Discussion: MAOIs & Marijuana

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MAOIs & Marijuana​

Monoamine Oxidase Inhibitors (MAOIs) work by inhibiting the activity of monoamine oxidase, an enzyme responsible for breaking down monoamines (such as serotonin, norepinephrine, and dopamine) in the brain. By inhibiting this enzyme, MAOIs increase the levels of these neurotransmitters, which can help improve mood and alleviate symptoms of depression and certain anxiety disorders.

MAOIs common side effects include dizziness, sleep disturbances, weight gain, and sexual dysfunction. Potential interaction with various medications, leading to serotonin syndrome, a potentially life-threatening condition.

Marijuana (Cannabis). The active components of marijuana, such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with the endocannabinoid system by binding to cannabinoid receptors (CB1 and CB2) in the brain and throughout the body. THC's psychoactive effects are primarily mediated through its action on CB1 receptors, influencing pleasure, memory, thought, concentration, sensory and time perception, and coordinated movement.

Cannabis can impair short-term memory, coordination, and judgment. It also may increase the risk of psychiatric disorders, including psychosis, especially in vulnerable individuals.

The interaction between CBD, THC, and the cytochrome P450 (CYP) system plays a significant role in the pharmacokinetics of cannabis and its potential interactions with other drugs, such as MAOIs. The CYP system is a collection of enzymes responsible for the metabolism of many drugs in the liver. Both CBD and THC can affect the activity of these enzymes, influencing the metabolism and effects of other substances, including MAOIs.

CBD is a potent inhibitor of several CYP450 enzymes, particularly CYP3A4 and CYP2C19. By inhibiting these enzymes, CBD can reduce the metabolism of drugs that are substrates of these enzymes, potentially leading to increased plasma levels of these drugs and heightened risk of adverse effects. The inhibition of CYP3A4 and CYP2C19 by CBD could lead to increased levels of certain MAOIs in the blood, necessitating dose adjustments and careful monitoring for signs of toxicity or adverse reactions.

THC has been shown to both inhibit and induce certain CYP enzymes, though its effects are generally less pronounced than those of CBD. THC can inhibit CYP2C9 and CYP3A4 to a lesser extent, potentially affecting the metabolism of drugs metabolized by these enzymes. The inhibitory action of THC on these enzymes could similarly lead to increased concentrations of MAOIs or other co-administered drugs, enhancing the risk of side effects.

The combination of cannabis with MAOIs introduces complex pharmacokinetic interactions, primarily due to the influence of CBD and THC on the cytochrome P450 system. These interactions can lead to increased plasma concentrations of MAOIs and potentially heightened risks of adverse effects:

• Increased Plasma Concentrations of MAOIs: The inhibition of CYP450 enzymes by CBD and, to a lesser extent, THC can lead to decreased metabolism and clearance of MAOIs, resulting in higher plasma levels. This can enhance both the therapeutic effects and toxicity risk of MAOIs.
• Altered Cannabis Metabolism: Conversely, the presence of MAOIs may also affect the metabolism of THC and CBD, potentially altering the effects and side effects of cannabis. However, the specific impact would depend on the individual MAOI and its own interactions with the CYP system.
• Risk of Serotonin Syndrome: Both MAOIs and cannabis, particularly CBD, may increase serotonin levels. The combination could theoretically elevate the risk of serotonin syndrome, a potentially life-threatening condition characterized by symptoms such as confusion, agitation, rapid heart rate, and fluctuating blood pressure. The development of such a syndrome is unlikely, but the chances are not zero.
• Enhanced Pharmacodynamic Effects Beyond pharmacokinetic interactions, the combination of cannabis and MAOIs could result in additive or synergistic effects on mood, cognition, and cardiovascular function, necessitating caution.

It is also worth noting that MAOIs as antidepressants are most often used to treat psychological and psychiatric problems. The use of psychoactive substances against the background of treatment with psychoactive drugs in any case reduces the effectiveness of treatment, destabilizes the already disrupted brain systems, and increases the risks of exacerbations and adverse reactions.

We have not come across confirmed data on acute and fatal conditions associated with this combination. At the same time, there is no evidence of solid worthwhile positive recreational effects that could cover the risks of this combination.

Considering the above, we recommend treating this combination with great caution.