The Potential Therapeutic Benefits and Safety of Psychedelics in the Treatment of Mental Health Conditions: A Systematic Review
DOI:
https://doi.org/10.53819/81018102t4217Abstract
Mental illnesses pose social, economic, and health burdens worldwide. The increasing health burden and mental diseases pose the need for investigating other potential medications. The present review focuses on psychedelic medications. The Patient/Participant, Intervention, Outcomes, and Studies ([PICOS) protocol and the Preferred Reporting Items for Systematic Reviews (PRISMA) checklist guided the establishment of the inclusion criteria. Two reviewers sought eligible studies in electronic databases, including ProQuest, PubMed, Google Scholar, and Web of Science. A total of 17 articles met the inclusion criteria and were reviewed for the potential therapeutic effects of psychedelics, including 3,4-methylenedioxymethamphetamine (MDMA), Lysergic acid diethylamide (LSD), and psilocybin, in the management of psychiatric illnesses. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the level of certainty of evidence. Psychedelics’ positive therapeutic effects were reported across the 17 articles. The medications provided relief from psychotic experiences, reduced the severity of depression and anxiety, improved PSTD, improved social cognition, and elevated the mood of the participants. However, adverse effects, including increased irritability, insomnia, rumination, and low mood, were reported and posed the need for patient monitoring. Despite the long-term therapeutic benefits, psychedelics produced adverse effects when used to manage psychiatric illnesses. LSD, MDMA, and psilocybin are emerging as potential medications that could improve the overall quality of life, life satisfaction, and well-being of mentally ill patients.
Keywords: Psychiatric illness, psychedelics, MDMA, LSD, psilocybin treatment, depressive symptoms, disease severity, and therapeutic outcomes.
References
Amir-Behghadami, M., & Janati, A. (2020). Population, Intervention, Comparison, Outcomes and Study (PICOS) design as a framework to formulate eligibility criteria in systematic reviews. In Emergency Medicine Journal (Vol. 37, Issue 6). https://doi.org/10.1136/emermed-2020-209567
Bates, M. L. S., & Trujillo, K. A. (2021). Use and abuse of dissociative and psychedelic drugs in adolescence. In Pharmacology Biochemistry and Behavior (Vol. 203). https://doi.org/10.1016/j.pbb.2021.173129
Bender, D., & Hellerstein, D. J. (2022). Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research. In Psychopharmacology (Vol. 239, Issue 6). https://doi.org/10.1007/s00213-021-06049-6
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study. Journal of Psychopharmacology, 29(3). https://doi.org/10.1177/0269881114565144
Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies. In CNS Drugs (Vol. 34, Issue 9). https://doi.org/10.1007/s40263-020-00748-y
Carhart-Harris, R. L., & Goodwin, G. M. (2017). The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology, 42(11). https://doi.org/10.1038/npp.2017.84
Cuello-Garcia, C. A., Santesso, N., Morgan, R. L., Verbeek, J., Thayer, K., Ansari, M. T., Meerpohl, J., Schwingshackl, L., Katikireddi, S. V., Brozek, J. L., Reeves, B., Murad, M. H., Falavigna, M., Mustafa, R., Regidor, D. L., Alexander, P. E., Garner, P., Akl, E. A., Guyatt, G., & Schünemann, H. J. (2022). GRADE guidance 24 optimizing the integration of randomized and non-randomized studies of interventions in evidence syntheses and health guidelines. Journal of Clinical Epidemiology, 142. https://doi.org/10.1016/j.jclinepi.2021.11.026
Danforth, A. L., Grob, C. S., Struble, C., Feduccia, A. A., Walker, N., Jerome, L., Yazar-Klosinski, B., & Emerson, A. (2018). Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology, 235(11). https://doi.org/10.1007/s00213-018-5010-9
de Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., & Gobbi, G. (2021). Hallucinogens in mental health: Preclinical and clinical studies on LSD, psilocybin, MDMA, and ketamine. Journal of Neuroscience, 41(5). https://doi.org/10.1523/JNEUROSCI.1659-20.2020
Frampton, G., Whaley, P., Bennett, M., Bilotta, G., Dorne, J. L. C. M., Eales, J., James, K., Kohl, C., Land, M., Livoreil, B., Makowski, D., Muchiri, E., Petrokofsky, G., Randall, N., & Schofield, K. (2022). Principles and framework for assessing the risk of bias for studies included in comparative quantitative environmental systematic reviews. Environmental Evidence, 11(1). https://doi.org/10.1186/s13750-022-00264-0
