By Kelan Thomas
Given the current evidence for psychedelic “microdosing,” the risks may outweigh the benefits for many people.
This is because there is compelling theoretical evidence to suggest prolonged and repeated microdosing may cause valvular heart disease (VHD), and only weak survey evidence that it provides the benefits microdosers typically seek, such as enhanced cognition, or relief from depression and anxiety.
Prolonged receptor activation safety risk: 5HT2B and VHD
VHD is characterized by damage to the heart valves, which control the flow of blood into and away from the heart. VHD can cause shortness of breath, weakness, and sudden cardiac death.
One cause of VHD seems to be a certain class of medications: there is a consistent history of medications with strong serotonin 2B receptor (5HT2B) binding affinity being linked to the disease. In fact, a recent FDA regulatory forum toxicology expert review article has suggested that a medication’s 5HT2B binding affinity (Ki) was considered a better predictor of VHD risk than measures of functional activity such as EC50.
LSD and psilocybin (active metabolite psilocin) present concerns for VHD because they too bind to the 5HT2B receptor. Unfortunately, these psychedelics could potentially cause VHD when “microdosed” for many months to years.
Several medications with relatively strong 5HT2B receptor binding affinity (Ki < 500 nM) have been unquestionably associated with VHD, such as methylergonovine, methysergide, ergotamine, pergolide, cabergoline, fenfluramine (active metabolite norfenfluramine); where roughly 25% of patients developed new onset VHD, including some cases of heart valve thickening that required heart surgery and resulted in death.
In an epidemiologic case-control study of 29 MDMA users who averaged 3.6 tablets per week for 6.1 years, 28% had VHD confirmed by echocardiography versus none in the gender- and age-matched controls. This evidence demonstrates that chronically dosing another “psychedelic” with 5HT2B affinity, even when only taking a few doses per week, has also been associated with VHD.
Though derived from an epidemiologic study rather than a randomized controlled trial (RCT), this is a troubling statistic, since the psychedelics LSD and psilocybin used for microdosing have even stronger binding affinity for 5HT2B receptor than MDMA and its active metabolite MDA (+LSD Ki = 30 nM, psilocin Ki= 3.6 nM; MDMA Ki = 500 nM, MDA Ki = 100 nM), in addition to their “psychedelic” 5HT2A receptor effects.
Is there evidence that microdosing is effective?
Recent evidence from randomized controlled trials evaluating LSD and psilocybin microdosing has not demonstrated antidepressant, anxiolytic or pro-cognitive effects.
The most recently published RCT with groups assigned to placebo, LSD 13 mcg, or 26 mcg, produced negligible acute changes in mood or cognition in healthy volunteers, but did demonstrate modest changes on subjective ratings of items such as “feeling a drug effect.” Another study with the same dosing groups, plus an arm with LSD 6.5 mcg, also found a few dose-dependent acute changes on subjective ratings like “vigor,” while other measures of mood, cognition and physiologic response were unaffected. An RCT with slightly different microdosing groups of placebo, LSD 5 mcg, 10 mcg, and 20 mcg demonstrated no differences in perception, mentation, or concentration for older adults, but LSD did produce temporal dilation of suprasecond intervals in time perception. Another study using the same dosing groups found that LSD 20 mcg acutely decreased self-rated concentration, while attention, cognitive control, and mood were not affected; however, there was inter-individual variability in LSD effects on mood and cognition, which suggests that some people may be more responsive to microdosing.
The largest “self-blinding” RCT to date, with 191 participants who were on average microdosing LSD 13 mcg or psilocybin mushrooms 0.2 g every 3-4 days for 4 weeks, has demonstrated equal improvement for both placebo and microdosing groups, which suggests that beneficial effects could be explained by the placebo response. A safety RCT of placebo, LSD 5 mcg, 10 mcg, and 20 mcg microdosing every 4th day over 3 weeks also found no changes in cognition, balance and proprioception for older healthy volunteers. Another recent RCT investigated standardized quantities of Psilocybe galindoi truffles 0.7 g (corresponding to 1/10th medium-high dose) microdosed 5-7 times spread over 3 weeks, which demonstrated no effect on emotion processing or symptoms of anxiety and depression compared with placebo.
Conclusion
It is important to differentiate the potential risk associated with prolonged and repeated microdosing from the very limited physiological safety risk posed by a few “macrodoses” given weeks or months apart for psychedelic-assisted therapy. That said, given the lack of clinical trial evidence showing any clear benefit for microdosing, and the concerning theoretical safety risk of VHD, it is worth proceeding with caution and, at the very least, taking some weeks off between 4-week microdosing intervals. I would also encourage long-term microdosing researchers and microdosing survey app developers to begin collecting routine echocardiography results to systematically evaluate the risk of VHD.
Dr. Kelan Thomas, PharmD, MS, BCPS, BCPP is an Associate Professor of Clinical Sciences at Touro University California College of Pharmacy.
