Everyone wants to feel better and lead healthier happier lives and it is reasonable in many ways to think that natural earth medicines could potentially be safer than pharmaceuticals. However, these natural treatments can be harmful as well as helpful – the reality is that with any ingested substance there are real risks to human health that must be weighed against any potential benefits. Paracelsus, a Swiss physician and philosopher famously said 500 years ago, “What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison.” (1) A more recent 2016 journal article went on to clarify this statement as it relates to science today: “From a public health viewpoint, toxicology needs to provide better guidance on decision-making under ever-present uncertainty. In this role, we need to learn from the stalwart Paracelsus the insistence on relying on facts rather than authority alone to protect against chemical hazards,” and also that, “...in principle, any substance, including any drug or essential nutrient, has the capacity to harm a living organism and thus behave like a poison.” As a registered clinical pharmacist one of my ethical and professional duties is to ensure that patients are completely informed about all aspects of any given treatment and this unfortunately includes the bad as well as the good.
Thankfully here are very few significant extended risks with eating healthy, exercising, taking time to enjoy life and being social with others as well as hopefully having some kind of spiritual practice. But what about when all of these things just aren't working, or when they are not working well enough to enable someone to function to their maximum wellness potential? In my opinion, that is where medications come in, to fill the gaps where wholistic practices and lifestyle measures cannot help or are not helping enough. As a jaded lifetime practitioner of traditional western medicine I am against someone ingesting a substance to obtain better health when they are not following a wholistic healthy lifestyle as per the habits above. I have seen far too many patients fail or hurt themselves in the process (and have personally failed and hurt myself in my own health journey) when going down strictly the medication path without looking at, and taking care of, all other aspects of life first. But if a patient has already tried every imaginable non-drug measure available and still suffers from illness then there is definitely great potential in the utilization of safe and effective remedies being able to assist. As such I have dispensed and recommended a significant variety of both natural and synthetic treatments over my lengthy professional career in order to help many patients unable to succeed via other means with obtaining and maintaining their own personal health goals.
The mounting evidence for psychedelic medicine continues to show both high levels of safety and efficacy when administered in clinical settings and paired with therapeutic insight. There have been more than 36,000 research papers published on psychedelics since the late 50s and the rate and quality of research continues to rise. Many well done and relevant peer-reviewed studies demonstrate that the aggregate evidence for psychedelic therapy is indeed positive. The newest research has been done with great attention to extremely rigorous modern scientific standards and still continues to show astounding results. The psilocybin contained in 'magic mushrooms' has been granted 'Breakthrough Therapy' designation twice based on recent clinical trials by the US Food and Drug Administration (FDA). This process is designed to speed up the development of treatments that hold the potential for substantial improvement compared to currently available treatments. It is important to note that both of the clinical trials spurring the designations were specifically for single large doses of psilocybin (ie. macrodoses), not for continuous/repetitive smaller doses (ie. microdosing). (2) It is not the intention of this article to explore every psychedelic, rather, attention is given to psilocybin and specifically to the health differences between much larger doses commonly spaced out by a significant portion of time and smaller regular doses even with breaks in between.
