Microdosing Psilocybin and Psilocybin Assisted Psychotherapy – Safe and Effective?

adminBasic Science, Treatments of Depression Leave a Comment

Recently there has been a lot of interest in using psilocybin as a treatment for depression, anxiety and alcohol use disorder. We certainly need more safe and effective treatments.

It may be worth considering where we are in the evaluation of these agents. Right now there is a growing literature supporting the potential value of these agents, but there is not enough evidence to support their use in clinical care outside of research studies. Or at least, this is the July 2022 position of the American Psychiatric Association.

The process of developing new drugs involves three phases of clinical trials. Phase one is designed to see if there are any immediate risks to health from the medication and to get a rough idea of the right dose. Phase two is intended to gather more information about short term safety and is the first phase with enough patients recruited for the study that you can see a statistically significant result. Phase three involves the largest number of patients and if phase three studies are successful they will lead to an application for the FDA to approve the use of the drug for clinical care. Finally, phase four studies are often conducted after approval or during the approval process, they are studies that last at least a year and are intended to demonstrate “long term” safety.

If a medication is immediately toxic, it won’t get past phase one. For most medications, it is not clear that the benefits outweigh the risks until phase three studies are completed. And for some medications, it is only during phase four studies, or, even, sometimes, only after the drug enters the market, that it becomes clear that there is a significant severe adverse effect associated with long term use of the medication.

Right now, psilocybin, and other similar drugs, are mostly in phase two or phase three trials. There is enough data to suggest that they hold promise. There isn’t enough data to say that they are safe and effective. There isn’t enough data to say what dose should be used or who should be excluded from treatment. Nor is there enough data to say whether the drugs should be used as part of a process of change that includes therapy, or not. Finally, we won’t know enough about longer term adverse effects until phase four trials, or, possibly, not until the first year after they are approved.

An article posted on the Bill of Health website of the Harvard Law School, suggests that some caution about the long term safety of these substances may be in order.

The article notes that there is evidence linking valvular heart disease to medications which strongly bind to serotonin 2B receptors.

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.

Safety First: Potential Heart Health Risks of Micro-dosing

An article in Regulatory Forum Review suggests that binding to 2B receptors is a strong predictor of cardiac toxicity.

This is relevant to a discussion of the safety of psilocybin because LSD and psilocybin, in addition to binding to serotonin 2A receptors (associated with their psychomimetic effects), also bind very strongly to serotonin 2B receptors.

An alternative view is espoused by Dr. Bill Sukula in a review of the literature posted on his website. He notes that there is no evidence showing that there is a toxic effect of psilocybin in human studies… “[toxicity] is theoretically possible, [but] it has not been experimentally evaluated in any published peer-reviewed human trials…” So, it depends on whether you feel reassured that there is no data showing it is harmful or worried because there is no data showing it is safe.

I would suggest that the APA’s view is a reasonable summary of the state of the research. These drugs seem very promising, but we need larger clinical trials, including studies that follow patients for more than a few weeks, before we can recommend their use in clinical practice.


Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. Published online August 24, 2022. doi:10.1001/jamapsychiatry.2022.2096

Kranzler HR, Hartwell EE. Treating Alcohol Use Disorder With Hallucinogens—Renewed Interest After a 50-Year Hiatus. JAMA Psychiatry. Published online August 24, 2022. doi:10.1001/jamapsychiatry.2022.2029

Griffiths  RR, Johnson  MW, Carducci  MA,  et al.  Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial.   J Psychopharmacol. 2016;30(12):1181-1197. doi:10.1177/0269881116675513

Ross  S, Bossis  A, Guss  J,  et al.  Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.   J Psychopharmacol. 2016;30(12):1165-1180. doi:10.1177/0269881116675512

Bogenschutz  MP, Forcehimes  AA, Pommy  JA, Wilcox  CE, Barbosa  PC, Strassman  RJ.  Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study.   J Psychopharmacol. 2015;29(3):289-299. doi:10.1177/0269881114565144

Johnson  MW, Garcia-Romeu  A, Cosimano  MP, Griffiths  RR.  Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.   J Psychopharmacol. 2014;28(11):983-992. doi:10.1177/0269881114548296

Carhart-Harris  R, Giribaldi  B, Watts  R,  et al.  Trial of psilocybin versus escitalopram for depression.   N Engl J Med. 2021;384(15):1402-1411. doi:10.1056/NEJMoa2032994

Davis  AK, Barrett  FS, May  DG,  et al.  Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial.   JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285

Carhart-Harris  RL, Bolstridge  M, Rucker  J,  et al.  Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.   Lancet Psychiatry. 2016;3(7):619-627. doi:10.1016/S2215-0366(16)30065-7

Papoian T, Jagadeesh G, Saulnier M, Simpson N, Ravindran A, Yang B, Laniyonu AA, Khan I, Szarfman A. Regulatory Forum Review*: Utility of in Vitro Secondary Pharmacology Data to Assess Risk of Drug-induced Valvular Heart Disease in Humans: Regulatory Considerations. Toxicol Pathol. 2017 Apr;45(3):381-388. doi: 10.1177/0192623317690609. Epub 2017 Jan 1. PMID: 28421966.