Antidepressant Drugs Blunting Subjective Psychedelic Effects
In addition to the risk of serotonin syndrome, the subjective effects of the psychedelic experience may be altered if psychedelics are combined with antidepressants. Anecdotal evidence suggests that the acute use of SSRIs, as well as chronic use of tricyclic antidepressants, can alter the subjective effects of psychedelics. Regarding tricyclic antidepressants, this observation could be related to postsynaptic receptor sensitization and increased dopamine levels, which indirectly lead to an increase in serotonin neurotransmission.
Conversely, chronic administration of SSRIs or MAOIs have been shown to decrease the subjective effects of psychedelics. Concerning SSRIs, a possible reason for this could be that the chronic administration of SSRIs causes downregulation of 5-HT2A receptors. This, in turn, may make someone less sensitive to substances affecting these receptors, such as psychedelics. Therefore, this decrease in subjective effects may result from 5-HT2AR downregulation. Concerning MAOIs, chronic administration has been shown to trigger serotonin receptor desensitization, which could explain the observed decrease in subjective psychedelic effects.
The precise mechanisms underlying the modulation of the psychedelic experience by antidepressants are still unclear, and further research should be conducted in order to gain a better understanding. Moreover, the risk of serotonin syndrome cannot be ignored due to the observation of blunted subjective effects of psychedelics following 5-HT2AR down-regulation. Specifically, it might be the case that serotonin syndrome depends on the rate of occupied 5-HT receptors, whereby a higher rate of occupied receptors could be reached more easily when the global number of receptors is lowered. Moreover, several inter-individual variations, such as genetic variations in the enzymes responsible for drug metabolism, could also play a role in the occurrence of serotonin syndrome!