Marijuana addiction and your genes: what the science shows

Cannabis (marijuana) is legal for adults in Canada and in many US states, and people hear conflicting claims about whether it is addictive. The short answer is that cannabis can be addictive, and some people are more at risk than others. Genes are part of the reason, along with age at first use, how often and how much a person uses, and their mental health.

This article explains what genetic studies have found about cannabis addiction, how it is linked with depression and schizophrenia, and where pharmacogenetics fits in: how your genes affect the way your body processes THC, and which medications interact with cannabis.

Is cannabis addictive?

Yes. Like other substances that affect the brain, cannabis can lead to addiction, called cannabis use disorder. People with cannabis use disorder keep using cannabis despite problems at work, school or home, find it hard to cut down, and may have withdrawal symptoms such as irritability, poor sleep and low appetite when they stop.

A large US survey estimated that about 9% of people who use cannabis develop dependence at some point in their lives. That is lower than for nicotine, alcohol or cocaine, but cannabis dependence tends to develop sooner after first use: half of the cases appeared within about five years. The risk is higher for people who start young, use daily, or have other mental health or substance use problems.

What did the JAMA Psychiatry study find?

Studies of twins and families have long shown that genes explain part of the risk of cannabis addiction, but for many years no specific genetic variants had been confirmed. In 2016, a genome-wide association study published in JAMA Psychiatry analyzed the DNA of almost 15,000 African American and European American participants. It found variants in three regions, in or near the genes RP11-206M11.7, SLC35G1 and CSMD1, that were linked to the severity of cannabis dependence. The authors described these as the first specific risk variants identified for cannabis dependence. Several of the genes involved play roles in brain development and in how nerve cells handle calcium.

What have larger studies found since?

Genetic studies of cannabis use have grown much larger. A 2018 study of more than 184,000 people identified several genetic regions linked to ever having used cannabis, including the gene CADM2, which has also been linked to risk-taking. In 2023, a study of more than one million people from European, African, admixed American and East Asian ancestries found 22 genetic regions linked to cannabis use disorder in people of European ancestry and a few more in other ancestry groups.

These results show that the genetic risk of cannabis addiction is spread across many genes, each with a small effect. No single gene determines whether a person will become addicted. Currently there are no clinically validated genetic tests to predict the risk of cannabis addiction or risk of cannabis-induced psychosis.

How are cannabis addiction, depression and schizophrenia linked?

The 2016 JAMA Psychiatry study also found that the genetic risk of cannabis dependence overlaps with the genetic risk of major depression, and that variants in genes linked to schizophrenia were associated with cannabis dependence. The 2018 study found genetic overlap with smoking, alcohol use, schizophrenia and risk-taking, and its analysis suggested that genetic risk of schizophrenia may increase the likelihood of using cannabis.

There are several possible explanations, and they are not mutually exclusive. Some of the same genetic variants may contribute to several conditions. Some people with depression or psychotic symptoms may use cannabis to cope with how they feel. And cannabis use itself, especially frequent use of high-THC products, is linked to a higher risk of psychosis in some people. If you have a personal or family history of psychosis or schizophrenia, talk to your doctor before using cannabis.

Does cannabis help chronic pain?

Many people use medical cannabis for chronic pain, but the benefits are smaller than often claimed. A 2021 international clinical practice guideline, based on a series of systematic reviews, found only small to very small improvements in pain, physical functioning and sleep. It made a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids only when standard care is not enough, with shared decision-making about the benefits and harms.

Cannabis has also not been shown to replace opioids. In a four-year Australian study of more than 1,500 people with chronic non-cancer pain who were prescribed opioids, those who used cannabis did not have less pain, and there was no evidence that cannabis reduced their opioid use. Learn more in our article on medical marijuana for chronic pain.

Genes do matter for some pain medications. People who are CYP2D6 poor metabolizers convert little or no codeine (in Tylenol No. 3, for example) or tramadol into their active pain-relieving forms, so these medications may not relieve their pain. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend that poor metabolizers avoid codeine and tramadol and use a different pain medication. This does not apply to every opioid: for oxycodone (in OxyContin and Percocet), CPIC found the evidence too limited to make a genotype-based recommendation.

How do your genes affect how you process THC?

THC (delta-9-tetrahydrocannabinol), the main compound in cannabis that causes a "high", is broken down in the liver mainly by the enzyme CYP2C9, with help from CYP3A4. The CYP2C9 gene has common variants that reduce the enzyme's activity. In a study of 43 healthy volunteers, people with two copies of the CYP2C9*3 variant had about three times as much THC in their blood after an oral dose as people with two normal copies, and people carrying CYP2C9*3 tended to feel more sedated.

