Does CBD interact with Xanax and other benzodiazepines (tranquilizers and sedatives)?
- Alprazolam (Xanax) is mainly metabolised by CYP3A4 (a type of enzyme that belongs to the CYP450 family), as confirmed by a Japanese study in the Yamagata University School of Medicine(1). Found mostly in the liver and small intestine, the CYP3A4 enzyme is responsible for breaking down many of the medicines that enter the body.
- In a Japanese study published in Life Sciences, it was indicated that CBD (cannabidiol) most potently inhibited the catalytic activity of the human CYP3A system of enzymes(2).
- When the CYP450 family of enzymes is influenced in this way, it leads to higher levels of certain drugs in the system at one time, which can cause unwanted side effects, and sometimes, an overdose(3).
- Authors of a study published in Cannabis and Cannabinoid Research do not recommend that cannabis can or should be used as an alternative or supplement to medically indicated and prescribed benzodiazepines(4).
- Given that the benzodiazepines are metabolized by the same enzymes that CBD inhibits, taking CBD with Xanax or any other benzodiazepine is not recommended. It is crucial to consult with a doctor experienced in cannabis use before including CBD in a regimen.
Can CBD be taken with Xanax?
People who have anxiety may have an imbalance of chemicals in the brain, and Xanax aids in correcting these.
Veterinarians also use Xanax for dogs suffering from anxiety or panic. Even if the U.S. Food and Drug Administration (FDA) has not approved Xanax as veterinary medicine, veterinarians still prescribe this as an “off-label” or “extra-label” drug.
Alprazolam (Xanax) is a benzodiazepine. Benzodiazepines are categorized under a group of medicines called central nervous system (CNS) depressants, which are medicines that calm down the nervous system by acting on the GABA receptors(5).
Enzymes are proteins made from amino acids, and they help speed up chemical reactions in the body.
A family of enzymes, called Cytochrome P450, are essential for the metabolism of many medicines and compounds within the human body.
CYP3A4, which belongs to the CYP450 family, contributes to the detoxification of the bile acid, the termination of steroid hormones activity, and elimination of chemicals in food and medicines.
Alprazolam (Xanax) is mainly metabolised by the CYP3A4 system of enzymes, as confirmed by a Japanese study in the Yamagata University School of Medicine(6).
Mainly found in the liver and the intestine, CYP3A4 is an enzyme involved in the metabolism of almost half the drugs in use today(7).
The drugs affecting CYP3A4 activity inhibit or induce the metabolism of the benzodiazepines metabolized by this enzyme. The enzymes cause side effects or reduce the therapeutic effects of these drugs(8).
There have been no clinical trials or case studies documenting a Xanax and CBD interaction.
However, CBD has been shown to inhibit the cytochrome P450’s ability to metabolize certain drugs, leading to an overall increase in processing times(9).
In a Japanese study published in Life Sciences, it was indicated that CBD most potently inhibited the catalytic activity of human CYP3A enzymes, especially CYP3A4 and CYP3A5(10).
When the CYP450 system is influenced in this way, it leads to higher levels of certain drugs in the system at one time, which can cause unwanted side effects, and sometimes, an overdose(11).
This interaction is due to how CBD interacts with the endocannabinoid system, a complex cell-signaling system in the body. If the side effects are not correctly understood, the risks could be dangerous.
When more of the medication enters the bloodstream than average, it could increase the side effects of Xanax.
Common side effects of Xanax include fatigue, changes in patterns and rhythms of speech, memory problems, poor coordination, lack of appetite, irritability or trouble sleeping.
Less common side effects of Xanax include ear congestion, vomiting of blood, hyperventilation, irregular heartbeats, seizures, and uncontrolled twisting movements of the legs, neck, trunk, or arms(12).
Thus, consult with a doctor experienced in cannabis use before including CBD in a regimen that includes Xanax.
Also, using Xanax with other medications like itraconazole (Sporanox) or ketoconazole (Nizoral) is not recommended, as using any of them together may increase the chance of serious side effects.
However, there may be cases when the combination of Xanax with other medications, such as the ones mentioned above, is unavoidable. In situations like this, the doctor may change the dose or how often Xanax is used, or give special instructions about the use of food, alcohol, or tobacco(13).
