall et al., 1988;

                             Flaum & Schultz, 1996; Johnson & Milner,

                             1966).

 

                    9.4.3.2  Peripheral nervous system

 

                             No relevant data

 

                    9.4.3.3  Autonomic nervous system

 

                             Stimulation of alpha-adrenergic

                             receptors produces mydriasis, increased

                             metabolic rate, diaphoresis, increased

                             sphincter tone, peripheral vasoconstriction

                             and decreased gastrointestinal motility.

    

                             Stimulation of ß-adrenergic receptors

                             produces increased heart rate and

                             contractility, increased automaticity and

                             dilatation of bronchioles.

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             Myalgia, muscle tenderness, muscle

                             contractions, and rhabdomyolysis, leading to

                             fever, circulatory collapse, and

                             myoglobinuric renal failure, can occur with

                             amphetamines (Kendrick et al.,

                             1977).

 

             9.4.4  Gastrointestinal

 

                    Most common symptoms are nausea, vomiting,

                    diarrhoea, and abdominal cramps. Anorexia may be

                    severe. Epigastric pain and haematemesis have been

                    described after intravenous amphetamine use. A case of

                    ischaemic colitis with normal mesenteric arteriography

                    in a patient taking dexamphetamine has been described

                    (Beyer et al., 1991).

 

             9.4.5  Hepatic

 

                    Hepatitis and fatal acute hepatic necrosis have

                    been described

                    (Kalant & Kalant, 1975).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Renal failure, secondary to

                             dehydration or rhabdomyolysis may be

                             observed.

 

                    9.4.6.2  Other

 

                             Increased bladder sphincter tone may

                             cause dysuria, hesitancy and acute urinary

                             retention. This effect may be a direct result

                             of peripheral alpha-agonist activity.

    

                             Spontaneous rupture of the bladder has been

                             described in a young woman who took alcohol

                             and an amphetamine-containing diet tablet

                             (Schwartz, 1981).

 

             9.4.7  Endocrine and reproductive systems

 

                    Transient hyperthyroxinaemia may result from

                    heavy amphetamine use (Morley et al., 1980).

 

             9.4.8  Dermatological

 

                    Skin is usually pale and diaphoretic, but

                    mucous membranes appear dry. Chronic users may display

                    skin lesion, abscesses, ulcers, cellulitis or

                    necrotising angiitis due to physical insult to skin,

                    or dermatologic signs of dietary deficiencies, e.g.

                    cheilosis, purpura.

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    Mydriasis may be noted.

                    Diffuse hair loss may be noted.

                    Chronic users may display signs of dietary

                    deficiencies.

 

             9.4.10 Haematological

 

                    Disseminated intravascular coagulation is an

                    important consequence of severe poisoning (Kendrick et

                    al., 1980).

                    Idiopathic thrombocytopenic purpura may occur.

 

             9.4.11 Immunological

 

                    No relevant data.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbance

 

                             No relevant data

 

                    9.4.12.2 Fluid and electrolyte disturbance

 

                             Increase metabolic and muscular activity 

                             may result in dehydration.

 

                    9.4.12.3 Others

 

                             No data available

 

             9.4.13 Allergic reactions

 

                    No relevant data

 

             9.4.14 Other clinical effects

 

                    No relevant data

 

             9.4.15 Special risks

 

                    Pregnancy:  Eriksson et al. (1989) followed 65

                    children whose mother were addicted to amphetamine

                    during pregnancy, at least during the first trimester.

                    Intelligence, psychological function, growth, and

                    physical health were all within the normal range at

                    eight years, but those exposed throughout pregnancy

                    tended to be more aggressive.

    

                    A case report describes a normal female infant born to

                    mother who took up to 180 mg/day of dexamphetamine for

                    narcolepsy throughout pregnancy (Briggs et al., 1975).

    

                    Breast-feeding:  Amphetamine is passed into breast

                    milk and measurable amounts can be detected in

                    breast-fed infant’s urine. Therefore lactating mothers

                    are advised not to take or use amphetamine.

 

        9.5  Other

 

             Amphetamine withdrawal syndrome:  Abrupt discontinuance

             following chronic use is characterised by apathy, depression,

             lethargy, anxiety and sleep disturbances. Myalgias, abdominal

             pain, voracious appetite and a profound depression with

             suicidal tendencies may complicate the immediate

             post-withdrawal period and peak in 2 to 3 days. To relieve

             these symptoms, the user will often return to use more

             amphetamine, often at increasing doses due to the tolerance

             which is readily established. Thus a cycle of

             use-withdrawal-use is established (Kramer et al., 1967; Hart

             & Wallace, 1975). Physical effects are not life threatening

             but can lead to a stuporose state (Tuma, 1993); the

             associated depression can lead to suicide. It may take up to

             eight weeks for suppressed REM (rapid eye movement) sleep to

             return to normal (Brust 1993).

