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:

1. 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
2. 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-HT_1A, 5-HT_1B, 5-HT_2A etc).

Psilocybin is chemically similar to serotonin and acts primarily upon the 5-HT_2A receptor in the brain where it exerts its psychoactive effects.

Psilocybin has also been shown to have an affinity for cardiac 5-HT_2B 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-HT_2B receptor in cardiac tissue, leading to valvular strands and valve dysfunction.

Because psilocybin also has an affinity for cardiac 5-HT_2B 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-HT_2B 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

The post Does Psilocybin Cause Heart Valve Damage? A Review of the Research appeared first on Dr Bill Sukala.

This article, in particular, has attracted both a lot of praise from critical thinking scientists and criticism from its marketers.

Spend a few hours reading through the comments on this article and you’ll see just how emotional and heated the debate has become.

I’ve since closed the comments section due to emotional rants and vitriolic personal attacks, not to mention having to repeat myself over and over again. But anyway….

A search of PubMed and other medical databases turns up very few results on the term “pyroluria” as a clinical entity.

A Google Scholar search shows more results, but many of these are of questionable repute and are not peer-reviewed.

A bog standard Google search reveals a huge number of alternative health sites, many of which happen to sell testing kits and claim to have the cure.

In my own sleuthing, I found the most common search queries to be “is pyroluria real?” “how do I get diagnosed?” and “can it be treated or cured?”

Before you break out your credit card in paralysing fear and start buying expensive online tests and supplements, you need to arm yourself with the facts.

Please take the time and read this article in its entirety, as it provides balance to much of the marketing hype you’ll find on the internet and social media.

Origins

Back in the 1960s, during the heyday of the psychedelic revolution, the originators of the pyroluria hypothesis (Hoffer and colleagues) figured that since the effects of LSD were similar to those with schizophrenia that perhaps they could derive some insights from “trippers.”

They looked for biomarkers in the urine of subjects on LSD, one of which was identified as kyrptopyrrole.

They assumed that since kryptopyrrole is present in the urine of those taking LSD and those with schizophrenia, then it must be a factor in the development of a host of other mental and physical disturbances (mentioned below).

What is pyroluria?

Pyroluria promoters claim that it is a genetically-determined chemical imbalance associated with haemoglobin synthesis (the molecule that carries oxygen in your blood).

People with the condition produce too much kryptopyrrole as a byproduct of haemoglobin production and it is excreted in the urine.

Proponents suggest that this excess kryptopyrrole binds vitamin B6 and zinc, renders them unavailable for their usual biological roles, and then excretes them through the urine as pyrroles.

Accordingly, sufferers may exhibit signs of vitamin B6 and zinc deficiency which could possibly account for symptoms like depression, anxiety, mood swings, nervousness, and a litany of other suggested ills.

Other names for pyroluria

Pyroluria goes by a number of names and spellings across the internet and all are used interchangeably.

• Pyrole disease (pyrrole disease)
• Pyrole disorder (pyrrole disorder and pyrolle disorder)
• Kryptopyrrole
• Kryptopyroluria (kryptopyrroluria)
• Mauve factor
• hemepyrole (hemepyrrole, hemopyrrole, hemopyrole)

Symptoms

Aside from those symptoms listed above, pyroluria promoters cast a massive net to include virtually every ache, pain, and sniffle imaginable.

However, I think it’s important to exercise caution when “diagnosing” yourself given that these symptoms are all quite disparate, vague, ambiguous, and nondescript, and could be attributed to virtually any trivial or serious illness.

I have extracted the following from several different sources to demonstrate how wide and far reaching the “symptoms” are.

• Abdominal pain
• Abnormal body fat distribution
• Acne
• Allergies
• Amnesia spells
• Anger – explosive
• Anxiety, nervous exhaustion
• Argumentative and/or angry demeanor, mood swings
• Cloudy thinking, poor memory
• Cold hands and feet
• Constipation
• Creaking in joints
• Delayed puberty
• Delusions
• Depression
• Difficulty remembering dreams
• Dramatic
• Drug and alcohol intolerance
• Dyslexia
• Early greying of hair
• Eczema
• Elevated eosinophils
• Emotionally unstable
• Fatigue
• Fluid retention
• Frequent colds, fevers, chills, ear infections as a child
• Hallucinations
• Hyper-pigmentation of the skin
• Hyperactivity
• Hypersensitivity to loud noises
• Hypoglycaemia
• Inability to think clearly
• Insomnia
• Intolerance to alcohol
• Intolerance to drugs
• Intolerance to some protein foods
• Joint pain
• Knee pain
• Lack of hair on head, eyebrows, and eyelashes areas
• Lack of regular menstrual cycle
• Loss of appetite
• Low libido
• Low tolerance to stress
• Male impotence
• Migraines
• Mood swings
• Morning nausea
• Motion sickness
• Much higher capability in the evening than mornings
• Nervous exhaustion
• Nervousness
• Overwhelmed in stressful situations
• Pale skin, poor tanning, sun burn easily
• Panic attacks
• Paranoia
• Pessimism
• Poor morning appetite, tendency to skip breakfast
• Preference for spicy or heavily flavoured foods
• Prone to stitches when running now or as a child
• Reading difficulties
• Seizures Sensitivity to bright light
• Sensitivity to smells
• Severe inner tension
• Significant growth after 16 years of age
• Skin rashes
• Social withdrawal
• Substance abuse
• Temper tantrums
• Tendency towards iron deficient anaemia
• Tingling in the arms and legs
• Tremors
• Unusual breath and body odour

