Research Explores if Cannabis and Psilocybin Will Interact with Antidepressants

Note: Veriheal does not support illegally consuming therapeutic substances like cannabis and psilocybin but acknowledges that it transpires because of the current illicit status of both, which we strive to change by advocating for research, legal access, and responsible consumption. Always consult a physician before attempting alternative therapies.

Cannabis and psilocybin have both been used to alleviate depression and anxiety, but did you know that both have the potential to interact with commonly used antidepressants? The consensus of most studies implies that some antidepressants and cannabinoids may mix okay while others will not. Let’s explore antidepressants and their interactions with both of these alternative plant medicines.

Antidepressants Explained

Antidepressants are a type of medication that helps relieve the symptoms of depression and anxiety. Antidepressants do not cure depression and may require experimenting with the guidance of a medical professional for several weeks until you find one that effectively treats symptoms while having minimum side effects.

Types of Antidepressants:

The type of antidepressant one is prescribed depends on the symptoms presented, possible side effects of the medication, family history, other medications being consumed and their interactions, and any other health conditions. The different types of antidepressants available include:

• Selective Serotonin Reuptake Inhibitors (SSRIs), such as fluoxetine, citalopram, and escitalopram
• Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), such as desvenlafaxine and duloxetine
• Atypical Antidepressants, such as vortioxetine
• Tricyclic Antidepressants (TCAs), such as amitriptyline and desipramine
• Monoamine Oxidase Inhibitors (MAOIs), such as phenelzine
• A Combination, such as taking an MAO-B with SSRIs, which is a common pairing in conditions such as Parkinson’s.

Potential Side Effects of Antidepressants 

Antidepressants have the power to help boost mood and help patients overcome the symptoms of depression. This also allows them to get back into the groove of participating in the activities they love and improve their overall quality of life. Medication is taken daily to increase the chances of working and maintain effectiveness. There are common side effects of antidepressants that one should be aware of.

Side effects of consuming antidepressants include the following (but may vary among types and individual experience):

• Nausea
• Weight gain
• Loss of sexual desire or arousal
• Fatigue and drowsiness
• Insomnia
• Blurred vision
• Dry mouth
• Constipation
• Agitation
• Irritability
• Increased anxiety
• Caring less about others
• Feeling suicidal
• Feeling emotionally numb or not like oneself
• Withdrawal

The potential side effects of antidepressants vary in likelihood, so different treatment options for depression should be first explored and discussed openly with your provider. You should report any side effects to your healthcare provider, or seek emergency care for suicidal thoughts or changes in mood.

Psilocybin Interaction with Antidepressants

Although psilocybin shows promise of treating depression, including those normally deemed hard-to-treat, the biggest concern is the possible risks associated with the interaction between antidepressants and psilocybin. Neuroscientist Camile Bahi explains that when looking at the safety of consuming psilocybin, it has been found to be relatively safe during clinical trials with the only reports including mild headaches, small increases in blood pressure, and nothing else that would require medical intervention. Unfortunately, there is still scarce research available on the exact interactions between psilocybin and antidepressants, mostly due to the illegal drug status of psilocybin in most locations.

Bahi explains that while psilocybin may be effective as an alternative for antidepressants, the interactions between psilocybin and antidepressant medications include risks of serotonin syndrome and a decrease in the psychedelic effects of psilocybin. While a decrease in the psychedelic effects of “magic mushrooms” may make recreational users who are also on antidepressants a bit sad, the focus here is on medical interactions. The most significant concern being that regular use of psilocybin combined with antidepressants could potentially leave patients at risk of serotonin syndrome; therefore, antidepressants may need to be stopped before starting psilocybin.

Serotonin Syndrome Explained

According to Bahi, serotonin syndrome is a “potentially lethal adverse drug reaction that is most likely to occur when two compounds are able to raise serotonin neurotransmission” when these two compounds are taken at the same time. Unfortunately, it was reported that 85% of physicians were not aware that this condition even existed. This problem, along with that of the syndrome’s lack of symptom specificity, makes it hard to diagnose and treat.

Bahi explains that the symptoms of this condition are often described as “a clinical triad,” which includes neuromuscular abnormalities (such as tremors), autonomic nervous system hyperactivity (such as increased heart rate), and changes in mental state (such as becoming agitated). The pathophysiology of this syndrome is not fully understood yet but appears to present as a result of producing excess serotonin neurotransmission—which could happen if one is regularly consuming psilocybin in combination with an antidepressant—both of which boost serotonin levels. Serotonin syndrome may occur with an accidental or intentional overdose of antidepressants and serotonergic agents like psilocybin, MDMA, and the like. Bahi concludes by stating that:

“It is impossible to state with certainty what the relationship is between serotonin syndrome and the pharmacology of psychedelics. Current knowledge is insufficient for formulating an accurate assessment of the risk, or a model of the modulation of both subjective and physiological effects arising from the combination of antidepressants and psychedelic substances.”

