Psychedelic microdosing

Dosage and administration

LSD and psilocybin, the latter often in the form of psilocybin-containing mushrooms, are the most commonly used psychedelics in microdosing. A microdose is considered to be between approximately one-twentieth to one-tenth of a typical recreational dose. 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. 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.

Side effects

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

Cardiovascular toxicity

Psychedelics, including LSD, psilocybin, dimethyltryptamine (DMT), mescaline, and many others, are potent serotonin 5-HT_2B receptor agonists in addition to the serotonin 5-HT_2A receptor agonism that mediates their hallucinogenic effects. 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. 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. Due to potent serotonin 5-HT_2B receptor agonism, long-term use of psychedelics, for instance microdosing, might produce heart and other organ toxicity. Conversely, infrequent macrodoses of psychedelics are thought to be safe.

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. 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. 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. 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. 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). Conversely, other psychedelics like psilocin, DMT, and mescaline have not been assessed in terms of this assay as of 2022. However, other research suggests that the toxicity may not be specifically or exclusively dependent on ERK2 signaling. More research is needed to determine whether long-term frequent use of psychedelics, including microdosing, may cause cardiac valvulopathy and other related toxicities.

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. Selective serotonin 5-HT_2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT_2B receptor activation. In addition, selective serotonin 5-HT_2B receptor antagonists, including peripherally selective drugs like VU0530244, are being investigated and developed for potential medical use. 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.

Neurological toxicity

LSD, one of the most commonly used psychedelics in microdosing, is unique among psychedelics in its pharmacology and effects in that it appears to have two temporally and qualitatively distinct phases of psychoactive effects. These include an initial psychedelic-like phase associated with serotonin 5-HT_2A receptor agonism and a subsequent paranoia- and psychosis-like phase associated with dopamine D₂-like receptor agonism. Relatedly, unlike other psychedelics, chronic administration of low and microdose-like doses of LSD in rodents has been found to produce long-lasting neuroadaptations resulting in adverse psychosis-like behavioral changes that persist long after LSD discontinuation. These symptoms included psychosis-like hyperlocomotion, decreased social interaction, hyperreactivity, marked aggression, and anhedonia. Some of the symptoms could be transiently reversed by dopamine D₂ receptor antagonists like haloperidol and olanzapine but not by the serotonin 5-HT_2A receptor antagonist volinanserin, suggesting association with dopamine receptor signaling rather than with the serotonin 5-HT_2A receptor. It is unknown whether similar effects may occur in humans. In contrast to chronic administration, single macrodoses of LSD do not produce such changes in rodents.

Pharmacology

The clinical pharmacodynamics and pharmacokinetics of microdosed LSD have been studied.

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. However, studies of the effects of very low doses of psychedelics date back as early as 1955. 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. He is said to have taken microdoses of LSD for most of the later years of his life. 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. 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. There has been a dramatic increase in interest in psychedelic microdosing as well as scientific research into the practice since 2018.

Society and culture

Psychedelic microdosing is frequently discussed on online forums such as the r/microdosing community on Reddit.