Galbraith, N., Boyda, D., McFeeters, D., & Hassan, T. (2021). The mental health of doctors during the COVID-19 pandemic. BJPsych Bulletin, 45(2). https://doi.org/10.1192/bjb.2020.44
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014). Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. Journal of Nervous and Mental Disease, 202(7). https://doi.org/10.1097/NMD.0000000000000113
Gasser, P., Kirchner, K., & Passie, T. (2015). LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects. Journal of Psychopharmacology, 29(1). https://doi.org/10.1177/0269881114555249
Glazer, J., Murray, C. H., Nusslock, R., Lee, R., & de Wit, H. (2023). Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity. Neuropsychopharmacology, 48(2). https://doi.org/10.1038/s41386-022-01479-y
Gómez-Busto, F. J., & Ortiz, M. I. (2020). Virtual reality and psychedelics for the treatment of psychiatric disease: A systematic literature review. Clinical Neuropsychiatry, 17(6). https://doi.org/10.36131/cnfioritieditore20200606
Granholm, A., Alhazzani, W., & Møller, M. H. (2019). Use of the GRADE approach in systematic reviews and guidelines. In British Journal of Anaesthesia (Vol. 123, Issue 5). https://doi.org/10.1016/j.bja.2019.08.015
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12). https://doi.org/10.1177/0269881116675513
Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstad, A. L., & Greer, G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry, 68(1). https://doi.org/10.1001/archgenpsychiatry.2010.116
Gross, J. J., Uusberg, H., & Uusberg, Andero. (2019). Mental illness and well-being: an affect regulation perspective. World Psychiatry, 18(2). https://doi.org/10.1002/wps.20618
Heal, D. J., Gosden, J., & Smith, S. L. (2018). Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans. In Neuropharmacology (Vol. 142). https://doi.org/10.1016/j.neuropharm.2018.01.049
Holze, F., Gasser, P., Müller, F., Dolder, P. C., & Liechti, M. E. (2023). Lysergic Acid Diethylamide–Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study. Biological Psychiatry, 93(3). https://doi.org/10.1016/j.biopsych.2022.08.025
Igelström, E., Campbell, M., Craig, P., & Katikireddi, S. V. (2021). Cochrane’s risk of bias tool for non-randomized studies (ROBINS-I) is frequently misapplied: A methodological systematic review. Journal of Clinical Epidemiology, 140. https://doi.org/10.1016/j.jclinepi.2021.08.022
Irizarry, R., Winczura, A., Dimassi, O., Dhillon, N., Minhas, A., & Larice, J. (2022). Psilocybin as a Treatment for Psychiatric Illness: A Meta-Analysis. Cureus. https://doi.org/10.7759/cureus.31796
J.J.H., R., J., I., & D.J., N. (2018). Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacology, 142.
Johansen, P., & Krebs, T. S. (2009). How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale. Journal of Psychopharmacology, 23(4). https://doi.org/10.1177/0269881109102787
Kayiteshonga, Y., Sezibera, V., Mugabo, L., & Iyamuremye, J. D. (2022). Prevalence of mental disorders, associated co-morbidities, health care knowledge and service utilization in Rwanda – towards a blueprint for promoting mental health care services in low- and middle-income countries? BMC Public Health, 22(1). https://doi.org/10.1186/s12889-022-14165-x
King, F., & Hammond, R. (2021). Psychedelics as Reemerging Treatments for Anxiety Disorders: Possibilities and Challenges in a Nascent Field. FOCUS, 19(2). https://doi.org/10.1176/appi.focus.20200047
Krystal, J. H., Kelmendi, B., & Petrakis, I. L. (2021). Psychotherapy-supported MDMA treatment for PTSD. Cell Reports Medicine, 2(8). https://doi.org/10.1016/j.xcrm.2021.100378
Lucas, P. J., Baird, J., Arai, L., Law, C., & Roberts, H. M. (2007). Worked examples of alternative methods for the synthesis of qualitative and quantitative research in systematic reviews. BMC Medical Research Methodology, 7. https://doi.org/10.1186/1471-2288-7-4
Magaraggia, I., Kuiperes, Z., & Schreiber, R. (2021). Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach. Neurobiology of Learning and Memory, 183. https://doi.org/10.1016/j.nlm.2021.107467
Malone, T., Mennenga, S. E., Ross, S., Bossis, A., Guss, J., Babb, J., Kalliontzi, K., Corby, P., Schmidt, B. L., Su, Z., Agin-Liebes, G., Cohen, B., & Belser, A. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of Psychopharmacology, 30(12).
