Top 10 Psychedelics and SSRIs

In this brief review, Robin Carhart-Harris discusses how serotonin is affected quite differently by SSRIs and psychedelics. He proposes the ways in which psychedelics affect serotonin and why they may work to help someone look at their environment in a new, better, way as opposed to conventional chronic medication with SSRIs. Interestingly, he notes that in spite of the prescription rates of SSRIs increasing year on year, widespread SSRI use has not noticeably impacted depression prevalence. He also questions the safety, efficacy, and general philosophy of psychopharmacotherapy.

In this theory-building paper, Robin Carhart-Harris and David Nutt discuss the mechanism of action of both psychedelics and SSRIs. The authors argue that psychedelics act on the serotonin (5-HT) 2a receptor which is responsible for active coping (actively addressing a source of stress) of adversity and that this is mediated by increased neuroplasticity. On the other hand, SSRIs act the 5-HT1a receptor which leads to passive coping (tolerating a source of stress). The theory offers an explanation for the different pathways and outcomes of psychedelics and more traditional medications/ways of coping.

This comprehensive review assesses the safety of combining psychedelics and SSRIs. The researchers describe the signs, symptoms, and risk factors of serotonin toxicity, and outline potential management strategies. Additionally, they identify the major risk stemming from psychotropics such as ayahuasca that contain monoamine oxidase inhibitors (MAOI) and the associated risk of neurotoxicity by increasing levels of serotonin at the synapse. MAOIs are another class of antidepressants that are commonly prescribed to treat depression.

This trial is one of the first studies to directly compare the effects of a psychedelic to that of an SSRI. The double-blind placebo-controlled trial (n=59) compared psilocybin (2x25mg; 3 weeks apart) to escitalopram (SSRI) over a six-week period. Large improvements in depression scores for those suffering from depression in both groups were found. Noteworthily, on the main measure of depression, the Quick Inventory of Depressive Symptomology, there was no significant difference between both groups. The study did find significant differences, favouring psilocybin, on the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, avoidance, flourishing, wellbeing, and suicidality.

MAPS have been making headwind with using MDMA to treat PTSD through various clinical trials which are now in Phase III. In this study, the researchers pooled the results of four Phase II trials (n=50) with MDMA-assisted therapy to explore the effect of tapering antidepressant medication has on treatment outcomes with MDMA. It was found that recently tapering off SSRIs may reduce treatment response, as measured using the Clinician-Administered PTSD Scale.

In this seminal paper, Matthew Johnson and colleagues at Johns Hopkins set out the commonly used guidelines for safety when doing research with psychedelics. It urges researchers to check for (a family history of) psychotic disorders, the need for trust with the monitors, and the risk of an overwhelming trip. In one section, the researchers discuss how certain medications may affect the psychedelic experience and recommend these individuals do not partake in psychedelic research. The authors state that SSRIs may attenuate the response to psychedelics and in some cases may lead to the development of serotonin syndrome (SS).

Although science has come a long way since this publication in 1996, it is one of the few to report the effects antidepressants have on the LSD experience. Katherine Bonson and colleagues investigated the effects of the chronic administration of antidepressants on self-administered LSD through structured interviews using a standardized questionnaire in 32 participants. 28 participants who had been taking antidepressants, including SSRIs for over three weeks, reported a subjective decrease or virtual elimination of their responses to LSD. Even in these early stages of psychedelic research, the authors proposed interactions at the 5-HT2 and 5-HT1A receptors as a possible mechanism of action for the attenuated response.