The therapeutic potential of microdosing psychedelics in depression

Classical psychedelics such as lysergic acid diethylamide (LSD) and psilocybin produce perceptual and subjective effects primarily via agonism at the serotonin 5-HT2A receptor. Kuypers summarises earlier controlled research showing that full psychedelic doses (for example, 100–200 mcg LSD or about 15 mg psilocybin) can increase positive mood, social behaviour and emotional empathy, and reduce recognition of negative emotional states. Alongside supervised clinical work suggesting a favourable safety profile and emerging therapeutic promise in affective and substance use disorders, anecdotal reports have popularised the repeated use of subperceptual doses — microdosing — as self-treatment for depression and related conditions. This review set out to examine whether experimental evidence supports the therapeutic potential and safety of microdosing for affective disorders. Kuypers therefore searched for controlled experimental human studies administering low doses of LSD or psilocybin and synthesised findings on psychological, cognitive and physiological effects to assess whether these effects plausibly relate to antidepressant mechanisms and whether repeated low-dose use appears safe.

Kuypers conducted a targeted literature search using a combined keyword string covering affective disorders, microdosing/low-dose terminology, and psychedelic substances. The author searched PubMed and MedLine and initially retrieved 23 hits. After removing six duplicates and five irrelevant records (for example studies using full psychedelic doses, radiolabelled compounds, DMT at low dose, or non-pharmacological uses of the acronym 'LSD'), 12 articles remained. Additional sources were added from a book on microdosing (n = 4), a review of long-term psychedelic effects (n = 1) and the author’s personal database (n = 7), while preclinical studies were excluded due to uncertain generalisability to humans. Papers based solely on self-reports from microdosers were excluded from the experimental dataset but were used in the introduction. The final dataset comprised 14 experimental human studies. Kuypers organised the review by substance (LSD, psilocybin) and provided extra methodological detail for older studies whose designs did not always meet modern standards. The review focused on human experimental work that administered low doses and assessed subjective experience, cognitive or affective measures, physiological parameters, and where available, neuroimaging or receptor occupancy data. The extracted text indicates that methodological details of individual studies are presented in tables referenced in the paper; however, not all sample sizes or procedural specifics are clearly reported in the extracted sections.

Overall dataset and scope: Fourteen experimental human studies met the inclusion criteria. Findings come mainly from small samples of healthy volunteers; a few studies included patient groups (anxiety related to life-threatening illness, obsessive compulsive disorder). LSD — older experimental work: Early dose–response experiments (Isbell et al.) administered a range of LSD doses (reported in the extraction as 0.25–2 mcg/kg or 10–180 mcg) and examined mental and physiological measures and tolerance. The lowest dose (0.25 mcg/kg) did not differ reliably from placebo, and repeated low doses (10–30 mcg twice daily for 3 days) produced transient tolerance to the mental effects of a subsequent higher dose (75 mcg). Greiner et al. conducted a descriptive dose-effect study across several low doses (reported case counts per dose are given) and suggested a threshold around 20 mcg for detectable effects; however, that paper reported changes qualitatively without formal statistics. McGlothlin et al. compared repeated high-dose LSD with control conditions that included a 25 mcg LSD group and an amphetamine group; the 25 mcg LSD condition was commonly labelled as 'pleasant' by participants and resembled stimulant effects in some measures, though the paper’s selective reporting and combined control groups limit inference about low versus high doses. LSD — recent controlled studies in healthy volunteers: A randomised, double-blind, placebo-controlled between-group study in elderly participants compared repeated low doses (extraction lists 0, 5, 10 and 20 but units in the extraction are unclear and likely micrograms) given six times every four days (n = 12 per group). The only statistically significant cognitive finding was overestimation of longer time intervals (≥2000 ms), most pronounced at the mid-range dose. Blood assays showed measurable plasma concentrations after the mid and high microdoses but not after the lowest dose, with an average half-life of about 8 hours; repeated dosing with interposed dose-free days did not change total plasma concentrations. Adverse events did not differ significantly from placebo although mild-to-moderate headache was more common in LSD groups. In a within-subject placebo-controlled study, Bershad et al. tested three LSD tartrate doses (6.5, 13 and 26 mcg tartrate, corresponding to about 5, 10 and 20 mcg base). Participants reported feeling under the influence at 13 and 26 mcg, with increases in both 'liking' and 'disliking' and higher self-rated anxiety, but no broad mood, cognitive or social behaviour impairments; small transient increases in systolic and diastolic blood pressure were observed at some doses. A functional imaging study administering 13 mcg LSD tartrate reported altered limbic connectivity — increased amygdala connectivity with angular and frontal gyri and decreased connectivity with superior temporal gyrus — and these connectivity changes correlated with increases in positive affect measured acutely. LSD — studies in patient samples: Gasser et al. evaluated LSD-assisted psychotherapy in patients with anxiety related to life-threatening illness and included a low-dose control arm (20 mcg). The low-dose arm (only three participants received 20 mcg in the extracted text) showed more frequent reports of anger, anxiety and abnormal thinking compared with the high-dose arm, while trait and state anxiety decreased after high-dose sessions and these reductions persisted up to 12 months. The small sample and fluctuating health status of participants limit conclusions about low-dose therapeutic effects. Psilocybin — healthy volunteer and naturalistic studies: Five studies tested low psilocybin doses. A naturalistic, uncontrolled study of self-administered psilocybin-containing truffles reported improved convergent (n = 27; 0.41 g truffles) and divergent (n = 33; 0.35 g truffles) thinking 1.5 hours after ingestion compared with baseline, though the lack of control conditions prevents attribution to the drug. Controlled laboratory work by Hasler et al. tested multiple doses including a low dose (reported as 45 mcg/kg or about 2.3 mg for a 70 kg person) and found only a decrease in heart rate 6 hours after ingestion; no other differences versus placebo were detected. Griffiths et al. reported mild psychedelic effects after a 5 mg/70 kg dose compared with placebo. Psilocybin — receptor occupancy and patient study: Madsen and colleagues used positron emission tomography to link psilocybin dose (3–30 mg in the extracted text) to 5-HT2A receptor occupancy and subjective intensity, reporting that receptor occupancy rose with dose and paralleled reported psychedelic intensity. The extracted text contains inconsistent numerical details for the lowest dose’s occupancy (one passage reports 43% occupancy at 3 mg and average intensity of 40%, another passage in the discussion reports a 2% occupancy at 3 mg described as 'non-substantial'); the exact occupancy for the low dose is therefore unclear in the extraction. Moreno et al. administered escalating doses of psilocybin to nine patients with obsessive compulsive disorder, including a low dose (reported as 25 mcg/kg = 1.75 mg/70 kg in the extraction) and observed symptom reduction relative to baseline after the low dose; the small sample restricts generalisability. Adverse events and physiological effects: Across studies, single acute low doses were generally well tolerated in healthy volunteers. Reported adverse effects included transient increases in anxiety and physical discomfort on dosing days and more frequent mild headaches after microdoses of LSD compared with placebo. Physiological effects were minimal overall; one study reported small, clinically irrelevant increases in systolic and diastolic blood pressure at some LSD microdoses. The reviewers recommend monitoring cardiac parameters in repeated-dose studies because of theoretical concerns about 5-HT2B-mediated valvular effects from serotonergic agents at higher cumulative exposures. Evidence for tolerance after very frequent dosing was observed in older experiments when low doses were given twice daily for several days, but transient tolerance was reversed after dose-free days.