Firstly, it is important to note some of the overall positives of this miraculous substance. I am definitely not against psychedelic therapy as this is my chosen area of expertise and passion but I would prefer that these powerful tools be used in the safest, most efficacious, and legal ways possible. The societal and environmental risks of negative outcomes from risky behaviors slowing or halting their eventual widespread availability and use is much too great. A repeat of what happened in the 60's leading to renewed prohibition would be terrible for humanity and the planet. “Of all psychedelic drugs, psilocybin is reported to have the most favorable safety profile … psilocybin is the most studied psychedelic,” and psilocybin also has a “low addictive/abuse potential”. Some short and long-term positive effects of psilocybin treatment may include but are not limited to: positive changes in personality and increased altruism, enhanced feelings of connectedness, enhanced-nature relatedness, pro-environmental behavior, decreased violent and criminal behavior, reduced suicidal ideation, protection against suicidality and psychological distress, tempered politically authoritarian views, an increase in the personality domain of openness, reduction of egotistical attitudes, narcissism and greater prosocial behavior, sustained/persisting improvements in attitudes and behavior, improved psychological flexibility and feelings of personal meaningfulness (and subsequently improved psychological outlook), the ability to reframe how a patient views their medical conditions, themselves, their lives and relationships with others, an increase in one’s subjective sense of wellbeing, quantum change (meaningful personal transformations), enhancement of “meaning responses”, and increased meditation depth. (3)
Regarding efficacy of microdosing, the science is mixed and limited by expectation bias also known as the “placebo effect”. Most clinical trials with psilocybin treatment showing significant efficacy over a long duration of time involve large intermittent doses like the studies resulting in 'Breakthrough Therapy' status discussed above, with microdosing trials showing relatively mixed and hazy results. For example, a double-blind placebo-controlled study on microdosing in 2022 found that “...low doses of psilocybin mushrooms can result in noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function. We conclude that expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.” (5) However, another study “followed psilocybin microdosers (n = 953) and non-microdosing comparators (n= 180) for approximately 30 days and identified small- to medium-sized improvements in mood and mental health that were generally consistent across gender, age and presence of mental health concerns, as well as improvements in psychomotor performance that were specific to older adults,” although the researchers admitted that “In addition to small samples in subgroups, observational design, and a generally exploratory approach, interpretation is further limited by potential response bias related to participant self-selection and recruitment through venues that are favorable toward psychedelic use, which may have resulted in overrepresentation in our sample by individuals who respond favorably to microdosing.” Additionally, the scientists in this paper mentioned another study that “followed 81 microdosers for four weeks also reported improvements across several domains of psychological well-being, including enhanced emotional stability and decreased anxiety and depression. However, supplementary analyses suggested that these positive effects may be attributable to expectancies.” (6) Additionally, a 2021 journal article stated that “All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between groups differences were observed … The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.” (7) Another study corroborates this stating, “Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.” (8)
On the contrary, perhaps a large part of the intense and sustained beneficial healing effects that can arise from larger doses of psychedelic substances are in fact due to 'mystical' types of experiences and 'ego death’. What is 'ego death'? Also known as 'ego dissolution' or 'ego loss' the term is used for good reason: the process can actually feel as if one is physically dying. The 'ego' can be defined as: “...what we know and who we believe ourselves to be” and “...everything you have ever been told and shown about the world, about who you are, how things work, and what actions and reactions are adequate.” So one may be left believing that one no longer exists when everything one knows about oneself melts away and disappears. This is the awesome power of 'ego death'. By reaching this transformative state the patient has no choice but to “...let go of all that we are and to make peace with the infinite offer[ing] unparalleled potential to positively redefine how we live when we come back. Facing our mortality inevitably makes us more human and allows us to let go of negative attachments, which some spiritual traditions say are the root cause of all suffering. The experience makes us more present and more connected to our primordial nature and to everything that exists. As Stanislav Grof, one of the pioneers of research on altered states of consciousness described it, 'Ego dissolution is an ecstatic state, characterized by the loss of boundaries between the subject and the objective world, with ensuing feelings of unity with other people, nature, the entire Universe, and God.' ” (9) Perhaps this is intimidating to a prospective patient hoping for significant change with little mental work and minimal distress, however, there are already a slew of readily available anti-depressants, nerve tranquilizing and numbing anxiolytic agents on the market today that easily offer a similar experience to prospective microdosers. If a patient really wanted to avoid the truly special and transformative psychedelic experience they could simply opt instead for one of the many pre-existing well-researched treatments already on the market. The very idea of microdosing with a psychedelic is counterintuitive, at least in this regard. In contrast, heroic doses of most western medical pharmaceuticals are typically lethal and non-therapeutic.
