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Most of the recent clinical trials about psychedelics either asked participants to stop taking their antidepressant medication before enrolling in studies or rejected patients that were taking antidepressants. Similarly, some psychedelic retreat centers only allow participants who are not currently taking antidepressants.

As psychedelics have shown initial promise in treating hard-to-treat depression,1,2 an often-raised concern relates to the possible risks of the interaction between antidepressant drugs and psychedelics. This article aims to investigate this issue and provide some preliminary answers.

Classical psychedelics are defined by their ability to act as serotonin receptor agonists, particularly at the Serotonin 2A receptor (5HT2AR).3,4 Accordingly, many of the subjective and biological effects of classical psychedelics are blocked after administering 5HT2AR antagonists such as ketanserin.5,6 Classical psychedelics have been shown to be relatively safe in the context of clinical trials, with notable side effects being mild headaches, small elevations in blood pressure, and acute anxiety, none of which commonly require medical intervention.2,7,8 Although the exact mechanisms of action and the pharmacokinetics of these molecules are not completely understood, two particular issues have been raised when it comes to their interaction with antidepressant drugs: the so-called serotonin syndrome and a decrease in subjective psychedelic effects.

SEROTONIN SYNDROME: ANTIDEPRESSANTS AND PSYCHEDELICS

Serotonin syndrome is a potentially lethal adverse drug reaction that is most likely to occur when two compounds able to raise serotonin neurotransmission are taken simultaneously. However, it is also known to occur after only one such compound.9 Serotonin is produced from the amino acid L-tryptophan and its effects are regulated by re-uptake mechanisms, feedback loops, and enzymes such as monoamine oxidase. Serotonin acts on the nervous system both at the central and at the peripheral level. In the central nervous system, it plays a role in awareness, behavior, muscle tone, body temperature, and pain. In the periphery, it regulates vascular tone, nociception (pain perception), and gastric activity.10 The effects of serotonin are mediated through 7 receptors types (from 5-HT1 to 5-HT7) and at least 14 subtypes.3

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