High-dose psilocybin has shown potential in treating various psychiatric disorders, but its perceptual and cognitive effects, along with the risk of adverse events, highlight the need for alternative treatment approaches. One such approach is the use of low-dose psilocybin, which does not significantly alter cognition or perception. While low-dose psilocybin has garnered growing interest in the psychiatric community, its therapeutic efficacy remains unclear and warrants further investigation. This systematic review aims to evaluate the efficacy and safety of low-dose—whether in the form of microdosing or low-dose control conditions in clinical trials—psilocybin for mental disorders.
Methods:
We conducted a systematic review of all empirical evidence involving low-dose psilocybin in human subjects for psychiatric treatment from inception to June 2024. We also searched for relevant registered clinical trials on clinicaltrials.gov.
Results:
We identified five registered clinical trials and six publications, including randomized controlled trials (RCTs) (3, 50%), secondary outcome studies (2, 33%), and case report (1, 16%). Four studies (66%) included concurrent psychotherapy. Doses ranged from 1–3 mg per 70 kg as a single dose or 0.1–0.2 g of dried psilocybin-containing mushrooms every 3 days for up to 3 years. Two RCTs studied treatment-resistant depression with 1, 10, and 25 mg psilocybin doses. In the 1 mg group, 18% of participants showed a significant response, 8% achieved remission, and the Montgomery–Åsberg Depression Rating Scale score improved by −5.4 (95% confidence interval [CI]: −8.1 to −2.7) at week 3, though only 10% maintained this by week 12. Another study found transient improvements in anxiety and cognitive function with 1 mg. One trial reported no significant improvement with 1–3 mg doses, though 12% achieved anxiety remission and 16% depression remission. An RCT comparing 25 mg to 1 mg plus escitalopram found higher response rates with 25 mg than 1 mg group, although no significant difference in rumination or thought suppression between groups was observed.
Conclusion:
The empirical evidence for the efficacy of low-dose psilocybin in treating mental disorders is limited. The current research is constrained by a lack of well-designed studies that compare low-dose psilocybin to placebo. To better understand its potential, future research should include large, rigorous RCTs specifically focused on assessing low-dose protocols.
BradshawAJ, Ramírez-CruzV, AwanAR, et al.Phylogenomics of the psychoactive mushroom genus Psilocybe and evolution of the psilocybin biosynthetic gene cluster. Proc Natl Acad Sci U S A, 2024; 121(3):e2311245121; doi: 10.1073/pnas.2311245121
LoweH, ToyangN, SteeleB, et al.The therapeutic potential of psilocybin. Molecules, 2021; 26(10):2948; doi: 10.3390/molecules26102948
4.
HadarA, DavidJ, ShalitN, et al.The psychedelic renaissance in clinical research: A bibliometric analysis of three decades of human studies with psychedelics. J Psychoactive Drugs, 2023; 55(1):1–10; doi: 10.1080/02791072.2021.2022254
5.
Dinis-OliveiraRJ. Metabolism of psilocybin and psilocin: Clinical and forensic toxicological relevance. Drug Metab Rev, 2017; 49(1):84–91; doi: 10.1080/03602532.2016.1278228
6.
GlatfelterGC, PottieE, PartillaJS, et al.Structure–activity relationships for psilocybin, baeocystin, aeruginascin, and related analogues to produce pharmacological effects in mice. ACS Pharmacol Transl Sci, 2022; 5(11):1181–1196; doi: 10.1021/acsptsci.2c00177
7.
MacCallumCA, LoLA, PistawkaCA, et al.Therapeutic use of psilocybin: Practical considerations for dosing and administration. Front Psychiatry, 2022; 13:1040217; doi: 10.3389/fpsyt.2022.1040217
8.
VargasMV, DunlapLE, DongC, et al.Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science, 2023; 379(6633):700–706; doi: 10.1126/science.adf0435
9.
MallaroniP, MasonNL, ReckwegJT, et al.Assessment of the acute effects of 2C‐B vs. psilocybin on subjective experience, mood, and cognition. Clin Pharmacol Ther, 2023; 114(2):423–433; doi: 10.1002/cpt.2958
10.