    

             “Overamped”:  When the intravenous dosage is increased too

             rapidly the individual develops a peculiar condition referred

             to as “overamped: in which he or she is conscious but unable

             to speak or move. Elevated blood pressure, temperature and

             pulse as well as chest distress occurs in this setting. Death

             from overdose in tolerant individuals is infrequent.

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             General supportive measures should be used. These

             should include stabilisation of the airway, breathing, and

             circulation; relief of agitation, adequate hydration, and

 

             control of core temperature. Convulsions, hyperthermia, and

             rhabdomyolysis may require specific treatment. Activated

             charcoal may be helpful for decontamination after oral

             ingestion. Ipecacuanha is contra-indicated because of its

             stimulant properties. There are no effective methods of

             enhancing elimination and no antidote.

    

             Agitation and convulsion can be treated with diazepam. If

             agitation is severe, then chlorpromazine may have specific

             advantages over other major tranquillisers (Espelin & Done,

             1968; Klawans, 1968). Parenteral dosages of 0.5 to 2

             milligrams per kilogram have been used in Infants (Espelin &

             Done, 1968).

    

             Severe hyperthermia (core temperature greater than 40°C)

             requires forced cooling by fans, tepid sponging or other

             means, and may also require the administration of diazepam or

             dantrolene or both agents in order to eliminate muscle

             activity.

    

             Rhabdomyolysis associated with muscle overactivity can cause

             hyperkalaemia or renal failure, and should be treated

             conventionally. Dialysis may be needed if renal failure

             supervenes.

    

             Acute severe hypertension (diastolic blood pressure greater

             than 100 mmHg) can be controlled by infusion of sodium

             nitroprusside by continuous intravenous infusion at an

             initial rate of 3 mcg/kg/min, titrated to achieve the desired

             response.

    

             Patients who are addicted to amphetamines may develop the

             withdrawal syndrome described in 9.5.

 

        10.2 Life supportive procedures and symptomatic/specific 

             treatment

 

             Treatment is supportive. Administration of 

             supplemental oxygen, establishment of intravenous access and

             monitoring of vital signs including core temperature, and

             cardiac rhythm are recommended. The following may be

             necessary according to clinical indication:

    

             -Maintenance adequate airway and ventilation

             -Rehydration with intravenous fluids

             -Control of seizures

             -Control of agitation with benzodiazepines

             -Control of severe hypertension (diastolic blood pressure

             greater than 110 mmHg)

             -Control of hyperthermia

             -Treatment of hyperkalaemia

             -Cardiac intensive care for ischaemia or arrhythmia

 

        10.3 Decontamination

 

             No regime of oral decontamination has been demonstrated

             to improve outcome. Ipecacuanha is contra-indicated. Oral

             activated charcoal may be helpful following oral overdosage.

 

        10.4 Enhanced elimination

 

             No regime of decontamination has been demonstrated to

             improve outcome. Forced acid diuresis has been abandoned as a

             decontamination procedure. Neither haemodialysis nor charcoal

             haemoperfusion is likely to be of benefit.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    There is no antidote to amphetamine poisoning.

 

             10.5.2 Children

 

                    There is no antidote to amphetamine poisoning.

 

        10.6 Management discussion

 

             There are differences between dexamphetamine and

             related compounds such as 3,4-methylenedeoxymetamphetamine

             (“ecstacy”); for example, hyperthermia appears to be more of

             a problem with the latter, and this may be because of the

             association between use and frenetic physical activity

             (“rave” dancing) (Henry et al., 1992).

    

             In the past, energetic gastric decontamination procedures

             were suggested (Espelin & Done, 1968). There is no evidence

             that such procedures improve outcome in amphetamine

             poisoning, and they are potentially hazardous.

    

             Oral activated charcoal is probably the safest option for

             decontamination, but is only likely to bind drug in the

             stomach if a substantial oral dose of amphetamine has been

             taken, and the charcoal is given within an hour or two of

             ingestion. If should only administered to patients in whom

             swallowing and gag reflexes are intact. In drug smugglers who

             have swallowed supposedly inert packages of amphetamines

             (“stuffers” or “packers”), and who develop symptoms because

             of leakage from the packages, then repeated doses of oral

             activated charcoal with a cathartic are likely to be

             worthwhile.

    

             Forced acid diuresis has now been abandoned as an elimination

             treatment, because it is intrinsically difficult and

             potentially dangerous.

    

 

             Treatment of agitation in amphetamine poisoning is required

             when a patient is a danger to himself or herself, or to

             others. Because poisoning is associated with sympathetic

             overactivity, and chlorpromazine has alpha-adrenoreceptor

             antagonist actions, chlorpromazine has been recommended as

             the sedative treatment of choice (see 10.1). There is no

             study to demonstrate that chlorpromazine is in fact superior

             to benzodiazepine.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             Ingestion of 2.2g (28mg/kg) in a 21 year old man

             resulted in severe toxicity (Ginsberg et.al., 1970).

