Psychedelics such as lysergic acid diethylamide (LSD) and psilocybin have shown a beneficial effect on substance use disorder (SUD) symptoms. In this systematic review, we aimed to assess the efficacy and safety of psychoactive tryptamines in patients with an SUD or non-substance-related disorder (i.e., gambling disorder) in order to provide a comprehensive overview of the available evidence and identify potential research gaps.
Methods:
A systematic literature search was performed in eight different databases up to February 2024. Clinical trials were included that assessed the efficacy and safety of psychoactive tryptamines other than psilocybin and ibogaine. A quality assessment of the included trials was done based on the revised Cochrane risk-of-bias tools.
Results:
A total of four clinical trials (three randomized controlled trials and one single-arm clinical trial; n = 176 patients) were included, all in patients with alcohol use disorder. Dipropyltryptamine and diethyltryptamine were the two investigated psychoactive tryptamines. Abstinence ranged from 10% (duration of follow-up unknown) to 38% at 26 weeks of follow-up, and severity of alcohol use did not differ between the psychoactive tryptamine group and the control groups. Adverse effects were not well reported in the trials.
Conclusion:
Studies assessing the efficacy of psychoactive tryptamines other than psilocybin and ibogaine in addiction are scarce and show limited evidence for effectiveness in the treatment of addictive disorders.
FrancoR, Rivas-SantistebanR, LilloJ, et al.5-Hydroxytryptamine, glutamate, and ATP: Much more than neurotransmitters. Front Cell Dev Biol, 2021 2021;9:667815. April-Perspective.
4.
CoppolaM, BevioneF, MondolaR. Psilocybin for treating psychiatric disorders: A psychonaut legend or a promising therapeutic perspective? J Xenobiot, 2022; 12(1):41–52.
5.
SchultesRE, HofmannA, RätschC. Plants of the gods: their sacred, healing, and hallucinogenic powers. Rev. and expanded ed ed. Healing Arts Press: Rochester, Vt.; 2001.
6.
HofmannA, HeimR, BrackA, et al.Psilocybin, a psychotropic substance from the Mexican mushroom Psilicybe mexicana Heim. Experientia, 1958; 14(3):107–109.
7.
RydzyńskiZ, CwynarS, GrzelakL, et al.Preliminary report on the experience with psychosomimetic drugs in the treatment of alcoholism. Act Nerv Super (Praha), 1968; 10:273.
8.
RydzyńskiZ, GruszczyńskiW. Treatment of alcoholism with psychotomimetic drugs. A follow-up study. Act Nerv Super (Praha), 1978 Feb;20(1):81–82.
9.
BöszörményiZ. Psilocybin and diethyltryptamine: Two tryptamine hallucinogens. Neuropsychopharmacology, 1961; 2:226–229.
10.
van der MeerPB, FuentesJJ, KapteinAA, et al.Therapeutic effect of psilocybin in addiction: A systematic review. Front Psychiatry, 2023; 14:1134454.
11.
MashDC, KoveraCA, BuckBE, et al.Medication development of ibogaine as a pharmacotherapy for drug dependence. Ann N Y Acad Sci, 1998; 844:274–292.
12.
BelgersM, LeenaarsM, HombergJR, et al.Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Transl Psychiatry, 2016; 6(5):e826-e826.
13.
KöckP, FroelichK, WalterM, et al.A systematic literature review of clinical trials and therapeutic applications of ibogaine. J Subst Abuse Treat, 2022; 138:108717.
14.
DunlapLE, AndrewsAM, OlsonDE. Dark classics in chemical neuroscience: 3,4-Methylenedioxymethamphetamine. ACS Chem Neurosci, 2018; 9(10):2408–2427.
15.
BarkerSA. N, N-Dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function. Front Neurosci, 2018; 12:536.
16.
BöszörményiZ, SzáraS. Dimethyltryptamine experiments with psychotics. J Ment Sci, 1958; 104(435):445–453.
17.
SchimmersN, BreeksemaJJ, Smith-ApeldoornSY, et al.Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: A systematic review. Psychopharmacology (Berl), 2022; 239(1):15–33.
