Serotonergic Psychedelics and Antidepressants

Serotonergic psychedelics are a subclass of psychedelic substances with a method of action strongly tied to the neurotransmitter serotonin. Serotonin (often referred to as 5-HT or 5-hydroxytryptamine) is a naturally-occurring neurotransmitter which has been linked to positive mood, alterations in mood and affect, certain involuntary muscle control, and countless other functions still being explored. Most novel psychedelics fit within this familiar class of psychedelics and have overlapping pharmacology with their classic predecessors including lysergamides (LSD), tryptamines (psilocybin and DMT), and phenethylamines (mescaline).

serotonin molecule
Serotonin

 

Considering the analogy of a lock & key system, serotonergic psychedelics have very strong structural similarities to the serotonin neurotransmitter (the “key”), and it is well understood that serotonergic psychedelics produce their effect by acting as strong partial agonists at the 5-HT2A receptors (this receptor being the “lock”). How this lock & key process produces the psychedelic experience is still unclear, but it is likely that it acts by increasing excitation in the cortex, possibly by specifically facilitating sensory input from the thalamus. The psychedelic key, in this case, when it arrives at the 5-HT receptor lock, mimics the neurotransmitter serotonin and makes sharper and more active neuronal connections.

5ht2a receptor illustration
representation of the 5-HT2A receptor with its seven helices

 

Considering the analogy of a lock & key system, serotonergic psychedelics have very strong structural similarities to the serotonin neurotransmitter (the “key”), and it is well understood that serotonergic psychedelics produce their effect by acting as strong partial agonists at the 5-HT2A receptors (this receptor being the “lock”). How this lock & key process produces the psychedelic experience is still unclear, but it is likely that it acts by increasing excitation in the cortex, possibly by specifically facilitating sensory input from the thalamus. The psychedelic key, in this case, when it arrives at the 5-HT receptor lock, mimics the neurotransmitter serotonin and makes sharper and more active neuronal connections.

As psychedelics have shown initial promise for hard-to-treat depression and other mental health diagnoses, an often-raised concern relates to the possible risks of the interaction between antidepressant drugs and psychedelics. Many antidepressant medications such as tricyclics, SSRI’s and SNRI’s function by increasing or altering the levels of serotonin in the brain; and 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: serotonin syndrome and a decrease in subjective psychedelic effects.

Serotonin syndrome is a dangerous and potentially adverse drug reaction that is most likely to occur when two compounds that raise serotonin neurotransmission are taken simultaneously. This has also been known to occur after only one such compound, most commonly resulting from an overconsumption of serotonin-modulating antidepressant medication. The severity of serotonin syndrome can vary from mild to life-threatening. Its symptoms are often described as a clinical triad:
• neuromuscular abnormalities (such as tremor or muscle hypertonicity leading to hyperthermia),
• autonomic nervous system hyperactivity (leading to increased heart rate and diarrhea), and
• changes in mental state (such as agitation or delirium).

Although is no empirical data on the interaction between psychedelics and antidepressants, and whether this raises the risk of serotonin syndrome, it is well-known that serotonergic psychedelics have 5-HT agonist properties, and therefore the potential to increase serotonin neurotransmission with coadministration. For this reason, it is recommended to taper antidepressant medication with medical supervision before engaging in any psychedelic therapy or usage.

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 use of SSRIs and tricyclic antidepressants can alter or decrease the subjective effects of the psychedelic experience. Relating back to the analogy of a lock & key, being on antidepressant medications that already increases our serotonin fundamentally occupies the “lock” receptor that a psychedelic key would fit into – making the psychedelic “key” less able to engage and ultimately making one less sensitive to the experience induced by the psychedelic substance.The precise mechanisms underlying the modulation of the psychedelic experience and serotonin neurotransmission by antidepressants are still unclear, but considering the number of individuals considering psychedelic use to address mental health concerns and with the potential risks of dangerous interaction, further research needs to be conducted in order to gain a better understanding.


Sources:
Canal C. E. (2018). Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action. Handbook of experimental pharmacology, 252, 227–260. https://doi.org/10.1007/164_2018_107

Bahi, Camile. (2020). Antidepressants & Psychedelics: What do we know and what could be the risks? MIND foundation. Retrieved from: https://mind-foundation.org/psychedelic-antidepressant-interactions/