Finally, let's talk more about human health impacts now that we've discussed some of the potential benefits of microdosing vs. macrodosing. As discussed above, physically and psychologically, magic mushrooms are generally very safe when used appropriately in clinical environments with significant therapeutic oversight. However, many journal articles have discussed a distinct and very real possibility of heart valve dysfunction with the repeated and extended dosing common to microdosing practices. When researchers asked the question 'Is Microdosing Safe?' in the paper entitled “Microdosing psychedelics: More questions than answers? An overview and suggestions for future research” they stated that: “Other potential and serious adverse events are cardiac valvulopathies due to repeated activation of serotonin 5-HT2B receptors, which psilocin activates along with many other serotonin receptors. Several drugs have recently been pulled from the market due to this concern. The first example of this was the diet medication Phen/Fen, which had an unacceptably high fatality rate due to its effects on 5-HT2B receptors in the heart (Connolly et al., 1997). Another example is methysergide … It remains to be seen whether repeated low-dose psilocybin administration in preclinical studies might produce valvular hyperplasia, and whether or not this would translate to the human user population.” (9) The 2022 microdosing study mentioned above also stated that, “...future research should also explore the potential impact of microdosing on aspects of human physiology that could compromise its long-term safety; for instance, by addressing the potential consequences of chronic 5-HT2B receptor stimulation on the health of the circulatory system, among other important points.” (5) Interestingly, drugs that block rather than activate this receptor have been studied to treat heart disease as stated in this 2018 psilocybin review article: “Damage to the cardiac valves is possible with frequent long-term use due to psilocin’s 5-HT2B receptor activity at the heart, which induces the proliferation of cardiac fibroblasts, resulting in a stiffening of the cardiac valves (5-HT2B receptor antagonists are currently under review for the prevention of cardiac remodeling in adults with heart disease).There has been one anecdotal case of a psilocybin-related fatality in a post- heart-transplant patient that could have been related to this mechanism.” (11)
Dr. Bryan Roth, MD, PhD was the scientist who discovered in 2000 that norfenfluramine, the active metabolite of fenfluramine, had a high affinity to 5-HT2B receptors that caused inappropriate stimulation of valve cells resulting in overgrowth. Pergolide, another drug (used in Parkinson's disease) was removed from the market due to valvulopathy and similarly activated 5-HT2B receptors. Pergolide's affinity for the 5-HT2B receptor is very similar to psilocin's affinity, and the blood level of psilocin with even a small 3mg to 6mg “microdose” is enough to activate these receptors. Pergolide doses that were associated with valve damage were 2mg per day, so similar receptor affinities and similar doses could theoretically cause similar damage, but high quality studies with psilocybin have not yet been undertaken to specifically investigate this further. (12) Therefore, one can only make conclusions based on similarities to other drugs, however, the risk with pergolide was correlated to the cumulative total dose, so the higher the total amount of pergolide the person received the higher the risk of heart damage. This issue needs to be investigated as soon as possible and completely understood for psilocybin before making any long-term microdosing safety conclusions.
In summary, the available evidence currently demonstrates that psilocybin macrodoses within a clinical framework of psychedelic assisted therapy greatly surpasses the popular trend of microdosing in both critical dimensions of efficacy and safety. It remains to be seen whether or not the risks proposed are real or simply theoretical, but the pharmacological similarities to other drugs that have been removed from the market is a strong signal that warrants legitimate robust investigation. One of the challenging issues for expanding psychedelic medicine over the years has been a lack of public funding for scientific research, and though this is starting to change within the current 'psychedelic renaissance', a number of legal and bureaucratic hurdles continue to exist that makes studying these compounds challenging if not impossible for many. Research into using psychedelics for the treatment of mental health problems tapered off in the 1970s and remained effectively shut down for several decades. Losing 50 years of important time learning about these molecules may have caused an unimaginable level of harm to both humanity and the planet. Being disregarded for decades because of political, not scientific, fears has resulted in a distinct dearth of evidence surrounding these stigmatized substances and it is only with continued research that the deeper mysteries of these highly misunderstood but intriguing molecules may finally come to light.