    

             An 18 month old male infant ingested an unknown amount of

             amphetamine, subsequently detected in the urine. He had a

             history of restlessness and vomiting for 10 hours and was

             admitted to hospital with mild fever (38°C), pulse rate of

             140 per minute and respiratory rate of 34 per minute. He

             looked acutely unwell, hyperactive and combative and had

             normal pupils with a bi-lateral light reflex. Some irregular

             flushing was found over the skin of the trunk. He was given

             diazepam 10mg intravenously, 10% chloral hydrate 10ml

             rectally and haloperidol 20mg intravenously. After a sleep of

             20 hours normal activity resumed and the patient was

             clinically well and discharged (Soong et.al., 1991).

    

             A 20-month-old male infant was admitted to hospital with a

             history of being too restless, hyperactive and agitated to be

             manageable for several hours, and had not responded to 10mg

             diazepam given intravenously in a local medical clinic. He

             had dilated pupils, doll’s eyes and normal discs. Generalised

             hypperreflexia and a mild clonus were noted, but no focal

             neurological abnormalities could be found. His vital signs

             were – blood pressure 130/90 mmHg, pulse rate 150/min,

             respiratory rate 46/min and normal temperature. The clinical

             status remained unchanged for a further 18 hours and the

             patient then calmed down to sleep for 20 hours. Subsequently

             the parents found amphetamine powder spread near the infant’s

             bed (Soong, et.al., 1991).

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventive measures

 

             When prescribing amphetamines, due regard must be given

             to its potential for misuse and addiction.

 

        12.2 Other

 

             No data available.

 

  1. REFERENCES

 

        Bashour TT (1994) Acute myocardial infarction resulting from

        amphetamine abuse: a spasm-thrombus interplay?  Am Heart J, 128:

        1237-1239.

    

        Beyer K., Bickel JT & Butt JH (1991) Ischemic colitis associated

        with dextroamphetamine use. J Clin Gastroenterol, 13: 198-201.

    

        Birkhahn HJ & Heifetz M (1973) Accidental intra-arterial injection

        of amphetamine: an unusual hazard of drug addiction. Brit. J

        Anaesthesia, 45: 761-763.

    

        Briggs GG, Samson JH & Crawford DJ (1975) Lack of abnormalities in

        a newborn exposed to amphetamine during gestation. Am J Dis Child,

        129: 249-250.

    

        Briggs G, Freeman J & Yaffe S (1990) Drugs in pregnancy and

        lactation: a reference guide to fetal and neonatal risk, ed 3.

        Baltimore, Williams & Wilkins.

    

        Brust JCM (1993) Neurological aspects of substance abuse.

        Stoneham, Butterworth-Heineman.

    

        Budavari S ed. (1996) The Merck Index: an encyclopedia of

        chemical, drugs, and biological, 12th ed. Rahway, New Jersey, Merck

        and Co., Inc.

    

        Call TD, Hartneck J, Dickinson WW, Hartman CW & Bartel AG (1982) 

        Acute cardiomyopathy secondary to amphetamine abuse. Ann Int Med,

        97: 559-560.

    

        Carson P, Oldroyd K & Phadkle K (1987) Myocardial infarction due

        to amphetamine. Brit Med J, 294: 1525-1526.

    

        Derlet RW, Price P, Horowitz BZ & Lord RV (1989) Amphetamine

        toxicity: experience with 127 cases. J Emerg Med, 7: 157-161.

    

        Dollery CT (1991) Therapeutic drugs. Edinburgh Churchill,

        Livingstone.

    

        Ellenhorn, M.J. (1997) Ellenhorn’s Medical Toxicology, 2nd edition.

        Baltimore, Williams and Wilkins.

    

        Eriksson M, Billing L, Steneroth G & Zetterstrom R (1989)  Health

        and development of 8-year-old children whose mothers abused

        amphetamine during pregnancy. Acta Paediatrica Scandinavica, 78:

        944-949.

    

        Espelin DE, Done AK (1968) Amphetamine poisoning. Effectiveness of

        chlorpromazine. New Eng J Med, 278:1361-1365.

    

 

        Flaum M & Schultz SK (1996) When does amphetamine-induced

        psychosis become schizophrenia?  Am J Psych, 153: 812-815.

    

        Ginsberg MD Hertzman M & Schmidt-Nowara WW (1970) Amphetamine

        intoxication with coagulopathy, hyperthermia and reversible renal

        failure. A syndrome resembling heatstroke. Ann Intern Med, 73:

        81-85.

    

        Hall RCW, Popkin MK, Beresford TP & Hall AK (1988) Amphetamine

        psychosis: clinical presentation and differential diagnosis.

