Why Psychedelics Work Differently for People on Antidepressants

Of course, everyone experiences drug interactions differently and it’s the same with mental health medication – whether you’re mixing your meds with shroom chocolates in a field, or a bump of ketamine at the afters. To ascertain what’s safe, silly, or probably pointless when it comes to psychedelics and antidepressants, VICE hunted down a hive of the world’s most respected minds in drugs research and therapy.

You’ve likely heard of the neurotransmitter serotonin: It helps regulate emotions and is sometimes called the “happy hormone”. SSRI antidepressants principally work by inhibiting the receptors that transport it, thus keeping the brain’s levels of mood-increasing serotonin topped up.

Both LSD and psilocybin (found in magic mushrooms) activate a subtype of your serotonin receptors called 5-HT2A: This is where visuals happen, a hub of the psychedelic experience. SSRI’s blunting of serotonin receptors means that, theoretically, the drug can’t access 5-HT2A to work its magic. Have you ever stood outside a house party, super pumped with a bag of cans, banging on the door while the host doesn’t get your calls to let you in? This is like that. Kind of.

Professor David Nutt, chief research officer of ketamine therapy clinic Awakn and one of the most knowledgeable voices in drugs and psychedelic therapy, confirms this. “Many people using psilocybin and LSD in non-clinical settings report lesser effects if they are on SSRIs,” says Nutt, who has proposed that SSRIs and psychedelics could one day work in tandem in previous research. “But there’s still a lot of uncertainty in this area.”

There’s a lack of data but older research points in the direction of blunting, too: A small-scale 1996 paper with 32 subjects that used antidepressants found that 28 (88 percent) reported a “subjective decrease or virtual elimination of their responses to LSD”.

But is it potentially dangerous? There’s better news here, as Nutt says: “There are no significant adverse effects reported from combining the two at the threshold combination: 200 µg of LSD / 25mg of psilocybin.” However, a review by the John Hopkins Center for Psychedelic and Consciousness Research into the use of psychedelics and the mood stabiliser lithium (mainly prescribed for bipolar disorder) found that 47 percent of 62 online trip reports involved seizures.

As with LSD, a nose through the dusty shelves of Reddit suggests that a greater proportion of antidepressant users report a blunting of psilocybin’s effects when mixed with antidepressants.

A 2022 John Hopkins study, conducted via an online survey, found that “serotonergic antidepressants appear to weaken psilocybin’s effects, relative to a non-serotonergic antidepressant”. In this paper’s case, it compared SSRIs and SNRIs with the NDRI bupropion (better known by brand name Welbutin, which doesn’t work on the serotonin receptors). The paper also suggests these reduced effects with magic mycelium could last three months after someone has stopped taking an SSRI or SNRI.

Reid Robison, chief clinical officer at Numinus therapeutic psychedelic services, suggests a view on why users of mental health medication could record weaker trips. “One part may be a unique ability to put up walls,” he says. “Someone may have a condition of over-control, like OCD, anorexia, extreme anxiety, resulting in tight reins over world experience. That can limit psychedelic experience as much, or more, as an antidepressant dose.”

Whilst this combination is again generally considered safe, there are anecdotal reports of a psilocybin comedown. “The day after shrooms or truffles I feel emotionally flat and very empty,” fluoxetine-prescribed Kate, 27, tells VICE. “This is always at odds my friends who aren’t on antidepressants, who report feeling happier than usual.” Kate has asked for her name to be anonymised for privacy reasons, like others in this piece.

Dr. Matthew Johnson from John Hopkins University says: “It could theoretically be the case that folks with depression are more prone to a low after a psilocybin session and that being on an SSRI might affect it as well. But the definitive studies comparing relevant groups have simply not been done.” The one solid thing we know, he says, is that SSRIs and similar drugs can lead to a reduced psychedelic session.

Many people don’t realise MDMA is classed as a psychedelic, but it bears similarities to LSD and psilocybin in the activation of serotonin. Put simplistically, though, LSD and psilocybin bind to the serotonin receptors without activating the joy-inducing neurotransmitter’s levels in the brain, while MDMA unleashes a biblical flood down your neural pathways.