The US Food and Drug Administration (FDA) lists CYP2C9 intermediate and poor metabolizers in its table of pharmacogenetic associations for dronabinol, a prescription form of THC: these people may have higher drug levels and a higher risk of side effects, and should be monitored. The effect is likely to matter most for edibles and other products taken by mouth, which pass through the liver before reaching the rest of the body. A 2019 study that modelled THC levels in healthy volunteers with known CYP2C9 genotypes found that the liver's clearance of THC depends on CYP2C9 genotype. It also concluded that when THC is inhaled, its elimination depends mainly on blood flow through the liver, so changes in CYP2C9 activity are expected to matter less than with edibles.

Reduced CYP2C9 function works much like taking a medication that blocks the enzyme: either way, THC is cleared more slowly. If you are a CYP2C9 intermediate or poor metabolizer, a usual dose of an edible may affect you more strongly and for longer.

Which medications interact with cannabis?

Cannabis can change how other medications work, and other medications can change how cannabis affects you. Examples include:

• Cannabidiol (CBD) and clobazam. CBD can block the enzyme CYP2C19, which raises the levels of the active form of clobazam, an anti-seizure medication. People who are CYP2C19 intermediate or poor metabolizers already have higher levels, and the FDA recommends dose adjustments for them.
• Smoking cannabis and clozapine or olanzapine. Smoking cannabis, like smoking tobacco, speeds up the enzyme CYP1A2, which lowers the levels of these antipsychotics. When a person stops smoking, levels can rise within days, sometimes enough to cause side effects.
• Medications that cause drowsiness. Combining cannabis with opioids, benzodiazepines, sleep medications, some antidepressants or alcohol increases drowsiness and slows reaction time.

Always tell your doctor and pharmacist if you use cannabis or CBD products, including occasionally, so they can check for interactions.

How can Pillcheck help?

Pillcheck does not test for genetic risk of addiction. It shows how your genes affect the way your body processes medications. Pillcheck reports on CYP2C9, which affects THC and many other medications, as well as CYP2D6 (codeine, tramadol and many antidepressants), CYP2C19 (clobazam, many antidepressants and clopidogrel) and CYP1A2. A Pillcheck pharmacist reviews your results together with your current medications, including any cannabis or CBD products you use, and can share recommendations with your doctor. If you use cannabis to manage mood or anxiety, learn more about Pillcheck for mental health.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• Cannabis can be addictive. About 9% of people who use it develop dependence, and the risk is higher with early, frequent or heavy use.
• Genes explain part of the risk. Large studies have found many genetic regions, each with a small effect, and genetic links with depression and schizophrenia. Currently there are no clinically validated genetic tests to predict the risk of cannabis addiction or risk of cannabis-induced psychosis.
• For chronic pain, cannabis offers small benefits at best, and it has not been shown to replace opioids.
• The CYP2C9 gene affects how quickly THC is cleared. People with reduced CYP2C9 function may have higher THC levels, especially from edibles.
• Cannabis and CBD can interact with medications such as clobazam, clozapine and olanzapine, and add to the drowsiness caused by opioids, benzodiazepines and alcohol.

Frequently asked questions

Can a genetic test tell me if I will become addicted to cannabis?

No. The genetic risk of cannabis use disorder is spread across many genes, each with a small effect, and environment and mental health matter too. Currently there are no clinically validated genetic tests to predict the risk of cannabis addiction or risk of cannabis-induced psychosis.

Why does the same edible affect me more than my friends?

Many factors play a role, including how often you use cannabis, your body weight and what you have eaten. Genes can matter too: people with reduced CYP2C9 function clear THC more slowly, so the same dose can lead to higher levels and stronger, longer-lasting effects.

Is CBD safe to take with my medications?

Not always. CBD can block metabolism of some medications by competing with key liver enzymes, including CYP2C19, and raise their levels. Ask your pharmacist to check your medications before you start CBD.

If codeine doesn't work for me, will cannabis work instead?

Not necessarily. If codeine doesn't relieve your pain, you may be a CYP2D6 poor metabolizer, and other pain medications that do not depend on CYP2D6 may work better. Cannabis offers only small benefits for chronic pain in studies. Talk to your doctor or pharmacist about your options.

References

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9. Wolowich WR, Greif R, Kleine-Brueggeney M, Bernhard W, Theiler L. Minimal physiologically based pharmacokinetic model of intravenously and orally administered delta-9-tetrahydrocannabinol in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2019;44(5):691-711. doi:10.1007/s13318-019-00559-7
10. US Food and Drug Administration. Table of pharmacogenetic associations. fda.gov
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