Associated conditions

Similar to the host of symptoms listed above, proponents suggest it is associated with numerous other health conditions. But all are unclear about whether or not pyroluria causes these conditions or the other way around (the chicken or the egg conundrum).

• ADD/ADHD
• Epilepsy
• Autism, Aspergers, Down syndrome, learning difficulties
• Depression, manic depression, bipolar disorder, schizophrenia
• Allergies
• Alcohol/substance abuse
• Criminal behaviour/violent offences
• Neurosis
• Lung cancer
• Tourette’s syndrome

Is pyroluria a real?

I don’t think there’s any question that pyrroles exist.  And yes, pyrroles can be found in the urine.

The symptoms people experience are also likely real, but whether or not these symptoms are a cause and effect result of excess pyrroles in the urine is yet to be proven.

In a critical article by Yale Professor Dr Steven Novella published on ScienceBasedMedicine.org he points out that the theory fails to stand up to scientific scrutiny.

Hoffer and associates contend that kryptopyrrole is found in the urine of schizophrenics, but other investigators failed to replicate these findings:

• Gendler PL, Duhan, HA, Rapoport H. Hemopyrrole and kryptopyrrole are absent from the urine of schizophrenics and normal persons. Clin Chem. 1978 Feb;24(2):230-3.
• Jacobson SJ, Rapoport H, Ellman GL. The nonoccurrence of hemo- and kryptopyrrole in urine of schizophrenics. Biol Psychiatry. 1975 Feb;10(1):91-3.
• Irvine DG. Hydroxy-hemopyrrolenone, not kryptopyrrole, in the urine of schizophrenics and porphyries. Clin Chem. 1978 Nov;24(11):2069-70.

Referring to the pyroluria hypothesis, Novella adds:

“Studies in the 1970s, however, discredited the hypothesis and it was discarded as a failed hypothesis. The published literature entirely dries up by the mid 1970s. But the originators of the idea did not give up, and continue to promote the idea of pyroluria to this day.”

Based on the available preponderance of evidence, I’m inclined to believe that it is not a real disorder or disease.

Despite its debunking, Hoffer didn’t give up so easily. Instead, he went on the offensive. Novella continues:

“In this case Hoffer decided that he was not the victim of a failed hypothesis, but rather the victim of a conspiracy of mainstream psychiatry that was simply closed to his revolutionary ideas. He founded the journal Orthomolecular Psychiatry, now the Journal of Orthomolecular Medicine – a fringe journal in which he could continue to publish his ideas.”

Critical thinking around pyroluria

I find it concerning that there is so much pro-pyroluria information on the internet, yet the vast majority of alternative practitioners (located mainly in the US and Australia) are basing its validity on the same faulty, debunked evidence from Hoffer and colleagues.

Strong marketing in Australia

I have also noticed a telling anomaly in my analytics for this particular article. Australia has about three times the number of visits compared to the United States, despite the fact that Australia has only 7.5% of the population of the states.

Other countries listed below Australia and the United States represent a minuscule number of visits.

Does this mean pyroluria has been eradicated in every other country except for Australia and the US?

To corroborate this data, I did a search on Google Trends to see how the countries compared.

In the following image, you’ll see that interest in the terms “pyrrole disorder” in the United States is virtually non-existent by comparison to Australia. Interest peaked around 2013 and has since dwindled considerably.

To further corroborate these data, I decided to have a look at search volumes for these terms in Google AdWords for both Australia and the United States. In the images below, you will see that, despite pyrrole disorder being invented in the United States, monthly search volumes are quite low (100 to 1K) and the cost to buy this keyword is only $0.04.

In the image below you will see the same information for Australia. Notice the significantly higher number of average monthly searches and a suggested bid of over 10 times that of the United States.

Taken as a whole, this information suggests that there is clearly a concerted marketing effort to promote and market pyrrole disorder in Australia.