Can another benzodiazepine be a substitute for Xanax so CBD oil can be taken?
Cytochrome P450(CYP)3A4 is one of the CYP enzymes catalyzing oxidative metabolism, and is involved in the metabolism of many drugs.
Among benzodiazepines, alprazolam, triazolam, brotizolam and midazolam are mainly metabolized by CYP3A4. Meanwhile, quazepam, diazepam (Valium) and flunitrazepam are partly metabolised by this enzyme(14).
Thus, taking CBD oil with any other benzodiazepine may lead to the same interactions, given that the benzodiazepines mentioned above are metabolized by the same enzymes that CBD inhibits.
Can CBD replace Xanax?
There is no specific study that shows CBD as a safe replacement for Xanax or any benzodiazepine medication.
The only study that came close to examining the possible impact of THC (tetrahydrocannabinol) and CBD among subjects who used benzodiazepine is that of a 2019 study published in the journal Cannabis and Cannabinoid Research(15).
Researchers of the said study found that approximately 45 percent of the subjects had stopped taking benzodiazepine within about six months of beginning medical cannabis. Many of them also reported decreased daily distress due to medical conditions after being prescribed cannabis.
However, medical cannabis given to the subjects contained varying levels of THC and CBD(16).
Thus, it cannot be concluded that it was CBD alone that brought about the improved condition among the subjects who discontinued their use of benzodiazepines.
Also, the distribution of cannabinoid (CBD and THC) proportions was not significantly different among patients who continued and those who discontinued benzodiazepines.
The researchers were not able to gain access to information on cannabis strains, growth and producers. Nor were they able to generalize the results to products that were available in Canada.
Still, study author Chad Purcell and his team from Dalhousie University do not recommend that cannabis can or should be used as an alternative or supplement to medically indicated and prescribed benzodiazepines (17).
Also, one essential reminder is not to stop taking Xanax without checking first with a doctor.
The doctor will want the Xanax dose gradually reduced before completely stopping it, which may prevent a worsening of the medical condition and reduce any possibility of withdrawal symptoms, like convulsions (seizures), stomach or muscle cramps, sweating, tremors, vomiting, or unusual behavior.
Note that Xanax may be habit-forming. Thus, if the medicine is not working as well, do not use more than the prescribed dose, and call a doctor for instructions.
Also, do not take other medications, including prescription or nonprescription over-the-counter medicines or supplements, unless they have been discussed with a doctor(18).
What to Know Before Using Alprazolam
When using medication, the risks must be weighed against its benefits. For taking alprazolam, the following points should be considered:
Tell the doctor of any unusual or allergic reaction to this medicine or any other medicines. Also, tell a healthcare professional of any other forms of allergies, such as allergies to foods, preservatives, dyes, or animals. For non-prescription products, carefully read the ingredients on the package label.
Appropriate studies have not been done on the relationship of age to the effects of alprazolam in children. Safety and efficacy have not been known.
Studies conducted to date have not demonstrated geriatric-specific problems that would limit the usefulness of alprazolam in the elderly.
However, older adults are likely to have unwanted effects (e.g., severe drowsiness, dizziness, confusion, clumsiness, or unsteadiness) and kidney, liver, or lung problems, which may require caution and an adjustment in the dose for patients receiving this medicine.
Studies in pregnant women have shown a risk to the fetus, according to Mayo Clinic. However, the benefits of therapy in a life-threatening situation or a severe disease may outweigh the potential risk.
Studies of alprazolam use in breastfeeding women have demonstrated harmful infant effects, according to Mayo Clinic. An alternative to this medicine should be prescribed, or breastfeeding should be stopped while using this medicine.
Alprazolam and Other Drug Interactions
Specific medicines should not be used together at all. However, in some cases, two different medicines may be used together even if an interaction might occur.
In these cases, a doctor may want to change the dose, or other precautions may be necessary.
When one is taking this medicine, a healthcare professional must know of any of the medicines listed below. Taking this medicine with any of the following medicines is discouraged.
A doctor may decide not to treat individuals with this medication or change some of the other medicines they take.
Taking this medicine with any of the following medications is usually not recommended, but may be required in some cases. If both medicines are prescribed together, a doctor may change the dose, and how often the medicines are used.
For a complete list, click here(19).