“There are several studies that gave MDMA and an SSRI to healthy volunteers and compared the effects to MDMA alone. These studies show that even a single dose of an SSRI can reduce the psychological effects of MDMA by as much as 80 percent,” says Matt Baggott, an MDMA research heavyweight and CEO of Tactogen, which develops MDMA-like compounds for medicinal use.

With this in mind, you might consider whether it’s really worth taking in the first place, especially since there’s a lot of speculation that MDMA and SSRIs mixed together also pose the risk of serotonin syndrome. This is a sometimes fatal condition caused by a high level of serotonin in your body, with symptoms ranging from tremors to a coma. But Baggott says “the combination of MDMA and an SSRI in reasonable doses [typically 80mg to 125mg, or around half a pill, depending on its strength] does not seem to be dramatically riskier than MDMA itself” and that “it’s probably clearer for people to think about overheating as a risk of MDMA as opposed to serotonin syndrome”.

MDMA affects your ability to thermoregulate. This, combined with being in environments like sweaty clubs or hot festivals, and dancing whilst not hydrating enough, are the common causes of overheating. 

And what of comedowns? They’ve long been considered an unavoidable symptom of taking ecstasy. So much so that popping over the counter 5-HTP pills (which help the body produce serotonin) post-rave is considered a pretty standard hack to beat comedowns into submission –  despite not being rigorously researched. 

Interestingly, Baggott tells VICE that taking an SSRI after a MDMA roll “probably works” in alleviating a comedown. He points to animal studies that suggest SSRIs given shortly after MDMA may protect the brain from the negative effects of this overstimulation. He also ran a small, unpublished study with people who typically recorded a comedown post-MDMA, and did not normally take SSRIs.

“When I gave them MDMA in a laboratory setting, they performed worse at a demanding cognitive task at both five and 26 hours after MDMA.” In a separate session he gave them MDMA, followed three hours later by the SSRI citalopram. He says that this “prevented MDMA-induced performance difficulties without noticeably changing the main emotional effects of MDMA. This supports the idea that SSRIs can reduce the undesirable after-effects of MDMA.”

This could mean that timing your prescribed antidepressant medication a few hours after you use MDMA helps with the comedown, but of course, this experiment occurred in a controlled lab. It certainly doesn’t mean that the everyday raver should just start popping SSRIs without a prescription – especially with ecstasy pill strength at record, unpredictable levels. 

“Alcohol and other drugs can also add concerns,” says Baggott. “Settings like festivals that require physical endurance aren't the best place for complex or novel drug combinations.” 

Perhaps comedowns are even more about the physical tolls – dancing loads, not sleeping or eating properly – than we realise, as a 2022 article published in A Journal of Psychopharmacology found that clinical use of MDMA did not typically result in a “Blue Monday”.

Ketamine stands alone in that it appears to be unaffected by SSRIs. It’s also generally considered to be a relatively safe combination, which is comforting knowledge with a substance lauded for being “wonky”.

“Ketamine works on a completely different neurotransmitter system – the glutamate – for the most part,” says Robison. “And some of its effects are more independent of the neurotransmitters compared to the other psychedelics.” That’s why you might be able to feel ketamine more intensely than other drugs that cause blunting, like MDMA.

He also points out that ketamine blocks the brain’s “lateral habenula burst mode”. The lateral habenula is a region associated with negative emotions and is not primarily targeted by SSRIs, so taking ketamine in addition to an SSRI might be effective at improving your mood. That’s one of the reasons ketamine has been developed as a medicine and therapeutic tool, helping people with treatment-resistant depression.

“Ketamine helps you feel a little lighter and less stressed out,” continues Robison. “It may only last a week or two, but might be useful for someone needing to be pulled out of an episode, or depression.” Of course, Robison’s observations are regarding prescribed, clinically trialled ketamine – not some untested shard you bought from a man in a cloak at Glastonbury’s Stone Circle. Its likelihood of inducing a comedown in these recreational situations is increased – especially when mixed with alcohol, which can be a dangerous combination regardless.

I know it’s festival season and people are literally slathering to get loose, but please don’t be tempted to come off your meds for a higher than high high without consulting your doctor first – your mind, body and soul will thank you.

@dhillierwrites