18.
HolzeF, LeyL, MüllerF, et al.Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology, 2022; 47(6):1180–1187.
19.
SpillaneJF. Debating the controlled substances act. Drug Alcohol Depend, 2004; 76(1):17–29.
20.
Dos SantosRG, OsórioFL, CrippaJA, et al.Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and Lysergic Acid Diethylamide (LSD): A systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol, 2016; 6(3):193–213.
21.
VolkowND, BoyleM. Neuroscience of addiction: Relevance to prevention and treatment. Am J Psychiatry, 2018; 175(8):729–740.
22.
FuentesJJ, FonsecaF, ElicesM, et al.Therapeutic use of LSD in psychiatry: A systematic review of randomized-controlled clinical trials. Front Psychiatry, 2019; 10:943.
23.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Syst Rev, 2021; 10(1):89.
24.
HusainMI, LedwosN, FellowsE, et al.Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action? Front Psychiatry, 2022; 13:1076459.
25.
SterneJA, HernánMA, ReevesBC, et al.ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ, 2016; 355:i4919.
26.
SterneJAC, SavovićJ, PageMJ, et al.RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ, 2019; 366:l4898.
27.
VourlekisA, FaillaceL, SzaraS. Psychotherapy combined with psychodysleptic tryptamine derivatives and an active placebo. Neuro-Psycho-Pharmacology, 1967:1116–1118.
28.
FaillaceLA, VourlekisA, SzaraS. Hallucinogenic drugs in the treatment of alcoholism: A two-year follow-up. Compr Psychiatry, 1970; 11(1):51–56.
29.
GrofS, SoskinRA, RichardsWA, et al.DPT as an adjunct in psychotherapy of alcoholics. Int Pharmacopsychiatry, 1973; 8(1):104–115.
30.
RheadJC, SoskinRA, TurekI, et al.Psychedelic Drug (DPT)-Assisted psychotherapy with alcoholics: A controlled study. J Psychedelic Drugs, 1977; 9(4):287–300.
31.
FrecskaE, BokorP, WinkelmanM. The therapeutic potentials of ayahuasca: Possible effects against various diseases of civilization. Front Pharmacol, 2016; 7:35.
32.
de VosCMH, MasonNL, KuypersKPC. Psychedelics and neuroplasticity: A systematic review unraveling the biological underpinnings of psychedelics. Front Psychiatry, 2021; 12:724606.
33.
van ElkM, YadenDB. Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review. Neurosci Biobehav Rev, 2022; 140:104793.
34.
ZafarR, SiegelM, HardingR, et al.Psychedelic therapy in the treatment of addiction: The past, present and future. Front Psychiatry, 2023; 14:1183740.
35.
GlazerJ, MurrayCH, NusslockR, et al.Low doses of Lysergic Acid Diethylamide (LSD) increase reward-related brain activity. Neuropsychopharmacology, 2023; 48(2):418–426.
36.
GriffithsRR, JohnsonMW, RichardsWA, et al.Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol, 2018; 32(1):49–69.
37.
LiJ-X, RiceKC, FranceCP. Behavioral effects of dipropyltryptamine in rats: Evidence for 5-HT1A and 5-HT2A agonist activity. Behav Pharmacol, 2007; 18(4):283–288.
38.
ReissigCJ, EcklerJR, RabinRA, et al.The 5-HT1A receptor and the stimulus effects of LSD in the rat. Psychopharmacology (Berl), 2005; 182(2):197–204.
39.
DoddS, NormanTR, EyreHA, et al.Psilocybin in neuropsychiatry: A review of its pharmacology, safety, and efficacy. CNS Spectr, 2023; 28(4):416–426.
40.
Erkizia-SantamaríaI, Alles-PascualR, HorrilloI, et al.Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response. Biomed Pharmacother, 2022; 154:113612.
41.
BerendsenHHG, JenckF, BroekkampCLE. Selective activation of 5HT1A receptors induces lower lip retraction in the rat. Pharmacol Biochem Behav, 1989; 33(4):821–827.
42.
