Cannabis and Antidepressants: Side Effects and Risks

Millions of Americans take antidepressants, regarded as the first-line treatment for depression and other mental health conditions such as anxiety ^[1], and millions of Americans also use cannabis. The CDC estimated that 48.2 million Americans used cannabis in 2019. ^[2] With so many Americans using antidepressants or cannabis, it is important to consider and understand the potential side effects and risks of cannabis use while taking anti-depressants.

Cannabis affects almost every system in the body, and the main effect for most people who use it is to feel high. However, some unwanted experience effects like severe anxiety, panic, paranoia, and psychosis can also occur. ^[3]

Physical effects of cannabis use

Cannabis, also known as marijuana or weed, contains over 400 chemicals, including 60 cannabinoids. The plant, flowers, seeds, and stalks all contain cannabinoids. ^[3] THC amounts vary depending on how cannabis products are created with different plant strains and oils. ^[3] The most potent compound and the most well-known and studied is tetrahydrocannabinol (THC). ^[3] Cannabinol and cannabidiol are two other compounds commonly studied. ^[3]

Cannabis products are typically smoked and inhaled or eaten when combined with food products.

When cannabis is smoked, around 50% of the THC is inhaled and absorbed by the lungs. Within minutes, THC reaches the bloodstream and the brain. ^[3] THCs effects are felt between 30 minutes and 2 hours after ingesting a cannabis product because it takes longer to enter the bloodstream after being processed by the liver and by slow absorption in the gut. ^[3]

Cannabis consumption affects almost every system in the body. The main effect of recreational use is a euphoric feeling described as a “high.” ^[3] Some people can experience adverse effects, such as severe anxiety, panic, paranoia, and psychosis. ^[3] People using cannabis may experience things differently; colors may appear brighter and more intense; they may have altered spatial awareness and impaired perception of time. ^[3]

Heavy, consistent, and long-term use of cannabis may impair people who use it even though they are not high, according to research on their long-term and chronic use of the drug. Long term, heavy use, such as in those with a marijuana use disorder, impairs attention, memory, and the ability to process complex information. ^[3]

How do antidepressants affect the brain?

There are five main types of antidepressant medication: Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and norepinephrine reuptake inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), Monoamine Oxidase Inhibitors (MAOIs), and atypical antidepressants. ^[1] Each one affects the brain differently by targeting different neurotransmitters. ^[4]

The three neurotransmitters most prescribed antidepressants target are serotonin levels, norepinephrine, and dopamine, and they each serve different functions in the brain and body. ^[4]

Dopamine plays important roles in executive functioning (e.g., working memory, self-control, organizing, prioritizing, and problem-solving), learning, motor control, and emotion. ^[4] Serotonin regulates several brain processes, such as regulating mood, perception, anger, and appetite, ^[5] and body functions, such as cardiovascular, bladder, and bowel functioning and control. ^[4]

Norepinephrine plays two roles; one is a neurotransmitter involved in bodily processes such as sleep, stress, focus, and attention. The other essential function is forcing the contraction and rate of the heart and is involved in the flight or fight response. ^[4]

SSRIs are the first-line treatment for depression and anxiety, but SNRIs are also commonly prescribed. The main difference between the two is that SSRIs increase serotonin in the brain, and SNRIs increase serotonin and norepinephrine in the brain. ^[1]

Atypical antidepressant medication, like other antidepressants, change the levels of serotonin, dopamine, or norepinephrine in the brain. However, they work differently and, in some people, are more likely to cause adverse effects.

TCAs interact with five different neurotransmitters; they block alpha cholinergic, muscarinic, and histaminergic receptors, as well as the reuptake of serotonin and norepinephrine. Each drug within the TCA category of antidepressants can affect specific neurotransmitters differently. The way TCAs combine with different chemical structures in the body makes them more likely to produce more significant side effects. ^[6]

MAOIs are a different class of antidepressants. Like other prescription medications, they have several dietary restrictions and are known to cause serious side effects and safety concerns, so they are only considered as a treatment option after exhausting other medication treatment options. ^[7]

What are the risks of mixing cannabis and antidepressants?

CYP1A2 is an enzyme that helps the body break down and eliminate chemicals, hormones, and drugs from the body. ^[8] Smoking marijuana may affect how medications are metabolized by this enzyme and cleared from the body, which results in lower amounts of the antidepressant in your body. This may result in antidepressants not working as well to control the symptoms for which they were prescribed. ^[8]

It is often thought that weed is harmless, but when mixed with certain medications, you may have a higher risk of experiencing side effects or more adverse reactions. There are known drug-to-drug interactions that can occur between weed and antidepressants. These can vary depending on the type of antidepressant you are taking. Here are some of the potential interactions an antidepressant drug with cannabis:

SSRIs

A growing body of evidence indicates that SSRIs like sertraline and citalopram, metabolized by the enzyme CYP2C19, are impacted by concentrations of CBD and THC. ^[9] Because cannabis prevents the body from metabolizing and eliminating SSRIs from the body as it usually would, cannabis can raise the levels of SSRIs in your bloodstream. When SSRI levels are excessively high, it may lead to serotonin syndrome, which can be fatal. ^[10]

SNRIs

Some SNRIs, like duloxetine, is metabolized through the liver and eliminated from the body through different enzymes (CYP1A2). Cannabinoids can interfere with the enzyme, increasing the amount of duloxetine in the blood and a higher likelihood of side effects. ^[8] Severe and potentially fatal side effects are possible, including serotonin syndrome, hyponatremia, hemorrhagic events, and QT interval prolongation, just to name a few. ^[8]

TCAs

Cannabis blocks the enzyme CYP2D6, which can increase the concentrations of SSRIs, TCAs, and other drugs in the blood. Amitriptyline is one TCA that is likely to create significant side effects when combined with cannabis and may lead to life-threatening interactions. Amitriptyline combined with cannabis has caused cognitive changes, delirium, and life-threatening interactions such as sustained supraventricular tachycardia (a dangerous and possibly fatally high heart rate). ^[11]

MAOIs

Cannabis can also interact with MAOIs. MAOI medications such as tranylcypromine, phenelzine, and isocarboxazid can cause these medications to stay in the circulatory system (heart, blood vessels, blood) longer than they should, which means it can cause unpleasant side effects. ^[12]