Psychedelics and SSRIs – What do we know?

Psychedelics are being employed all around the world for a variety of purposes. Some use them to have a great time with friends whilst strolling around in a forest. Others deepen their relationship with themselves, their loved ones, nature and their place in the universe. Traditionally many psychedelics have been used in rituals and for healing. Today they are making their re-entry into use by (psycho)therapists. That brings us to the topic of this essay, psychedelics and selective serotonin reuptake inhibitors (SSRIs).

Psychedelics have shown to be of help to people suffering from depression (see the mentioned studies below) and are now being reintroduced to the therapeutic toolkit. But at the same time, many of the patients who can be helped most are currently on SSRIs. So how do we square that circle and find a way for both ways of looking at the problem to coexist? We will take a look at the action of both compounds, the current research on psychedelics (mainly psilocybin), and how people (should) go about combining both modalities.

The research into psychedelics is promising and real-life results from retreats paint a positive picture. We need to remain cautious and future research could be done on how to best combine SSRIs and psychedelics. Currently one stops the former for at least two weeks before starting the latter. But should one start with SSRIs again after that or could psychedelics tackle the underlying psychological problems? Here are our thoughts.

Serotonin, SSRIs, and Psychedelics

“Serotonin is a key neuromodulator known to be involved in brain development, perception, cognition, and mood.” writes Robin Carhart-Harris (2018) for World Psychiatry. It’s one of the most complex neurotransmitters, one about which we don’t know all its secrets. It has many different functions and for this essay, we look mostly at its role in relation to well-being and happiness.

SSRIs work by increasing the amount of serotonin that is available. This is done by limiting the reuptake of serotonin and thus more is available to do its work. The effect of SSRIs should alleviate the symptoms of depression and they seem to have a synergetic effect with psychotherapy (working better together than both alone). But the side-effects are quite significant and many people speak of dampened/flattened emotions and affect.

Still, SSRIs (and other depression drugs) represent a €16 billion market (Zion Research). A market that has done little to dampen the prevalence of depression, a disease that now affects 264 million people worldwide (WHO). And one that disproportionally affects the young at a prevalence of 13% for those between 18-25 (in the US, NIMH). So could psychedelics offer another narrative?

Psychedelics have been shown to not dampen the psychological response to your world, but to give you a new perspective to look at it, a more positive one. Some of the (pilot) studies discussed below have shown a significant decrease in depressive symptoms lasting not days but months. They could offer a way to get people of medical drugs and towards enjoying life more fully.

In your brain, psychedelics allow some novel connections to be made, it allows you to see things in a new light. Some areas (namely the Default Mode Network, DMN) dampens down, while others get more connected (Carhart-Harris et al, 2012). This happens because psychedelics bind to the same receptors as serotonin. The effects of a few hours ‘trip’ can last up to a year.

One reason why psychedelics might work so well is that they are not magic bullets (specifically targeted, SSRIs) but rather magic shotguns*. The underlying (brain chemistry) problems of depression (and other mental illnesses) may also not have one specific (chemical) origin and thus casting a wider net might be more beneficial. This way it can be argued, that because psychedelics do so much in the brain is why they are so effective.

*the magic bullets vs magic shotguns concept is adapted from a paper by Roth, Sheffer, and Kroeze (2004)

The Effectiveness of Psychedelics for Depression

The first clinical study into psychedelics (psilocybin) with psychological support for treatment-resistant depression (two or more treatments already tried) was done in 2016. Carhart-Harris and colleagues (2016) gave 12 trial participants a hefty dose of psilocybin and provided psychological support before, during, and after the trial. Their results speak for themselves and even at three months, the participants reported a markedly reduced amount of depressive symptoms.

In this initial study, 58% of participants had long-term positive effects, something that is unheard of in the treatment of depression, especially when someone has already tried various other methods. Another study by Roseman and colleagues (2018) looked more specifically at brain measures (about which more in a second) but also found that patients “described a greater willingness to accept all emotions post-treatment (including negative ones). These effects were often contrasted with those of their previous depression treatments which they described as working to reinforce emotional avoidance and disconnection. Conversely, psilocybin was said to make emotional ‘confrontation’ more likely, and the accompanying psychological support helped patients achieve an emotional breakthrough (catharsis) and resolution.”

Different Effects in the Brain

In the brain, psilocybin increases the amygdala response to fearful faces (one day after the session), this, in turn, was predictive of how much people were helped by the treatment. The amygdala response is the opposite for people treated with SSRIs. As Roseman and colleagues (2018) put it, “This suggests fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.”

Working on the following thesis by Carhart-Harris (2018) “…serotonin differentially encodes behavioral and physiological responses to uncertainty“, I propose that psychedelics offer a way to reevaluate past behaviour, patterns, and routines and let someone revise this. Whilst on the other hand SSRIs may make this possible not by not actively reevaluating past behaviour, but by dampening the emotional response and thus over time (more gradually) let someone encode/make better behaviours, patterns, and routines.

SSRIs and Psychedelics Together

SSRIs down-regulate the primary serotonin receptor target of psilocybin (5-HT_2A) and thus it’s hypothesized that the use of SSRIs may dampen the effect of psychedelics. One study by Bonson, Buckholtz, and Murphy (1996) showed that (based on structured interviews), 88% of the participants (n=32) who used SSRIs had lower of no effects when using LSD.

Many of the current retreats like Synthesis and Essence advise participants to stop with SSRIs at least six weeks before coming to a retreat. From Synthesis: “If you decide to taper off on your own accord, please make sure to do this under supervision of a licensed medical professional. Synthesis does not recommend tapering off SSRIs and or other medication related to depression. We currently don’t accept anyone who has been on SSRIs and other prescription medication more recently than 6 weeks.”

This seems like sensible advice but on the other hand, also looks like too much precaution. All SSRIs except fluoxetine (Prozac) are out of some’s system within a few days (Harvard, MAPS (page 59), and a good blog by Spirit Pharmacist). So possibly the advice could be more personalized in the future as we learn more about their interaction effects. One other concern to be taken seriously is the possible harm that could be done by tapering off for six weeks (of which in most cases five weeks are without SSRIs in your system).

People who take psychedelics in their own home (recreationally, but in many cases with a specific goal in mind) have often experimented with combining them with SSRIs. The report that you can find online (e.g. on r/psychonaut) indicates that for some the effects of psychedelics are dampened. Generally, the advice by others is also to stop with SSRIs, but that is not always followed. There is also a lot of mention of serotonin syndrome, which the literature describes as something very rare and not something to actively worry about.

Psychedelics Instead of SSRIs

The use of psychedelics and SSRIs together is debatable and without more research, it can’t be said how quickly or how safely they are to combine. I would argue that rather than looking at how to combine both, we should be looking at how to use (and scale up the use of) psychedelics to reevaluate past experiences and live a full life going forward. Although SSRIs have done wonders for many people, they don’t seem to lead to less depression overall and leave many feeling blunted. In a brave new future, I hope that many will be able to use psychedelics to flourish and enjoy life to the fullest.