SRI and non-SRI patients experience similar antidepressant effects of psychedelics

Increasing research is showing that psychedelics hold promise as potential new treatments for mental health conditions. However, how psychedelics interact with commonly prescribed antidepressants – serotonin reuptake inhibitors (SRIs) – is largely unknown.

This is a barrier to the advancement of psychedelics as mental health treatments, as those who may need these treatments the most are likely to be taking, or have taken at some point, SRIs.

Typically, due to this lack of knowledge on the safety of taking psychedelics when on antidepressants, many participants of clinical trials are required to stop using them for two weeks before taking part in a trial.

Additionally, some research has suggested that those taking SRIs may experience less therapeutic effects from psychedelics, such as psilocybin, than those who have never taken them. For example, one study found that patients who had been taking the antidepressant Escitalopram experienced fewer therapeutic effects than those who had not.

Now, a new survey study of people using psychedelics in real-world settings has investigated the interaction between these two medicines, comparing the acute psychedelic effects and subsequent changes in wellbeing and depressive symptoms in those on psychiatric medication and those who are not. 

For this study, the team analysed the subjective differences and changes in wellbeing and depressive symptoms in participants both before and after the psychedelic experiences.

They found that patients who were not taking SRIs experienced significantly more intense subjective effects than those who were not. This group also experienced stronger mystical experiences and more challenging emotional breakthrough experiences.

However, they also found that both groups had similar drug-induced visual experiences.

Importantly, they found that the group who were taking antidepressants reported similar improvements in wellbeing and depressive symptoms following the psychedelic experience to those who were not taking them. 

Speaking to Psychedelic Health, study co-lead Tommaso Barba, at the Centre for Psychedelic Research, Imperial College London, commented: “I think we don’t have a definitive answer yet, the combination seems to work and it seems to induce a therapeutic response, if this response is lower than on people who are not on these drugs is still a sort of open question. 

“Our study suggests it’s not lower, but it’s a naturalistic survey study, with overall small sample and lack of laboratory controls.”

Barba points to a study that suggests people on SRIs have reduced intensity of the acute psychedelic experience, but notes this only occurred in half of the participants, and highlights another study that showed that psilocybin therapy seems efficacious in patients that were also using SRIs, as the reductions in depression were comparable to another study that involved patients who were not on medications.

“What is lacking now is a randomised trial in which two groups, one on SRI and one not, are directly compared in laboratory settings,” said Barba.

“I think that the current evidence, with other results, show that taking people off SRIs before psilocybin therapy was associated with reduced therapeutic efficacy compared to people who were unmedicated at the entrance of the trial, suggesting that discontinuing medications is not warranted, and maybe people are not required to do so and could be kept on them.”

In their paper, the research team concludes that: “Individuals presumed to be on serotonergic antidepressants during psychedelic use display reduced subjective effects but similar antidepressant effects compared to those not undergoing SRI treatment.

“Further controlled research is needed to comprehend the interplay between serotonergic antidepressants and psychedelics, illuminating potential therapeutic benefits and limitations in clinical contexts.”

For example, serotonin has been implicated in several major psychiatric disorders, with low levels contributing to conditions such as depression. SRIs work by making more serotonin available in the brain.

As highlighted by Thomas and Malcolm in a 2022 paper, mental health conditions that are targeted by psychedelic medicines are most often managed with SRIs, “so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.”

Serotonin toxicity is a condition that is often induced when two or more serotonin-elevating drugs are used in combination. The condition leads to too much serotonin within brain synapses and can sometimes be life-threatening, causing symptoms such as seizures, irregular heartbeat and unconsciousness.

Thomas and Malcolm emphasise that due to the ability of psychedelics and SRIs to increase serotonin, some combinations may present a significant risk of serotonin toxicity.

In this survey study, the researchers highlight that only two modern studies have investigated the interaction between SRIs and psychedelics which have presented partially contradictory results.

The team has also emphasised that their findings could have implications for modifying research design and inclusion criteria for certain clinical studies, as well as for informing future medical use of psychedelics in order to maximise positive outcomes and the efficacy of the treatments.

The study team included leading psychedelic researchers Tommaso Barba, Jessica Barbut Siva and Hannes Kettner at the Centre for Psychedelic Research, Imperial College London; Joanna Kuc, Experimental Psychology, University College London; Professor Robin Carhart-Harris, Ralph Metzner Distinguished Professor in the Department of Neurology at the University of California, San Francisco; Dr David Erritzoe, Clinical Director in Centre for Psychedelic Research & Clinical Senior Lecturer in Psychiatry at Imperial College London; Professor David Nutt, Professor of Neuropsychopharmacology at Imperial College London.