LSD microdosing three times per week was found in a preliminary 2024 randomized controlled trial to increasesleep duration by 24minutes on average one day after the microdose (but not the same night of the dose).[2][11] This included an increase in duration ofREM sleep.[2][11] In January 2026, the results of aphase 2b placebo-controlledclinical trial of LSD microdosing for major depressive disorder were disclosed.[12] This study has been said to be the largest and most rigorous trial of psychedelic microdosing to date.[12] It found that LSD microdosing was not effective and was actually outperformed by the placebo, acaffeine pill, in terms of depression improvement.[12]
The benefits of microdosing may in part or full be aplacebo mediated bypositive expectancy effects.[22][23][24][25] In people with major depressive disorder, placebos are known to produce substantial reductions in depressive symptoms all on their own and conventionalantidepressants barely outperform placebos inclinical trials.[26][27][28] Some researchers have proposed that psychedelics, in general, may beactive "super placebos" due to their powerful hallucinogenic effects and cultural associations.[29][30]
Tolerance andtachyphylaxis are known to rapidly develop to the hallucinogenic effects and to other effects of serotonergic psychedelics in both animals and humans.[31][32][33] This is thought to be mediated by rapid serotonin 5-HT2A receptordownregulation that is very slow to recover.[31][32] Tolerance and loss of effect could serve to limit the potential beneficial effects of psychedelic microdosing and this is a phenomenon that has been observed in existing clinical studies.[1][9] More research is needed to further assess this issue.[2]
LSD andpsilocybin, the latter often in the form ofpsilocybin-containing mushrooms, are the most commonly used psychedelics in microdosing.[34] A microdose is considered to be between approximately one-twentieth to one-tenth of a typicalrecreational dose.[3][9] Microdoses of psychedelics are 5 to 20μg for LSD, 1 to 5mg for psilocybin, 0.1 to 0.5g of psilocybin-containing mushrooms, and <75mg formescaline.[35][36][37][2][20] These psychedelics have perceptible psychedelic effects at minimum doses of 10 to 20μg for LSD, 3 to 5mg psilocybin, 0.5g psilocybin-containing mushrooms, and 100mg mescaline.[35][36][37][2]
The risk of cardiac valvulopathy and toxicity with long-term use of psychedelics is, aside from the case of MDMA, theoretical and has largely not been assessed or demonstrated in animals or humans.[41][42][43][51] It is notable in this regard that findings on the serotonin 5-HT2B receptor agonism of psychedelics including LSD, psilocybin, mescaline, anddimethyltryptamine (DMT) are conflicting, with some studies finding them to be potent serotonin 5-HT2B receptor agonists and others finding them to be very weak or negligible serotonin 5-HT2B receptor agonists, depending on the study andassay.[39][51][40] The cardiac toxicity of serotonin 5-HT2B receptor activation has been specifically linked toextracellular regulating kinase 2 (ERK2)signaling and not necessarily to otherdownstream signaling pathways.[43][51] LSD has been found to have low activity on a valvulopathogenic ERK2 serotonin 5-HT2B receptor agonism readout relative to known or suspected valvopathogens likenorfenfluramine, pergolide,methylergonovine (methylergometrine),ergonovine (ergometrine), cabergoline,dihydroergotamine, andergotamine.[43][51] This was in terms of both activational potency (EC50Tooltip half-maximal effective concentration = 110nM vs. 1.0–20nM, respectively) andefficacy (EmaxTooltip half-maximal effective concentration = 39% vs. 53–79%, respectively).[51] Conversely, other psychedelics likepsilocin, DMT, and mescaline have not been assessed in terms of this assay as of 2022.[51] However, other research suggests that the toxicity may not be specifically or exclusively dependent on ERK2 signaling.[43] More research is needed to determine whether long-term frequent use of psychedelics, including microdosing, may cause cardiac valvulopathy and other related toxicities.[44][41][42][43]
Selective serotonin 5-HT2A receptor agonists that do not activate the serotonin 5-HT2B receptor or otherserotonin receptors, such as25CN-NBOH,DMBMPP, andLPH-5, have been developed and are being studied.[52][53] Selective serotonin 5-HT2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT2B receptor activation.[53] In addition, selective serotonin 5-HT2B receptorantagonists, includingperipherally selective drugs likeVU0530244, are being investigated and developed for potential medical use.[47][54][55] Selective serotonin 5-HT2B receptor antagonism has been found to fully prevent thecardiotoxicity ofdexnorfenfluramine in animal studies, but clinical studies are needed.[56][57]
