Psilocybin, the active ingredient in magic mushrooms, has been shown in research studies to provide relief for end-of-life anxiety and depression (Grob et al, Griffiths et al, Ross et al) alcohol and tobacco addiction (Bogenschutz et al, Johnson et al) obsessive compulsive disorder (Moreno et al), and treatment-resistant major depression (Carhart-Harris et al).
But while the responsible use of psilocybin in controlled settings may have important therapeutic value, are there unwanted side effects which can potentially pose a health risk?
Recently, there has been a stir online about whether or not psilocybin or psilocin (psilocybin’s bioactive form in the body) can cause heart valve damage.
With my professional background in hospital-based cardiac rehabilitation and biomedical research, I was alerted by concerned psychonauts and asked my opinion about the likelihood of experiencing cardiac side effects.
Therefore, the purpose of this article is to:
- Evaluate the scientific literature that is currently being used to forward the idea that psilocybin can lead to heart valve damage in micro-dosers, recreational users, and research study participants; and
- Provide recommendations to guide future research in this space.
*Please contact me if you become aware of other relevant research so I may update this article.
Psilocybin’s physiological effects
Psychoactive mushrooms have been consumed for millennia, primarily for ceremonial purposes by indigenous cultures, but it wasn’t until the second half of the last century that they gained widespread attention in western culture and media.
Magic mushrooms and other psychedelic substances elicit mystical transcendent experiences which some users find deeply meaningful, spiritually significant, and which contribute to helping individuals make positive life changes for the better.
Under the effects of psilocybin, regions of the brain that do not normally overlap or cross-talk begin to communicate with each other. The default mode network, or DMN, is the region in the brain associated with your sense of self (or your ego, Latin for “I”). Psilocybin affects the DMN in ways that it temporarily quiets the sense of self and pushes it into the background for the duration of the experience.
The combined effect of hyper-connected brain regions and a quieted DMN allow you to see things from a different point of view, break unhelpful ruminative thinking patterns, and gain new perspectives and insights, all of which can help you reconcile and resolve issues in your life (i.e., depression, anxiety, trauma, and other issues).
Serotonin receptors
The chemical name for serotonin is 5-hydroxytryptamine, or 5-HT for short, and the receptors it acts upon are called 5-HT receptors. Within the 5-HT receptor family, there are different numbered and lettered subtypes referring to different types of receptors that elicit different physiological actions (i.e., 5-HT1A, 5-HT1B, 5-HT2A etc).
Psilocybin is chemically similar to serotonin and acts primarily upon the 5-HT2A receptor in the brain where it exerts its psychoactive effects.
Psilocybin has also been shown to have an affinity for cardiac 5-HT2B receptors, which could, in theory, play a role in heart valve disease.
Psilocybin and heart valve damage
Concern over psilocybin’s potentially harmful effects on heart valves stems from the fen-phen scare in the late 90s, as well as a link between the party drug MDMA and cardiac problems. Several other reports have also implicated serotonin receptors as the link between fen-phen and valve disease (Hutcheson et al, Rothman & Baumann).
The mechanism behind this damage appears to be the drug binding to the 5-HT2B receptor in cardiac tissue, leading to valvular strands and valve dysfunction.
Because psilocybin also has an affinity for cardiac 5-HT2B receptors, in theory, the assumption is that it may induce valve disease via the same mechanisms as other serotonin receptor agonists.
In the following discussion, I’ll break down the research which has been frequently cited on various websites and online forums.
Cardiotoxic effects of psilocin on rats
A 2006 study found that rats injected with 10µg per kg of psilocin showed subendocardial fibrosis and thickening of coronary arteries. Perivascular fibrosis, the deposition of connective tissue around the vessels, with proliferation of fibroblasts and connective tissue growth was also demonstrated. Electron microscopy revealed damage to cellular mitochondria as well.
Limitations
While these findings are certainly concerning, the study’s practical limitations must be put into perspective.
First, animal studies are only models that are suggestive of what could possibly occur in human tissue and are not always directly applicable to human physiology. If this same protocol was repeated in humans, the effects may or may not be the same – to my understanding, this research has not been conducted.
Second, this study did not directly evaluate psilocin’s effects on heart valve morphology. It’s not to say that it didn’t have an effect, but this outcome measure was not explicitly studied.
Third, the investigators injected pure psilocin directly into rats, in contrast to human consumption of the whole mycelial fruit (mushrooms) which must pass through the liver in digestion before entering the blood stream and can have an entirely different metabolic profile.
Depending on the psychoactive mushroom (there are hundreds), there are a number of other bioactive compounds, such as aeruginascin, baeocystin, or norbaeocystin, which could interact and moderate the effects of psilocybin or psilocin in the body.
Mycelial chitin is a fibrous biopolymer that is found in mushroom cell walls and has been shown to have numerous important bioapplications such as immunomodulation, antioxidant properties, cholesterol management, and wound healing.
Chitin is also chemically similar to cellulose, an insoluble fibre, and has been shown to have favourable effects on gut microbiota composition (which we know plays an important protective role in human health).
To put this further info perspective, you could look to the example of pure fructose, which has been shown to elicit adverse health effects in high doses in its purified form. However, fructose found naturally in fruit that is surrounded by other health-promoting constituents like fiber and other phytonutrients has no deleterious effects on human health.
Fourth, psilocin was administered to rats every other day for 12 weeks, which would constitute chronic exposure far greater than that experienced by most recreational mushroom users or research participants.
Also, consuming psychoactive mushrooms, particularly at higher doses, can be a difficult and challenging psychological experience, inducing uncomfortable physical body effects like nausea or vomiting such that it does not lend itself well to frequent abuse.