Kuypers interprets the assembled evidence as indicating that low doses of LSD and psilocybin produce subtle effects on selective cognitive processes (for example time perception, convergent and divergent thinking), brain circuits implicated in affective processing, and transient subjective changes, including both pleasant feelings and increased anxiety. These effects are milder versions of changes seen with full psychedelic doses and, importantly, were not associated with broad cognitive impairment in the reviewed experimental samples. The author suggests possible mechanisms linking microdosing to antidepressant effects: increased divergent thinking could reflect enhanced cognitive flexibility, while altered time perception and a heightened present-moment experience could foster mindfulness and reduce ruminative thinking, thereby ameliorating depressive symptoms. Neurobiological mechanisms are touched on: acute changes in limbic connectivity after low-dose LSD and dose-related 5-HT2A receptor occupancy after psilocybin might underpin behavioural effects, but the clinical relevance of small single-dose receptor changes is unclear from the available data. Kuypers highlights two important methodological caveats. First, expectancy and placebo effects may account for a substantial portion of self-reported benefits in observational surveys; placebo-controlled trials can address this but may themselves be subject to expectancy influences if active placebo conditions are not used. Second, the existing experimental literature is limited by small sample sizes, heterogeneous methods, and predominantly healthy volunteer samples, so it is premature to claim therapeutic efficacy in depressive disorders. On safety and trial design, the author notes that low doses were well tolerated in healthy volunteers but advises monitoring cardiovascular parameters in repeated-dose trials and careful management of concomitant serotonergic antidepressants given unknown interactions. Practical issues discussed for future clinical research include the need for psychological support around dosing days because transient anxiety can occur, clarifying whether LSD base or tartrate was used (dosage reporting differs across older and modern studies), and establishing optimal dosing regimens — evidence suggests daily dosing is unlikely to be efficacious whereas schedules with 1 day 'on' and 2 days 'off' (the so-called Fadiman cycle) may limit tolerance and align with user practice. Finally, Kuypers calls for head-to-head comparisons of low-dose LSD and psilocybin because users and some studies suggest LSD may show relatively more stimulating or cognitive effects while psilocybin may be experienced as softer or more affective; whether these differences are robust and therapeutically relevant remains to be tested.

Kuypers concludes that, although full psychedelic doses have shown preliminary efficacy in treating depression, the current experimental evidence for therapeutic benefit of microdosing is limited and inconclusive. Small, mostly healthy volunteer studies indicate subtle positive effects on cognitive and affective processes relevant to depression and an acceptable short-term safety profile, but the samples are too small and heterogeneous to support clinical recommendations. The author therefore argues that controlled clinical trials in depressed patients are warranted to determine the safety, efficacy, optimal dosing and mechanisms of microdosing as a potential adjunct or alternative psychiatric treatment.