Serotonin Syndrome and Psychedelics: What You Need to Know
As psychedelics enter the mainstream, including their use in therapy, there is more need than ever to consider the risks associated with their use. Generally, psychedelics are incredibly safe in terms of any physical danger they can pose to users. One major exception to this is serotonin syndrome—a dangerous reaction that can happen when serotonin in the brain gets too high. The medical community especially has been concerned about this possibility–but until very recently scientific research has not been done on this question due to widespread prohibition. Some feel the risk of serotonin syndrome has been considerably overstated by the medical community, others are still worried that it has been understated.
In this article, I’ve carefully sorted through the scientific literature to get an informed and grounded understanding of this risk. Translating the jargon as best I can, I lay out the circumstances in which it’s reasonable to be concerned, and where the fear is likely misplaced.
What Is Serotonin Syndrome?
Serotonin syndrome happens when there’s too much serotonin, a brain chemical that helps regulate mood, sleep, and other functions. Normally, serotonin keeps us balanced. But in very high amounts, it overstimulates certain receptors (especially 5-HT2A and, to a lesser degree, 5-HT1A) and things start to go wrong (Boyer & Shannon, 2005).
Doctors usually describe serotonin syndrome with three clusters of symptoms:
Changes in mood and thinking – confusion, restlessness, hallucinations, or even coma in extreme cases.
Body system overload – racing heart, high blood pressure, fever, sweating, or diarrhea.
Muscle problems – shaking, twitching, rigid muscles, or seizures.
It can range from mild (feeling shaky, sweaty, or nauseous) to life-threatening (seizures, dangerously high fever, or organ failure). How fast serotonin levels rise and how high they get usually determine how serious it becomes (Volpi-Abadie et al., 2013).
How Does It Happen?
Serotonin levels can get dangerously high in a few different ways:
Making more of it – supplements like L-tryptophan give your body extra raw material to make too much serotonin.
Breaking it down less – MAOIs (monoamine oxidase inhibitors) stop the enzyme that clears serotonin, so levels climb.
Recycling less – antidepressants like SSRIs and SNRIs block serotonin’s “reuptake,” letting it hang around longer in the synapse.
Releasing too much at once – certain drugs (like MDMA) cause neurons to dump stored serotonin into the synapse.
Direct stimulation – psychedelics like LSD or psilocybin behave like serotonin and stimulate those receptors.
Most serious cases involve more than one of these happening at the same time—for example, taking an SSRI (recycling less) while also using an MAOI (breaking it down less).
Psychedelics on Their Own: How Risky Are They?
To begin, let’s look at the risk of serotonin syndrome followed by taking psychedelics entirely on their own - that is, without combining them with other psychiatric medications. To do this, we have to break down the world of serotonin-affecting psychedelics into two general categories.
Classic Tryptamines (Psilocybin, LSD, DMT)
Tryptamines are a group of drugs that look a lot like serotonin in their chemical structure. Because of this, they easily “fit” into serotonin receptors and change the way the brain processes information. Well-known tryptamines include psilocybin (magic mushrooms), DMT, and LSD. These are often called the “classic psychedelics.”
With these, the risk is very low. They mimic serotonin at this receptor but do not increase overall serotonin concentration significantly (Nichols, 2016). This explains why, despite decades of recreational and ritual use, there are no well-documented cases of psilocybin or LSD causing serotonin syndrome by themselves at conventional doses (Malcolm & Thomas, 2022).
At extremely high doses, there’s a theoretical possibility because they stimulate 5-HT2A receptors. But in real-world medical literature, there are no confirmed cases of tryptamines causing serotonin syndrome on their own—even at high doses. When problems arise, it almost always involves other drugs, like antidepressants or MAOIs (Halman et al., 2024; Malcolm & Thomas, 2022).
The reason? These psychedelics are partial and selective agonists—meaning they only partly turn the serotonin receptor “on.” This seems to give them a safer profile.
Phenethylamines (MDMA, MDA, Mescaline)
Phenethylamines are a different group of drugs built around a structure that looks more like dopamine. Some phenethylamines are psychedelics, while others are just stimulating without psychedelic effects. Examples of psychedelic phenethylamines include mescaline (found in peyote), MDMA (ecstasy), and synthetic substances like 2C-B.
Some of these psychedelics (like mescaline) behave much more like tryptamines. They mainly stimulate serotonin receptors without causing huge serotonin release. The risk of serotonin syndrome associated with these is very low.
Other psychedelics in this category are more risky because they act on serotonin in multiple ways. For instance, MDMA and MDA don’t just act on 5-HT2A receptors—they also flood the brain with serotonin by forcing it out of storage and slowing reuptake. That makes serotonin levels spike higher than with psilocybin or LSD.
These drugs are a little riskier. Most of the time, MDMA doesn’t cause serotonin syndrome when used alone at conventional doses. To date, there have been no reported cases of serotonin syndrome from MDMA in clinical settings (Makunts et al., 2022). But there are some rare case reports where very high doses (or hot environments, like music festivals) pushed people into dangerous territory (Voizeux et al., 2019; Alo & Kioka, 2024).
Newer Synthetics (2C-I, 2C-B, Benzofurans)
Some newer lab-made psychedelic phenethylamines can be riskier. There are a few well-documented cases of serotonin syndrome from 2C-I and 2C-B taken alone at very high doses (Bosak et al., 2013; Spoelder et al., 2019). “Benzofurans” like 5-APB and 6-APB act a lot like MDMA but may be even stronger in how they raise serotonin. Studies suggest they carry a higher risk of serotonin syndrome, especially if mixed with other serotonergic drugs (Fuwa et al., 2016; Patel et al., 2025). However, even though these drugs are relatively new, many of them have been used recreationally for decades with only a very few confirmed cases of serotonin syndrome at unusually high doses.