        Psychiatric Med, 6: 73-79.

    

        Hardman JG, Limbird LE, Molinoff  PB, Ruddon RW & Goodman Gilman A

        (1996) Goodman & Gilman’s the pharmacological basis of

        therapeutics, 9th ed. New York, McGraw Hill.

    

        Hart JB & Wallace J (1975)  The adverse effects of amphetamines.

        Clin Toxicol, 8: 179-190.

    

        Henry JA, Jeffreys KS & Dawling S (1992) Toxicity and deaths from

        3,4-methylenedeoxymetamphetamine (“ecstasy”). Lancet, 340:

        384-387.

    

        Johnson J & Milner G (1966)  Psychiatric complications of

        amphetamine abuse. Acta Psychiatrica Scandinavica, 42:

        252-263.

    

        Kalant H & Kalant OJ (1975) Death in amphetamine users: causes and

        rates. Canad Med Assoc J, 112: 299-304.

    

        Kaku DA & Lowenstein DH (1990) Emergence of recreational drug

        abuse as a major risk factor for stroke in young adults. Ann Int

        Med, 113: 821-827.

    

        Kendrick WC, Hull AR & Knochel JP (1977)  Rhabdomyolysis and shock

        after intravenous amphetamine administration. Ann Int Med, 86:

        381-387.

    

        Klawans HL (1968) Chlorpromazine vs. amphetamine. New Engl J Med,

        279:329.

    

        Kramer JC, Fischman VS & Littlefield DC (1967) Amphetamine abuse.

        Pattern and effects of high doses taken intravenously. JAMA, 201:

        305-304.

    

        Mattson RH & Calverly JR (1968) Dextroamphetamine-sulphate-induced

        dyskinesias. JAMA, 204: 400-402.

    

        Morley JE, Schafer RB, Elson MK, Slag MF, Raleigh MJ, Brammer GL,

        Yuwiler A & Herschman JM  (1980) Amphetamine-induced

        hyperthyroxinemia. Ann Int Med,  93: 707-709.

    

 

        Packe GE, Garton MJ & Jenning K (1990) Acute myocardial infarction

        caused by intravenous amphetamine abuse. Brit Med J, 64:

        23-24.

    

        Reynolds JEF (1996) Martindale; The extra pharmacopoeia, 31st ed.

        London, Pharmaceutical Press.

    

        Schwartz DT (1981) Idiopathic rupture of the bladder. J Urol, 125:

        602.

    

        Selmi F, Davies KG, Sharma RR & Neal JW (1995) Intracerebral

        haemorrhage due to amphetamine abuse; report of two cases with

        underlying arteriovenous malformation. Brit J Neruosurg,  9:

        93-96.

    

        Soong WJ, Hwang BT, Tsai WJ & Deng JF (1991)  [Amphetamine

        poisoning in infants: report of 2 cases]. Chung-Hua-I-Hsueh-Tsa-

        Chih, 48: 228-231.

    

        Stockley IH (1994)  Drug interactions, 3rd ed. Oxford, Blackwell

        Science.

    

        Tuma TA (1993) Depressive stupor following amphetamine withdrawal.

        Brit J Hosp Med, 49: 361-363.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

        ADDRESS(ES)

 

        Authors:    Miss Glady Heedes

                    Senior Pharmacist-in-Charge

    

                    Mr John Ailakis

                    Clinical Pharmacist

    

                    Western Australian Poisons Information Centre

                    Princess Margaret Hospital for Children

                    GPO Box D184

                    Perth, WA 6001

                    Australia

    

                    June 1992

    

        Revised by: Dr Robin Ferner

                    West Midlands Centre for Adverse Drug Reaction

                    Reporting

                    City Hospital

                    Birmingham B18 7Q

                    United Kingdom

    

                    August 1997

    

 

        Peer Review:         INTOX 5 Meeting, September 1992: J-F Deng, R

                             Ferner, Landoni, Maramba, E Wickstrom

    

                             INTOX 10 Meeting, Rio, Brazil, September

                             1997: N Ben-Salah, A Borges, M Mathieu-Nolf,

                             L Murray, M-O Rambourg, R Ferner

    

        Editor:     Michael Ruse, IPCS (June, 1998)

  

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Why People are Turning to CBD for Children with Anxiety? CBD has become a popular OTC treatment that parents give their children, says Doris Trauner, M.D., professor of neurosciences and pediatrics at the University of California San Diego School of Medicine and a physician at San Diego’s Rady Children’s Hospital....

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CBD Oil for Candida

Why People are Turning to CBD for Candida? Candidiasis or thrush is a medical condition caused by Candida albicans, a yeast-like fungus. This type of fungus spreads over within the mouth and throat, and it usually infects men and women alike. Certain cannabinoids, like CBD, have been shown as a...

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