Psychedelic microdosing

Psychedelic microdosing is a form of drug microdosing in which sub-hallucinogenic doses of serotonergic psychedelics like LSD and psilocybin are taken for claimed cognitive and emotional benefits.^[1][2][3]

Uses, research, and effects

A variety of perceived benefits of psychedelic microdosing have been anecdotally claimed, such as beneficial effects on mood or well-being, anxiety, cognitive function, creativity, and productivity.^[4][5][6][3] In addition, people informally use microdosing to treat psychiatric conditions and it is being formally clinically studied for such purposes.^[5][7][8] Examples include for depression,^[9] anxiety,^[8] obsessive–compulsive disorder (OCD),^[8] post-traumatic stress disorder (PTSD),^[8] substance misuse,^[8] and schizophrenia,^[10] among others.^[8] There is very little scientific research on microdosing or its effects as of 2024 however and the claimed beneficial effects of microdosing have largely not been scientifically validated.^[2][1]

LSD microdosing three times per week was found in a preliminary 2024 randomized controlled trial to increase sleep duration by 24 minutes on average one day after the microdose (but not the same night of the dose).^[2][11] This included an increase in duration of REM sleep.^[2][11]

Psychedelics and microdosing are being͏͏ investigated͏͏ for potential͏͏ treatment of neurodegenerative disorders like͏͏ Alzheimer's disease.͏͏^[12][13] They are also being studied for treatment of depression in people with Alzheimer's disease.^[13] Certain psychedelics, like DOI and psilocybin, acting as serotonin 5-HT_2A receptor agonists, have been found to have potent anti-inflammatory effects at doses well below those that produce hallucinogenic effects in preclinical research and are being clinically investigated for the potential treatment of inflammatory conditions such as neuroinflammation.^{[14][15][16][17]} The anti-inflammatory effects of psychedelics may be involved in the possible benefits of microdosing.^[1][18] LSD microdosing is being clinically studied in the treatment of Alzheimer's disease for its anti-inflammatory effects.^[19][20]

The benefits of microdosing may in part or full be a placebo mediated by positive expectancy effects.^{[21][22][23][24]} In people with major depressive disorder, placebos are known to produce substantial reductions in depressive symptoms all on their own and conventional antidepressants barely outperform placebos in clinical trials.^[25][26][27] Some researchers have proposed that psychedelics, in general, may be active "super placebos" due to their powerful hallucinogenic effects and cultural associations.^[28][29]

Tolerance and tachyphylaxis are known to rapidly develop to the hallucinogenic effects and to other effects of serotonergic psychedelics in both animals and humans.^[30][31][32] This is thought to be mediated by rapid serotonin 5-HT_2A receptor downregulation that is very slow to recover.^[30][31] 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]

Dosage and administration

LSD and psilocybin, the latter often in the form of psilocybin-containing mushrooms, are the most commonly used psychedelics in microdosing.^[33] A microdose is considered to be between approximately one-twentieth to one-tenth of a typical recreational dose.^[3][9] Microdoses of psychedelics are 5 to 20 μg for LSD, 1 to 5 mg for psilocybin, 0.1 to 0.5 g of psilocybin-containing mushrooms, and <75 mg for mescaline.^{[34][35][36][2][19]} These psychedelics have perceptible psychedelic effects at minimum doses of 10 to 20 μg for LSD, 3 to 5 mg psilocybin, 0.5 g psilocybin-containing mushrooms, and 100 mg mescaline.^{[34][35][36][2]}

Side effects

Side effects of psychedelic microdosing with LSD or psilocybin may include increased blood pressure, anxiety, cognitive impairment, and physiological discomfort.^[37][6] The side effects of microdosing are generally infrequent, mild, dose-dependent, and short-lasting.^[37][6]