KrebsTS, JohansenP. Lysergic Acid Diethylamide (LSD) for alcoholism: Meta-analysis of randomized controlled trials. J Psychopharmacol, 2012; 26(7):994–1002.
43.
BogenschutzMP, RossS, BhattS, et al.Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: A randomized clinical trial. JAMA Psychiatry, 2022; 79(10):953–962.
44.
KranzlerHR, BurlesonJA, Del BocaFK, et al.Buspirone treatment of anxious alcoholics: A placebo-controlled trial. Arch Gen Psychiatry, 1994; 51(9):720–731.
45.
SavitzJ, LuckiI, DrevetsWC. 5-HT1A receptor function in major depressive disorder. Prog Neurobiol, 2009; 88(1):17–31.
46.
SariY, JohnsonVR, WeedmanJM. Chapter 10–Role of the serotonergic system in alcohol dependence: From animal models to clinics. In: (RahmanS, editor). Progress in Molecular Biology and Translational Science: Academic Press; 2011. p. 401–443.
47.
SzaraS, RocklandL, RosenthalD, et al.Psychological Effects and Metabolism of N,N-diethyltryptamine in Man. Arch Gen Psych, 1966; 15:320–329.
48.
BarsugliaJP, PolancoM, PalmerR, et al.A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder. Prog Brain Res, 2018; 242:121–158.
49.
BarbosaPCR, TófoliLF, BogenschutzMP, et al.Assessment of alcohol and tobacco use disorders among religious users of ayahuasca. Front Psychiatry, 2018; 9:136.
50.
DavisAK, BarsugliaJP, LancelottaR, et al.The epidemiology of 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption. J Psychopharmacol, 2018; 32(7):779–792.
51.
BarsugliaJ, DavisAK, PalmerR, et al.Intensity of mystical experiences occasioned by 5-MeO-DMT and comparison with a prior psilocybin study. Front Psychol, 2018; 9:2459.
(NIAAA) NIoAAaA. The Potential Therapeutic Effects of Psychedelic, N, N-dimethyltryptamine (DMT), on Alcohol Use Disorder (AUD). Available from: https://classic.clinicaltrials.gov/ct2/show/NCT06070649 [Last accessed: 20thMay].
54.
Loizaga-VelderA, VerresR. Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence—qualitative results. J Psychoactive Drugs, 2014; 46(1):63–72.
55.
PerkinsD, OpaleyeES, SimonovaH, et al.Associations between ayahuasca consumption in naturalistic settings and current alcohol and drug use: Results of a large international cross-sectional survey. Drug Alcohol Rev, 2022; 41(1):265–274.
56.
BerlowitzI, WaltH, GhasarianC, et al.Short-Term treatment effects of a substance use disorder therapy involving traditional amazonian medicine. J Psychoactive Drugs, 2019; 51(4):323–334.
57.
ButlerM, JelenL, RuckerJ. Expectancy in placebo-controlled trials of psychedelics: If so, so what? Psychopharmacology (Berl), 2022; 239(10):3047–3055.
58.
GründerG, BrandM, MertensLJ, et al.Treatment with psychedelics is psychotherapy: Beyond reductionism. Lancet Psychiatry, 2024; 11(3):231–236.
59.
GoodwinGM, MalievskaiaE, FonzoGA, et al.Must psilocybin always “assist psychotherapy”? Am J Psychiatry, 2024; 181(1):20–25.
60.
HovmandOR, PoulsenED, ArnfredS, et al.Risk of bias in randomized clinical trials on psychedelic medicine: A systematic review. J Psychopharmacol, 2023; 37(7):649–659.
61.
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.
62.
Fernandes-NascimentoMH, Viana-FerreiraK, NegrãoAB. Overview and Specificity of Psilocybin Use in the Treatment of Mental Disorders: A Scientometric Analysis Psychedelic Med (New Rochelle).0: Null. J Psychoactive Drugs, 2023; 55(1):40–50; doi: 10.1080/02791072.2022.2044096
63.
KirlićN, Lennard-JonesM, AtliM, et al.Compass psychological support model for COMP360 psilocybin treatment of serious mental health conditions. Am J Psychiatry, 2025; 182(1):126–132.
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