LSD, one of the most commonly used psychedelics in microdosing, is unique among psychedelics in itspharmacology and effects in that it appears to have two temporally and qualitatively distinct phases ofpsychoactive effects.[58][1][59][60] These include an initial psychedelic-like phase associated withserotonin5-HT2A receptoragonism and a subsequentparanoia- andpsychosis-like phase associated withdopamineD2-like receptor agonism.[58][59][60] Relatedly, unlike other psychedelics, chronic administration of low and microdose-like doses of LSD in rodents has been found to produce long-lastingneuroadaptations resulting in negative psychosis-like behavioral changes that persist long after LSD discontinuation.[58][1][59][60][61] These symptoms included psychosis-likehyperlocomotion, decreasedsocial interaction, hyperreactivity, markedaggression, andanhedonia.[58][59][60] Some of the symptoms could be transiently reversed by dopamineD2 receptorantagonists likehaloperidol andolanzapine but not by the serotonin 5-HT2A receptor antagonistvolinanserin, suggesting association withdopamine receptorsignaling rather than with the serotonin 5-HT2A receptor.[58][60] It is unknown whether similar effects may occur in humans.[1][60] In contrast to chronic administration, single macrodoses do not produce such changes in rodents.[62]
According to psychedelic researcherMatthew J. Baggott in 2023, the first documented instance of psychedelic microdosing may be theGrateful Dead's use of low and sub-psychedelic doses ofDOM as a mildstimulant in the late 1960s.[64] However, studies of the effects of very low doses of psychedelics date back as early as 1955.[7][3][65]Albert Hofmann first mentioned psychedelic microdosing and possible therapeutic benefits of the intervention likeeuphoria,antidepressant, and mild stimulant effects in a 1976High Times interview.[7][66][67] He is said to have taken microdoses of LSD for most of the later years of his life.[68]James Fadiman was responsible for introducing the modern paradigm and phenomenon of psychedelic microdosing, which had previously been largely unknown, with his 2011 bookThe Psychedelic Explorer's Guide.[69][66][70] Ayelet Waldman additionally helped to popularize microdosing with her 2017 bookA Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life.[69][71] There has been a dramatic increase in interest in psychedelic microdosing as well asscientific research into the practice since 2018.[69]
^Wong A, Raz A (October 2022). "Microdosing with classical psychedelics: Research trajectories and practical considerations".Transcult Psychiatry.59 (5):675–690.doi:10.1177/13634615221129115.PMID36317302.
^abcKuypers KP (2024)."Microdosing Psychedelics as a Promising New Pharmacotherapeutic".Modern CNS Drug Discovery. Cham: Springer Nature Switzerland. pp. 407–436.doi:10.1007/978-3-031-61992-2_26.ISBN978-3-031-61991-5. Retrieved28 May 2025.Decades earlier, Albert Hofmann, the "discoverer" of LSD and its hallucinogenic effects, mentioned that "very small doses, perhaps 25 micrograms," could be useful as an antidepressant (Ghose 2015; Horowitz 1976) or as a substitute for Ritalin (Fadiman 2017; Horowitz 1976). [...] Abramson et al. (1955) who conducted a range of experiments with LSD in the 1950s combined the data of 141 experimental sessions in 31 participants; eight of them received a dose between 1 and 25 mcg of LSD. [...]
^Wolf G, Singh S, Blakolmer K, Lerer L, Lifschytz T, Heresco-Levy U, Lotan A, Lerer B (January 2023). "Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation".Mol Psychiatry.28 (1):44–58.doi:10.1038/s41380-022-01832-z.PMID36280752.
^Nichols DE, Johnson MW, Nichols CD (February 2017). "Psychedelics as Medicines: An Emerging New Paradigm".Clin Pharmacol Ther.101 (2):209–219.doi:10.1002/cpt.557.PMID28019026.
^Flanagan TW, Nichols CD (2022). "Psychedelics and Anti-inflammatory Activity in Animal Models".Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 229–245.doi:10.1007/7854_2022_367.ISBN978-3-031-12183-8.PMID35546383.
^abKozlowska U, Nichols C, Wiatr K, Figiel M (July 2022). "From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders".J Neurochem.162 (1):89–108.doi:10.1111/jnc.15509.PMID34519052.One dosing method of psychedelics is the use of so called "microdoses"—very low concentrations of various psychedelics that do not reach the threshold of perceivable behavioral effects. This is usually 10% of active recreational doses (e.g., 10–15 µg of LSD, or 0.1–0.3 g of dry "magic mushrooms") taken up to three times per week.
^Ona G, Bouso JC (December 2020). "Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review".Neurosci Biobehav Rev.119:194–203.doi:10.1016/j.neubiorev.2020.09.035.PMID33031815.