The Real Concern: Drug Combinations
Where things get tricky is combinations. Many cases of serotonin syndrome come from stacking different drugs that all affect serotonin in different ways.
Tryptamines + Antidepressants (SSRIs, SNRIs)
Many people prescribed antidepressants wonder if it’s dangerous to take psychedelics while on them. Evidence suggests that classic tryptamines with SSRIs or SNRIs generally do not produce serotonin syndrome. Instead, the more common outcome is blunted psychedelic effects (Malcolm & Thomas, 2022; Halman et al., 2024).
There is only one documented case where polypharmacy tipped the balance: a woman on high-dose venlafaxine, bupropion, and trazodone developed serotonin syndrome after regularly taking a low (but unknown) dose of psilocybin (Amarnani et al., 2024). Still, this appears to be an outlier rather than the norm.
Tryptamines + MAOIs
This is where risks climb. MAOIs block serotonin breakdown, so when combined with tryptamines, serotonin levels can spike. Ayahuasca (which combines DMT with natural MAOIs from plants) is usually safe in traditional settings, but case reports of serotonin syndrome do exist (Ortega et al., 2012).
Most evidence suggests that combining Tryptamines with acute use of MAOIs (e.g. Syrian Rue or Ayahuasca vine) may increase the duration or intensity of psychedelic effects. Conversely, the extended use of pharmaceutical MAOIs over several days to weeks prior to tryptamine use can actually reduce, rather than increase, the psychedelic effects.
The biggest concern is 5-MeO-DMT with MAOIs, which has caused a few cases of serious poisonings and even deaths (Sklerov et al., 2005; Brush et al., 2004).
MDMA + SSRIs
Combining MDMA (a serotonin releaser) with SSRIs (reuptake blockers) is surprisingly not as dangerous as once thought. Instead of causing serotonin syndrome, SSRIs usually dampen MDMA’s effects. People often feel less euphoria because SSRIs block MDMA from working at its main “entry point” (Hysek et al., 2012). One notable exception to this is Wellbutrin, which appears to actually increase the effects of MDMA (Malcolm, 2024).
But here’s the catch: the body effects like increased heart rate and overheating can still happen. So even though it’s not a big serotonin syndrome risk, there is a risk of users getting in physical danger due to overdosing on MDMA in search of the euphoric effects. In rare cases where MDMA was combined with SSRIs and other drugs (e.g., amphetamines, opioids), serotonin syndrome was diagnosed post-mortem (Makunts et al., 2022).
MDMA + MAOIs
This is one of the highest-risk combinations. MDMA pushes out huge amounts of serotonin, and MAOIs block its breakdown. Together, they can overwhelm the system and cause a full-blown serotonin crisis (Luethi & Liechti, 2018).
Phenethylamines with less activity as serotonin releasers or reuptake inhibitors (like 2C-B and mescaline) appear to carry a lower risk of serotonin syndrome when combined with MAOIs. In these cases, the risk appears similar to combining most tryptamines and MAOIs (Rickli 2015; Hondebrink et al. 2018).
So, What’s the Takeaway?
Here’s the bottom line on psychedelics and serotonin syndrome:
Classic psychedelics (psilocybin, LSD, DMT, mescaline) are very unlikely to cause serotonin syndrome on their own.
MDMA and MDA have a low risk in clinical use but can become dangerous at high doses or in overheated settings.
New synthetics like 2C-I, 2C-B, and benzofurans can sometimes cause serotonin syndrome even without other drugs.
Combining any of these psychedelics with MAOIs is the riskiest scenario - with the greatest risk being combining MDMA with MAOIs.
Combining with SSRIs or SNRIs usually blunts psychedelic effects more than it creates danger—but edge cases exist.
Harm Reduction Tips
Don’t stack blindly – Mixing multiple drugs that affect serotonin is the most common trigger for serotonin syndrome.
Be extra cautious with MAOIs – Whether prescription or plant-based (like Syrian Rue), they raise the risk when mixed with psychedelics.
Know that SSRIs/SNRIs may dull effects – This can lead people to take more than intended, which may increase other risks.
Pay attention to environment – Heat and dehydration can make serotonin-related problems worse, especially with MDMA.
Avoid high doses of newer synthetic compounds– The newer or less-researched the drug, the harder it is to predict safety.
Final Thoughts
Serotonin syndrome is real, but in the world of psychedelics, it’s often misunderstood. The actual risk depends on the substance, the dose, and—most importantly—what else it’s combined with. Classic psychedelics alone have an excellent safety track record in this area. Problems usually arise when they’re mixed with antidepressants, MAOIs, or newer synthetic drugs.
By understanding how these risks work, people can make safer choices—whether they’re exploring psychedelics in a therapeutic, spiritual, or recreational context.
Limit of Liability Statement
The information provided in this article is for educational and informational purposes only. It is not intended to encourage, promote, or endorse the use of any drugs, supplements, or medications, whether legal or illegal. Psychedelics and other serotonergic substances can carry significant risks, especially when combined with other compounds. I make no guarantees, assurances, or warranties about the safety or outcomes of any choices individuals may make. Readers are solely responsible for their own decisions, and anyone considering the use of such substances should seek guidance from a qualified medical professional.
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