A Close Look at Benzodiazepines
An article on Harvard Health says that for many years, benzodiazepines continued to be the most popular prescription tranquilizers and sedatives(20).
Benzodiazepines, sometimes called benzos, have a standard basic chemical structure, and they increase the activity of the receptors for the neurotransmitter gamma-aminobutyric acid (GABA).
GABA inhibits the activity of neurons, slowing down the brain and nervous system, so benzos are calming and promote sleep.
Benzodiazepines differ primarily in how quickly they are absorbed, how long their effects last, and how long they take to leave the system.
Benzodiazepines are also prescribed for acute seizures, severe muscle spasms, tremors, and alcohol and drug withdrawal symptoms. However, their main uses are still in the treatment of insomnia and anxiety(21).
Meanwhile, according to an article posted by the Anxiety and Depression Association of America, benzodiazepines, such as alprazolam, clonazepam, diazepam, and lorazepam, promote relaxation and reduce muscular tension, including other physical symptoms of anxiety.
Benzodiazepines are also frequently used for short-term management of anxiety, such as for minor medical procedures(22).
Long-term Use of Benzodiazepines
In a 2015 study published by Australian Prescriber, the authors said that there are well-recognised harms from long-term use of benzodiazepines. These include dependency, cognitive decline and falls(23).
Over the last two decades, the quantity of benzodiazepines on every prescription has increased, and alprazolam became the second most popular drug(24).
Of specific concern are those who have been taking benzodiazepines for over six months. There are a few indications for long-term therapy, and they are controversial(25).
Benzo-related problems include misuse, dependency, driving impairment, and morbidity and mortality related to overdose and withdrawal(26).
In the elderly, benzos have been linked to cognitive decline, dementia and falls(27). Also, there is evidence of increased mortality with long-term use(28).
In February 2014, in response to a surge in illicit use, alprazolam was rescheduled to Schedule 8. Alprazolam has more significant toxicity in overdose and associated mortality compared with other benzodiazepines(29).
The effect of this rescheduling is yet to be determined, as this barrier to prescribing has placed a new focus on benzo dependence.
However, there is a lack of research on the optimal management of benzo dependence, according to the authors of the review published by Australian Prescriber(30).
Some benzodiazepines, like alprazolam, appear to have a higher propensity for misuse and are more dangerous in overdose.
The reasons for this propensity include perception of intoxication, potency relative to the formulation (e.g. a single 2 mg alprazolam tablet is equivalent to four 5 mg diazepam tablets), shorter half-life and risk of withdrawal phenomena(31).
A common approach is substituting these shorter half-life drugs, such as alprazolam, with more extended half-life drugs, such as diazepam(32).
When tapering benzodiazepines, fewer patients taking more extended half-life drugs drop out.
However, there is a lack of robust evidence supporting substitution. Studies in older patients have found gradual withdrawal without substitution can be successful(33).
Abrupt cessation of benzodiazepines after a period of 1–6 months of use can cause life-threatening seizures so the dose should be gradually reduced(34).
Benzodiazepines and Post-Traumatic Stress Disorder (PTSD)
Benzodiazepines were once the primary agents in PTSD treatment(35).
Individuals with post-traumatic stress disorder (PTSD) show a higher rate of panic disorder than other people. People with panic disorder regularly suffer intense episodes of anxiety, known as panic attacks(36).
Alprazolam and clonazepam have been used extensively, but the efficacy of benzodiazepines against the significant PTSD symptoms has not been proven in controlled studies(37).
These agents are effective against anxiety, insomnia and irritability, but they should be used with great caution because of the high frequency of comorbid substance dependence in patients with PTSD. Patients should be fully informed of the risks and benefits of these medications, including the risks of dependency and withdrawal after abrupt discontinuation.
Benzodiazepines are Not Recommended for People with PTSD or Recent Trauma
Although benzodiazepine drugs are widely used in patients with post-traumatic stress disorder (PTSD), available evidence suggests that they are not sufficient and may even be harmful, concluded a 2015 systematic review and meta-analysis in the July Journal of Psychiatric Practice(38).
“Benzodiazepines are ineffective for PTSD treatment and prevention, and risks associated with their use tend to outweigh potential short-term benefits,” wrote Dr Jeffrey Guina and colleagues from Wright State University, Dayton, Ohio.