Fifth, the typical doses consumed by humans both recreationally and in research studies are quite small. The psilocybin content of a mushroom fruit is approximately 1% (more or less depending on growth conditions).
So 1 gram of dried mushroom would yield about 10 mg of psilocybin.
If divided by body weight, then the amount of psilocybin per kilogram would be quite low.
For example, a 70 kg adult consuming 1 gram of mushrooms (containing ~10 mg of psilocybin) would take in around 0.14 mg per kg of body weight.
Mushroom microdosers, on the other hand, usually take an imperceptible sub-threshold dose equivalent to about 1/10th of 1 gram of dried mushroom. So dividing it by 10 yields a dose of around 0.014 mg of psilocybin per kg of body weight. And while microdoses are taken once every three days (72 hours), the regimen is only recommended to be carried out in short one week to three month periods, not for years on end.
Lastly, while this study demonstrated deleterious effects of psilocin on rat cardiac tissue, a 2020 in vitro rat study found that water extracts of psilocybe cubensis and panaeolus cyanescens mushroom did not aggravate endothelin-1-induced pathological cardiac hypertrophy and were shown to protect heart cells from tumor necrosis factor-α-induced injury and cell death.
Psilocybe semilanceata induced heart attack
A 1998 case report published in Clinical Toxicology described an 18 year old man who experienced cardiac arrhythmia and myocardial infarction (heart attack) after ingesting a potent strain of Psilocybe semilanceata mushrooms.
Limitations
The authors reported the patient had been consuming them frequently in the previous month up to his hospitalisation.
Though psilocybin can theoretically be abused like any other drug, it is generally considered safe in moderate doses both recreationally and in supervised research settings.
However, because the human body quickly builds a tolerance to psilocybin, higher doses are required after only a few days of repeated use in order to elicit an effect.
Though the exact quantity of mushrooms consumed is not stated in this case report, it is plausible the patient repeatedly took progressively higher doses of a high potency mushroom to overcome the tolerance and elicit a psychedelic effect, spiking his heart rate and blood pressure and provoking a heart attack.
Though the report outlines a potential risk associated with abusing mushrooms, it does not directly support the theory that psilocybin induces heart valve damage (valvular disease is different than a heart attack).
Meta-analysis on serotonergic medications
A 2019 meta-analysis of multiple studies carried out by Fortier and colleagues (excluding case reports, uncontrolled studies, and in vitro [test tube] studies) found that 5-HT receptor signaling induced by serotonergic appetite suppressants is associated with a direct functional role in pathological heart valve remodeling.
Limitations
First, this meta-analysis effectively established a mechanistic explanation that serotonergic prescription medications (i.e., fenfluramine, dexfenfluramine, and phentermine) act on 5-HT2B receptors to cause heart valve damage, but it does not support the hypothesis that psilocybin (either pure psilocybin or that found in mushrooms) can cause the same problems.
In fact, the authors did not include any studies on psilocybin which, to my knowledge, have not been conducted on humans to assess its effects on heart valves.
Second, fenfluramine and phentermine are pharmaceutical-grade drugs that were taken in higher doses for extended periods of time, as compared to psilocybin (pure or in mushrooms) which is taken infrequently and in small doses.
A study that looked at a dose-response relationship between fenfluramine and valve damage found that severe valvulopathy was observed in individuals who took ≥ 60 mg per day, which is a large contrast to 10-20mg of psilocybin as a single infrequent dose.
Lastly, back in the 1990s, there were a significant number of individuals directly harmed by fen-phen, enough so that it prompted FDA action, widespread drug recalls, and thousands of lawsuits.
By contrast, despite the countless number of people that have consumed psychedelic mushrooms since the 1950s or participated in recent psilocybin research trials, I am aware of no published case reports in the biomedical literature that have identified psilocybin as source of heart valve damage.
Future research on psilocybin and heart valve damage
As our understanding of psilocybin as an effective treatment for mental health issues deepens, it will be increasingly important to be able to demonstrate its safety profile before it’s formally approved for medical use.
Initially, future in vitro and animal studies should evaluate the effects of purified psilocybin and psilocin on heart valve morphology versus that found in whole mushrooms.
If valve damage is present, are there any differences between pure vs whole mushroom psilocybin and psilocin, and what mechanistic explanation could account for these differences?
Are there other factors in mushrooms or aspects of the digestive process which might moderate any potentially harmful aspects to purified psilocybin or psilocin.
Are there any dosage or frequency thresholds above which there might be an increased risk of harm to heart valve tissue?
In ongoing psychedelic research, inclusion of echocardiographic analyses of cardiac valve leaflets before and after psilocybin administration would be useful.
Research evaluating recreational psilocybin users should stratify participants by their duration of use (i.e., weeks, months, years), frequency of use in a given time period, usual dosages on each occasion (i.e., estimate of how much psilocybin per dose), and determine if there are any echocardiographic abnormalities compared to age-matched non-users.
For individuals presenting to their physicians with valve dysfunction, it should be documented if there was any psilocybin use.
Take home message
Psilocybin has been shown to provide relief from a variety of mental health issues when used responsibly and in controlled and supportive environments.
The safety profile of psilocybin in healthy adults is generally well established. But as with any drug, there are always risks, some known and others yet to be established.
Numerous lay websites and online forums have promoted the idea that psilocybin could cause heart valve damage. While this is theoretically possible, it has not been experimentally evaluated in any published peer-reviewed human trials and, as of this writing, appears to be primarily based on extrapolations from other studies on serotonergic drugs.
Moreover, to date, no case reports have appeared in the medical literature linking psilocybin to valvular damage.
Future psilocybin research must explore this question in greater depth and, where feasible, should include echocardiographic analysis of heart valves as an outcome measure