KaypakAC, RazA. Macrodosing to microdosing with psychedelics: Clinical, social, and cultural perspectives. Transcult Psychiatry, 2022; 59(5):665–674; doi: 10.1177/13634615221119386
11.
BonnieuxJN, VanderZwaagB, PremjiZ, et al.Psilocybin’s effects on cognition and creativity: A scoping review. J Psychopharmacol, 2023; 37(7):635–648; doi: 10.1177/02698811231179801
12.
Carhart-HarrisRL, GoodwinGM. The therapeutic potential of psychedelic drugs: Past, present, and future. Neuropsychopharmacology, 2017; 42(11):2105–2113; doi: 10.1038/npp.2017.84
13.
ReiffCM, RichmanEE, NemeroffCB, et al.; Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of Research. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry, 2020; 177(5):391–410; doi: 10.1176/appi.ajp.2019.19010035
14.
DavisAK, BarrettFS, MayDG, 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
YerubandiA, ThomasJE, BhuiyaNM, et al.Acute adverse effects of therapeutic doses of psilocybin: A systematic review and meta-analysis. JAMA Netw Open, 2024; 7(4):e245960; doi: 10.1001/jamanetworkopen.2024.5960
17.
ZeifmanRJ, SinghalN, BreslowL, et al.On the relationship between classic psychedelics and suicidality: A systematic review. ACS Pharmacol Transl Sci, 2021; 4(2):436–451; doi: 10.1021/acsptsci.2c00014
18.
McCroneP, FisherH, KnightC, et al.Cost-effectiveness of psilocybin-assisted therapy for severe depression: Exploratory findings from a decision analytic model. Psychol Med, 2023; 53(16):7619–7626; doi: 10.1017/S0033291723001411
19.
RyanRS, CopelloA, FoxAP. Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health. BMC Psychiatry, 2023; 23(1):160; doi: 10.1186/s12888-023-04628-9
20.
KuypersKP, NgL, ErritzoeD, et al.Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. J Psychopharmacol, 2019; 33(9):1039–1057; doi: 10.1177/0269881119857204
21.
PolitoV, LiknaitzkyP. The emerging science of microdosing: A systematic review of research on low dose psychedelics (1955–2021) and recommendations for the field. Neurosci Biobehav Rev, 2022; 139:104706; doi: 10.1016/j.neubiorev.2022.104706
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 2021; 372:n71; doi: 10.1136/bmj.n71
24.
HigginsJPT, AltmanDG, GøtzschePC, et al.; Cochrane Bias Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ, 2011; 343(oct18 2):d5928–d5928; doi: 10.1136/bmj.d5928
25.
GriffithsRR, JohnsonMW, CarducciMA, 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
26.
GoodwinGM, AaronsonST, AlvarezO, et al.Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med, 2022; 387(18):1637–1648; doi: 10.1056/NEJMoa2206443
27.
GoodwinGM, AaronsonST, AlvarezO, et al.Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life. J Affect Disord, 2023; 327:120–127; doi: 10.1016/j.jad.2023.01.108
28.
Carhart-HarrisR, GiribaldiB, WattsR, et al.Trial of psilocybin versus escitalopram for depression. N Engl J Med, 2021; 384(15):1402–1411; doi: 10.1056/NEJMoa2032994
29.
LyonsA. Self-administration of Psilocybin in the Setting of Treatment-resistant Depression. Innov Clin Neurosci, 2022; 19(7–9):44–47.
30.
BarbaT, BuehlerS, KettnerH, et al.Effects of psilocybin versus escitalopram on rumination and thought suppression in depression. BJPsych Open, 2022; 8(5):e163; doi: 10.1192/bjo.2022.565
31.
Garcia-RomeuA, BarrettFS, CarbonaroTM, et al.Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches. J Psychopharmacol, 2021; 35(4):353–361; doi: 10.1177/0269881121991822
32.
FadimanJ. The Psychedelic Explorer’s Guide. 1st ed. New York: Inner Traditions International, Limited; 2011.
33.
OnaG, BousoJC. Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review. Neurosci Biobehav Rev, 2020; 119:194–203; doi: 10.1016/j.neubiorev.2020.09.035
34.