Cannabis Interaction with Antidepressants

Both cannabis and antidepressants work to boost the “happy chemicals” in the brain such as dopamine. This may make consuming both seem appealing; however, the overall research on interactions between the two is still inconclusive. There is a theoretical risk to mixing cannabis with antidepressants. The enzymes that metabolize cannabinoids also metabolize certain antidepressants on this list. Any such serious interaction has yet to be seen according to updated and reviewed data, and serious interactions between cannabis and antidepressants are not as likely and documented as those between psilocybin and antidepressants (discussed above).

Research suggests that cannabis and tricyclic antidepressants (TCAs) are not a great combo as TCAs become elevated leading to a domino effect of symptoms such as tachycardia, dry mouth, and constipation. MAOI medications are also not recommended to use in conjunction with cannabis given the already long list of negative interactions these medications have when combined with certain foods and drugs.

The 2019 review study cited above investigated potential drug interactions with cannabis:

“…Russo (2016) mentioned that in extensive clinical application including complex drug regimens with opioids, tricyclic antidepressants, anticonvulsants etc, no drug interactions have been observed that would contraindicate or preclude the use of nabiximols with any specific pharmaceutical, although additive sedative effects are always possible [62]. MacCallum & Russo (2018) recently pointed out that there is no drug that cannot be used with cannabis, if necessary [63]. “

Talk to Your Doctor Before Mixing the Two 

The study concludes that there is still not enough clinical evidence on the interactions between pharmaceutical drugs and cannabis. Therefore, it’s important for the use of medical cannabis and certain drugs to be closely monitored—especially for those living with chronic diseases and kidney and liver conditions.

Essentially, the interaction between cannabis and antidepressants depends on the type of antidepressant and on the individual too. Anecdotal evidence will suggest that there isn’t much risk, but until research suggests otherwise, there isn’t a definite answer. This is why patients should always discuss using cannabis with their provider before attempting cannabis therapy to get a professional assessment on how it can impact the success of their current medications. Therapy, such as cognitive behavioral therapy (CBT) with a licensed provider, has also been shown to be about equally efficacious as taking antidepressants, and both should be first carefully considered between you and your provider.

Antidepressant Properties of Cannabis and Psilocybin

As discussed above, consuming psilocybin and antidepressants together may cause an increase in serotonin neurotransmission, and it can put patients at risk for developing serotonin syndrome. Thus, it’s best to avoid combining them. The same cannot be said for replacing antidepressants with psilocybin and cannabis, although science can not yet guarantee their entire safety alone or in combination. Anecdotal reports suggest that psilocybin and cannabis can be used synergistically, or in isolation, for effective antidepressant effects when taken properly.

Cannabis has been shown to assist with mood regulation and alleviation of depression. In fact, a study found that 95% of participants experienced significant relief from their depression symptoms. The cannabinoids in cannabis are said to regulate anxiety and depressive symptoms, much like antidepressants due to the fact that both interact with the endocannabinoid system (ECS).

Chronic antidepressants can modify the expression of dopamine, serotonin, norepinephrine, and CB1 receptors in the ECS to regulate mood and anxiety through the brain, while cannabinoids bind to the same receptor and also impact its expression. The CB1 receptors are located throughout the brain and assist with the functioning of emotion as well as response to stimuli.

Cannabinoids also have the ability to encourage homeostasis in the body through regulation of the ECS, which is similar to antidepressant treatments modulating the ECS system. It is also important to note that the cannabinoid called cannabidiol (CBD) was not linked to symptom relief; instead, it was tetrahydrocannabinol (THC) that showed the most promise. So ensure that your cannabis products are full-or broad-spectrum. Terpenes in cannabis are also thought to add antidepressant effects.

Research Comparing Psilocybin and Antidepressants

Not much research exists that compares psilocybin to traditional depression treatments. One study from John Hopkins University found that psilocybin was correlated with antidepressant effects in 24 participants. NPR covered JHU’s psilocybin study, which shows more supporting evidence for psilocybin’s potential antidepressant effects. However, the first study of such research directly comparing psilocybin and an antidepressant medication (the selective serotonin-reuptake inhibitor escitalopram) was published in April 2021. This randomized, double-blind, and controlled study found that the two therapies were about equal in their antidepressant effects in a 6-week period.

Despite little being known about the interactions between consuming cannabis and psilocybin in combination with antidepressants, what is known suggests that it is better to avoid a regimen of combined consumption of the organic solutions with the manmade ones. However, combining cannabis and psilocybin as a replacement for antidepressants may be worth considering if you want to steer clear of pharmaceutical medication. In order to do this successfully, always consult with your physician before weaning off of antidepressants or combining them with other therapies to ensure that there is minimal impact on your mental and emotional health.