^Dupuis D, Veissière S (October 2022). "Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos?".Transcult Psychiatry.59 (5):571–578.doi:10.1177/13634615221131465.PMID36263513.
^van Elk M, Yaden DB (September 2022). "Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review".Neurosci Biobehav Rev.140 104793.doi:10.1016/j.neubiorev.2022.104793.hdl:1887/3515020.PMID35878791.In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a 'super-placebo' (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility.
^Preller KH (November 2019). "The Effects of Low Doses of Lysergic Acid Diethylamide in Healthy Humans: Demystifying the Microdosing of Psychedelics".Biological Psychiatry.86 (10):736–737.doi:10.1016/j.biopsych.2019.08.021.PMID31648681.S2CID204800273.
^abLo DF, Zia H, Rajkumar P, Thakur A, O'Donnell H (January 2024). "Modern Psychedelic Microdosing Research on Mental Health: A Systematic Review".Prim Care Companion CNS Disord.26 (1).doi:10.4088/PCC.23r03581.PMID38228068.
^abcdeTagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease".J Psychopharmacol.37 (9):876–890.doi:10.1177/02698811231190865.PMID37572027.
^abcMcIntyre RS (2023). "Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents".Expert Opin Drug Saf.22 (10):881–883.doi:10.1080/14740338.2023.2248883.PMID37581427.
^Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants".Chem Rev.124 (1):124–163.doi:10.1021/acs.chemrev.3c00375.PMID38033123.
^abPeplow M (2024). "Next-generation psychedelics: should new agents skip the trip?".Nature Biotechnology.42 (6):827–830.doi:10.1038/s41587-024-02285-1.ISSN1087-0156.PMID38831049.Another problem is that some classical psychedelics are also agonists of the 5-HT2B receptor, which is expressed in heart tissue and can cause long-term cardiac problems. Kristensen's company Lophora aims to solve that with its lead compound LPH-5, a phenylethylamine derivative with an extra molecular ring that makes it less flexible. LPH-5 has a 60-fold higher selectivity for 5-HT2A over 5-HT2B.
^Padhariya K, Bhandare R, Canney D, Velingkar V (2017). "Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists".Cardiovasc Hematol Disord Drug Targets.17 (2):86–104.doi:10.2174/1871529X17666170703115111.PMID28676029.
^Baggott MJ (1 October 2023)."Learning about STP: A Forgotten Psychedelic from the Summer of Love"(PDF).History of Pharmacy and Pharmaceuticals.65 (1):93–116.doi:10.3368/hopp.65.1.93.ISSN2694-3034. Retrieved26 January 2025.The Grateful Dead learned they could use small amounts as a stimulant, an effect they used extensively during the recording of the album Aoxomoxoa in 1968 and 1969.143 The use of lower doses of DOM echoed DOET's "psychic energizer" effects and may be the first documented use of subpsychedelic doses of a psychedelic for cognitive enhancement, a practice that is now called microdosing.144
^abArchaic Revival (28 August 2023)."Beyond the Hype: Challenging the Effectiveness of Microdosing Schedules".Tripsitter. Retrieved27 April 2025.James Fadiman first ignited the microdosing craze with his 2011 book, The Psychedelic Explorer's Guide. Before this book, microdosing was largely unknown — though Albert Hofmann first mentioned the practice in a 1976 High Times article.
^Michael Horowitz (July 1976)."Interview: Albert Hofmann".High Times. No. 11. pp. 24–28, 31, 81. Archived fromthe original on 5 May 2025.High Times: What general medical uses might LSD be marketed for in the future? Hofmann: Very small doses, perhaps 25 micrograms, could be useful as a euphoriant or antidepressant.
^Cooke J (16 January 2021)."The Ultimate Guide to Microdosing Psychedelics".Tripsitter. Retrieved27 April 2025.Albert Hofmann, Ph.D. — the man who invented LSD — took microdoses of the substance for most of the later years of his life. He lived to the ripe old age of 102.
^abcMarks M, Cohen IG, Perez-Reyzin J, Angelatos D (13 January 2025)."Microdosing Psychedelics Under Local, State, and Federal Law".Scholarship Repository.103: 573. Retrieved27 April 2025.Despite this history, microdosing, as practiced today, is a relatively new trend that traces its roots to James Fadiman's 2011 book, which contains several case reports from people who report having microdosed. 252 The practice was also popularized by Ayelet Waldman in her autobiographical book, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life.253 Though people have likely microdosed for centuries in Mexico and elsewhere throughout the world, Fadiman and Waldman brought this mode of psychedelics consumption to a larger audience, garnering the media attention that has perpetuated the trend, and ultimately triggering an explosion of scientific research into microdosing since 2018.254