The likelihood of all this coming together by random chance is highly unlikely and would appear to be a deliberate result of human collusion.

Pyroluria testing

Despite evidence (or lack thereof) that suggests this condition isn’t a real disorder, there are still a large number of websites offering online testing kits ranging in price from $80 to $150.

Kryptopyrrole pyroluria urine test

The most common testing for pyroluria involves examining your urine for kryptopyrroles.

While kryptopyrroles are a real thing, whether or not they are the cause of your mood disorder has yet to be determined.

Testing conflicts of interest

In an earlier version of this article, I had a screenshot of a promoter’s website showing a long list of frightening symptoms next to buttons where you could click to buy the testing kit.

Though I didn’t list him by name and was only using the screenshot for educational purposes, he was convinced I was infringing upon his intellectual property.

In fact, I was not in breach of Australian copyright laws, but I thought I’d be a nice guy anyway and oblige him.

I took down the screenshot and replaced it with my own proprietary copyrighted mock-up below to give you an idea of the scare tactics being used to promote pyroluria (I know, I suck at photoshop!).

The most concerning thing about this sort of advertising is that the listed symptoms are so absurdly varied and wide-reaching that they’d apply to at least 99.8% of the  population.

In my view, I think this sort of marketing is deceptively biased and leverages on people’s fears and insecurities.

Treatment

I also noted that many pyroluria promoters list symptoms on their websites next to a regimen of dietary supplements purported to cure the condition.

The way many of these sites are laid out, there is sufficient information presented (such as the image above) that can scare and convince someone they are truly afflicted with this condition.

With no other corroborating tests aside from those sold on the websites or available in Bio-Balance approved labs, I would recommend people receive further evaluation and blood tests by their GP or a specialist to ensure that they don’t have a more serious condition such as cancer or other hormonal disturbances.

Vitamin B6 and zinc treatments

The most commonly recommended treatment is a regimen of vitamin B6 and zinc.

Some pyroluria promoters recommend the B6 and zinc in combination with other vitamin and minerals (manganese, magnesium, vitamin B3, and vitamin C), which they claim will enhance the treatment response

Some push the idea that pyroluria is a chronic condition that you are stuck with for the rest of your life. The obvious implication here is that you’ll need to buy their treatments indefinitely.

Treating depression and anxiety

Depression and anxiety can be very complex clinical entities that have a multitude of origins.

I would strongly recommend that you visit your doctor for a proper work-up and, if required, a referral to a psychologist for a more detailed evaluation.

In many cases, depression and anxiety may be caused by unhelpful thinking patterns (i.e., negative thinking) that can become hardwired in your brain.

Drug-free treatment options such as cognitive behavioural therapy (CBT) or dialectical behavioural therapy (DBT) which can help you identify and short-circuit those unhelpful thoughts to develop new, healthier ways of thinking (which then get hard-wired into your brain).

A healthy diet and exercise have also been shown to significantly improve signs of depression and anxiety – no drugs necessary.

Managing expectations

Having personally dealt with depression and anxiety at different stressful times in my life, I absolutely understand the desperation that comes with trying to find a solution.

You feel like there are no options or that you’ve tried everything. So when something like pyroluria comes along, you might think, “yeah, this has GOT to be it.”

The intention of improving can, by itself, help you improve. So when you start taking supplements thinking it will cure pyroluria, you may initially feel better due to your desire to get better.

However, I’ve received numerous emails over the past few years from people who said that, while they initially felt better after taking the vitamin/mineral supplements, once the excitement wore off, they reverted back to the way they were.

So if you do decide to take a supplement for pyroluria, monitor your moods using a mood tracking app (like Daylio or similar). In particular, see how you’re feeling two to three months later and if you are still feeling better.

Closing thoughts

Based on the available evidence, pyroluria appears to be more myth than true medical malady.

• The available evidence does not support the hypothesis that pyrroles are responsible for all the symptoms and conditions ascribed to pyroluria.
• Alternative practitioner websites employ terrifyingly sinister descriptions of pyroluria symptoms, but also happen to conveniently offer expensive tests and dietary supplement regimens to “correct” this disorder.
• The cause of mental conditions like anxiety, depression, and schizophrenia are multifaceted and would likely require more treatment than vitamin and mineral supplements.
• Modern western medicine clearly does not have all the answers but, in this particular case, the mere belief that pyroluria exists could be more anxiety-provoking and harmful to your well-being than pyroluria itself (if it were real).
• The symptoms listed across a variety of websites are extremely broad and vague and could apply to virtually anything. My concern is that a person suffering from a real medical condition might decide to forego getting a timely diagnosis and treatment which could save their lives (i.e., early cancer detection).

The post Pyroluria: Is It a Real Disease or Just a Myth? appeared first on Dr Bill Sukala.