SzigetiB, KartnerL, BlemingsA, et al.Self-blinding citizen science to explore psychedelic microdosing. Elife, 2021; 10:e62878; doi: 10.7554/eLife.62878
35.
MurphyRJ, MuthukumaraswamyS, de WitH. Microdosing psychedelics: Current evidence from controlled studies. Biol Psychiatry Cogn Neurosci Neuroimaging, 2024; 9(5):500–511; doi: 10.1016/j.bpsc.2024.01.002
36.
Dawood HristovaJJ, Pérez-JoverV. Psychotherapy with psilocybin for depression: Systematic review. Behav Sci (Basel), 2023; 13(4):297; doi: 10.3390/bs13040297
37.
HaikazianS, Chen-LiDC, JohnsonDE, et al.Psilocybin-assisted therapy for depression: A systematic review and meta-analysis. Psychiatry Res, 2023; 329:115531; doi: 10.1016/j.psychres.2023.115531
38.
van der MeerPB, FuentesJJ, KapteinAA, et al.Therapeutic effect of psilocybin in addiction: A systematic review. Front Psychiatry, 2023; 14:1134454; doi: 10.3389/fpsyt.2023.1134454
39.
LarsenSE, StirmanSW, SmithBN, et al.Symptom exacerbations in trauma-focused treatments: Associations with treatment outcome and non-completion. Behav Res Ther, 2016; 77:68–77; doi: 10.1016/j.brat.2015.12.009
40.
RomeoB, KarilaL, MartelliC, et al.Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis. J Psychopharmacol, 2020; 34(10):1079–1085; doi: 10.1177/0269881120919957
41.
RouaudA, CalderAE, HaslerG. Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins. J Psychopharmacol, 2024; 38(3):217–224; doi: 10.1177/02698811231225609
42.
Soto-AngonaÓ, ForteaA, ForteaL, et al.Do classic psychedelics increase the risk of seizures? A scoping review. Eur Neuropsychopharmacol, 2024; 85:35–42; doi: 10.1016/j.euroneuro.2024.05.002
43.
NayakSM, JacksonH, SepedaND, et al.Naturalistic psilocybin use is associated with persisting improvements in mental health and wellbeing: Results from a prospective, longitudinal survey. Front Psychiatry, 2023; 14:1199642; doi: 10.3389/fpsyt.2023.1199642
44.
SøndergaardA, MadsenMK, OzenneB, et al.Lasting increases in trait mindfulness after psilocybin correlate positively with the mystical-type experience in healthy individuals. Front Psychol, 2022; 13:948729; doi: 10.3389/fpsyg.2022.948729
45.
MadsenMK, FisherPM, StenbækDS, et al.A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding. Eur Neuropsychopharmacol, 2020; 33:71–80; doi: 10.1016/j.euroneuro.2020.02.001
46.
RavalNR, JohansenA, DonovanLL, et al.A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int J Mol Sci, 2021; 22(2):835; doi: 10.3390/ijms22020835
47.
GrayNA, MilakMS, DeLorenzoC, et al.Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder. Biol Psychiatry, 2013; 74(1):26–31; doi: 10.1016/j.biopsych.2012.11.012
WojtasA, BysiekA, Wawrzczak-BargielaA, et al.Effect of psilocybin and ketamine on brain neurotransmitters, glutamate receptors, DNA and rat behavior. Int J Mol Sci, 2022; 23(12):6713; doi: 10.3390/ijms23126713
50.
QuirozC, OrrúM, ReaW, et al.Local control of extracellular dopamine levels in the medial nucleus accumbens by a glutamatergic projection from the infralimbic cortex. J Neurosci, 2016; 36(3):851–859; doi: 10.1523/JNEUROSCI.2850-15.2016
51.
SakashitaY, AbeK, KatagiriN, et al.Effect of psilocin on extracellular dopamine and serotonin levels in the mesoaccumbens and mesocortical pathway in awake rats. Biol Pharm Bull, 2015; 38(1):134–138; doi: 10.1248/bpb.b14-00315
52.
VollenweiderFX, VontobelP, HellD, et al.5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man—a PET study with [11C] raclopride. Neuropsychopharmacology, 1999; 20(5):424–433; doi: 10.1016/S0893-133X(98)00108-0