Long-term toxicity

Psychedelics, including LSD, psilocybin, dimethyltryptamine (DMT), mescaline, and many others,^[38][39] are potent serotonin 5-HT_2B receptor agonists in addition to the serotonin 5-HT_2A receptor agonism that mediates their hallucinogenic effects.^{[40][41][42][43]} Long-term use of potent serotonin 5-HT_2B receptor agonists like fenfluramine, methysergide, ergotamine, cabergoline, pergolide, and MDMA is known to produce serious organ toxicity including cardiac fibrosis, valvulopathy, and pulmonary hypertension.^{[44][45][46][47][48]} Conversely, certain other serotonin 5-HT_2B receptor agonists, such as guanfacine, ropinirole, and oxymetazoline, have not been associated with such toxicities, perhaps due to factors like biased agonism and/or inadequate potency or exposure.^[44][48][49] Due to potent serotonin 5-HT_2B receptor agonism, long-term use of psychedelics, for instance microdosing, might produce heart and other organ toxicity.^{[43][40][41][42]} Conversely, infrequent macrodoses of psychedelics are thought to be safe.^[40][42][50]

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.^{[40][41][42][50]} It is notable in this regard that findings on the serotonin 5-HT_2B receptor agonism of psychedelics including LSD, psilocybin, mescaline, and dimethyltryptamine (DMT) are conflicting, with some studies finding them to be potent serotonin 5-HT_2B receptor agonists and others finding them to be very weak or negligible serotonin 5-HT_2B receptor agonists, depending on the study and assay.^[38][50][39] The cardiac toxicity of serotonin 5-HT_2B receptor activation has been specifically linked to extracellular regulating kinase 2 (ERK2) signaling and not necessarily to other downstream signaling pathways.^[42][50] LSD has been found to have low activity on a valvulopathogenic ERK2 serotonin 5-HT_2B receptor agonism readout relative to known or suspected valvopathogens like norfenfluramine, pergolide, methylergonovine (methylergometrine), ergonovine (ergometrine), cabergoline, dihydroergotamine, and ergotamine.^[42][50] This was in terms of both activational potency (EC₅₀Tooltip half-maximal effective concentration = 110 nM vs. 1.0–20 nM, respectively) and efficacy (E_maxTooltip half-maximal effective concentration = 39% vs. 53–79%, respectively).^[50] Conversely, other psychedelics like psilocin, DMT, and mescaline have not been assessed in terms of this assay as of 2022.^[50] However, other research suggests that the toxicity may not be specifically or exclusively dependent on ERK2 signaling.^[42] More research is needed to determine whether long-term frequent use of psychedelics, including microdosing, may cause cardiac valvulopathy and other related toxicities.^{[43][40][41][42]}

Selective serotonin 5-HT_2A receptor agonists that do not activate the serotonin 5-HT_2B receptor or other serotonin receptors, such as 25CN-NBOH, DMBMPP, and LPH-5, have been developed and are being studied.^[51][52] Selective serotonin 5-HT_2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT_2B receptor activation.^[52] In addition, selective serotonin 5-HT_2B receptor antagonists, including peripherally selective drugs like VU0530244, are being investigated and developed for potential medical use.^[46][53][54] Selective serotonin 5-HT_2B receptor antagonism has been found to fully prevent the cardiotoxicity of dexnorfenfluramine in animal studies, but clinical studies are needed.^[55][56]

Pharmacology

The clinical pharmacodynamics and pharmacokinetics of microdosed LSD have been studied.^[2][57][20]

History

According to psychedelic researcher Matthew J. Baggott in 2023, the first documented instance of psychedelic microdosing may be the Grateful Dead's use of low and sub-psychedelic doses of DOM as a mild stimulant in the late 1960s.^[58] However, studies of the effects of very low doses of psychedelics date back as early as 1955.^[7][3][59] Albert Hofmann first mentioned psychedelic microdosing and possible therapeutic benefits of the intervention like euphoria, antidepressant, and mild stimulant effects in a 1976 High Times interview.^[7][60][61] He is said to have taken microdoses of LSD for most of the later years of his life.^[62] James Fadiman was responsible for introducing the modern paradigm and phenomenon of psychedelic microdosing, which had previously been largely unknown, with his 2011 book The Psychedelic Explorer's Guide.^[63][60][64] Ayelet Waldman additionally helped to popularize microdosing with her 2017 book A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life.^[63][65] There has been a dramatic increase in interest in psychedelic microdosing as well as scientific research into the practice since 2018.^[63]

Society and culture

Psychedelic microdosing is frequently discussed on online forums such as the r/microdosing community on Reddit.^[1][6][66]

See also

• Psychedelic drug § Psychedelic afterglows
• Nootropic
• Psychedelic therapy
• List of investigational hallucinogens and entactogens