They also found evidence to suggest that using benzodiazepines in patients with recent trauma can even increase the risk of developing PTSD.
Potential Ways CBD Helps with Depression and Anxiety
CBD oil, which is derived from the cannabis plant, is available in tincture or vape liquid, or CBD-infused foods and beverages.
In one 2019 Brazilian study, subjects received either oral CBD or a placebo 90 minutes before they underwent a simulated public speaking test(40).
The researchers indicated that a 300-mg dose of CBD was the most helpful at significantly reducing anxiety during the test.
In the study, no significant differences in anxiety levels were observed on the subjects given the placebo, a 150-mg dose of CBD, and a 600-mg dose of CBD.
CBD has also exhibited antidepressant-like effects in some animal studies(42).
These characteristics are associated with CBD’s potential ability to trigger the brain’s receptors for serotonin, a neurotransmitter that regulates mood and social behavior.
For example, other studies have demonstrated that treatment with CBD improved complex, sleep‐related behaviors for people with Parkinson’s disease(43).
Also, animal and test-tube studies have shown that CBD may decrease inflammation and help prevent the neurodegeneration associated with Alzheimer’s disease(44).
In one study, researchers gave CBD to mice genetically predisposed to Alzheimer’s disease, finding that it helped prevent cognitive decline(45).
Though CBD is generally well-tolerated and considered safe, it may cause adverse reactions in some people.
Side effects noted in studies include(46):
- Changes in appetite and weight
CBD also interacts with several medications. Thus, before starting to use CBD oil, discuss it with a doctor to avoid potentially harmful interactions(47).
This reminder is essential when taking supplements or medications that come with a grapefruit warning.
Both CBD and grapefruit interfere with cytochromes P450 (CYPs), the enzymes that are essential to drug metabolism.
One study showed that CBD-rich cannabis extracts have the potential to cause liver toxicity(48).
Although the study above was done on mouse models, there have also been a handful of human studies related to chronic pain, anxiety, and stress.
A 2010 study published in the Journal of Psychopharmacology indicated that CBD oil was associated with a decreased level of subjective anxiety, suggesting that CBD can reduce anxiety in patients experiencing social anxiety disorders(49).
Clinical trials have shown promising results for treating anxiety symptoms with CBD. A 2011 study found that CBD helped lessen anxiety in subjects that were put through a stressful public speaking simulation(50).
A 2015 study published in Neuropathics found parallel evidence supporting CBD’s anxiolytic properties.
The authors stated, “Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with the need for further study”(51).
The National Institute on Drug Abuse (NIDA) recently concluded one of the most comprehensive CBD studies involving human subjects(52).
NIDA uses multiple sources to monitor the prevalence and trends regarding drug use in the United States(53).
Researchers of the said NIDA study evaluated CBD in comparison with THC, Alprazolam, and placebo in healthy recreational drug users to determine whether or not CBD should still be a Schedule I drug or be recommended for deregulation.
Subjects received different doses of the alprazolam capsule for 18 days. Then, a series of assessment questions were given, and vital signs and ECG readings were evaluated. Researchers completed the study in May 2018. However, results for publication are still pending.
The high rate of dependency and misuse among Xanax users may be the reason why there is an interest in alternative, Xanax-free treatments, including CBD oil.
CBD’s antidepressant-like and anxiolytic-like effects have been shown in several studies, such as the 2014 study that was published in the CNS and Neurological Disorders – Drug Targets(54).
However, CBD is also known to interact with several medications. Thus, before using CBD oil, discuss it with a doctor and ask for medical advice to avoid potentially harmful interactions.
To date, the U. S. Food and Drug Administration (FDA) has not approved an application for cannabis for the treatment of any disorder or medical condition except for one cannabis-derived drug, Epidiolex, and three cannabis-related drug products(55).
Epidiolex contains a purified form of the drug substance CBD for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients two years of age and older.
There have been no clinical trials or case studies, specifically documenting a Xanax and CBD interaction. However, taking CBD oil or CBD products with Xanax or any other benzodiazepine may lead to adverse interactions such as elevated levels due to reduced clearance from the body, given that benzodiazepines are metabolized by the same enzymes that CBD inhibits.
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