McGuinness, L. A., & Higgins, J. P. T. (2021). Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Research Synthesis Methods, 12(1). https://doi.org/10.1002/jrsm.1411
Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2019). MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology, 236(9). https://doi.org/10.1007/s00213-019-05249-5
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of ±3,4-methylenedioxymethamphetamine- assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: The first randomized controlled pilot study. Journal of Psychopharmacology, 25(4). https://doi.org/10.1177/0269881110378371
Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2013). A randomized, controlled pilot study of MDMA (±3,4- Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology, 27(1). https://doi.org/10.1177/0269881112464827
Ot’alora G, M., Grigsby, J., Poulter, B., Van Derveer, J. W., Giron, S. G., Jerome, L., Feduccia, A. A., Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, M. C., & Doblin, R. (2018). 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: A randomized phase 2 controlled trial. Journal of Psychopharmacology, 32(12). https://doi.org/10.1177/0269881118806297
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. In The BMJ (Vol. 372). https://doi.org/10.1136/bmj.n71
Preller, K. H., Schilbach, L., Pokorny, T., Flemming, J., Seifritz, E., & Vollenweider, F. X. (2018). Role of the 5-HT2A receptor in self- and other-initiated social interaction in lysergic acid diethylamide-induced states: A pharmacological fMRI study. Journal of Neuroscience, 38(14). https://doi.org/10.1523/JNEUROSCI.1939-17.2018
Raison, C. L., Jain, R., Penn, A. D., Cole, S. P., & Jain, S. (2022). Effects of Naturalistic Psychedelic Use on Depression, Anxiety, and Well-Being: Associations With Patterns of Use, Reported Harms, and Transformative Mental States. Frontiers in Psychiatry, 13. https://doi.org/10.3389/fpsyt.2022.831092
Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P., & Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. Journal of Psychopharmacology, 30(12). https://doi.org/10.1177/0269881116675512
Rucker, J. J. H., Iliff, J., & Nutt, D. J. (2018). Psychiatry & the psychedelic drugs. Past, present & future. In Neuropharmacology (Vol. 142). https://doi.org/10.1016/j.neuropharm.2017.12.040
Schlag, A. K., Aday, J., Salam, I., Neill, J. C., & Nutt, D. J. (2022). Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. In Journal of Psychopharmacology (Vol. 36, Issue 3). https://doi.org/10.1177/02698811211069100
Solmi, M., Radua, J., Olivola, M., Croce, E., Soardo, L., Salazar de Pablo, G., Il Shin, J., Kirkbride, J. B., Jones, P., Kim, J. H., Kim, J. Y., Carvalho, A. F., Seeman, M. V., Correll, C. U., & Fusar-Poli, P. (2022). Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. In Molecular Psychiatry (Vol. 27, Issue 1). https://doi.org/10.1038/s41380-021-01161-7
Sottile, R. J., & Vida, T. (2022). A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy. In Frontiers in Psychiatry (Vol. 13). https://doi.org/10.3389/fpsyt.2022.991753
Staines, L., Healy, C., Coughlan, H., Clarke, M., Kelleher, I., Cotter, D., & Cannon, M. (2022). Psychotic experiences in the general population, a review; Definition, risk factors, outcomes and interventions. In Psychological Medicine (Vol. 52, Issue 15). https://doi.org/10.1017/S0033291722002550
Steffen, A., Nübel, J., Jacobi, F., Bätzing, J., & Holstiege, J. (2020). Mental and somatic comorbidity of depression: A comprehensive cross-sectional analysis of 202 diagnosis groups using German nationwide ambulatory claims data. BMC Psychiatry, 20(1). https://doi.org/10.1186/s12888-020-02546-8
Thaipisuttikul, P., Ittasakul, P., Waleeprakhon, P., Wisajun, P., & Jullagate, S. (2014). Psychiatric comorbidities in patients with major depressive disorder. Neuropsychiatric Disease and Treatment, 10. https://doi.org/10.2147/NDT.S72026
Thomas, J., & Harden, A. (2008). Methods for the thematic synthesis of qualitative research in systematic reviews. BMC Medical Research Methodology, 8. https://doi.org/10.1186/1471-2288-8-45
Tupper, K. W., Wood, E., Yensen, R., & Johnson, M. W. (2015). Psychedelic medicine: A re-emerging therapeutic paradigm. CMAJ, 187(14). https://doi.org/10.1503/cmaj.141124
Vargas, M. V., Meyer, R., Avanes, A. A., Rus, M., & Olson, D. E. (2021). Psychedelics and Other Psychoplastogens for Treating Mental Illness. In Frontiers in Psychiatry (Vol. 12). https://doi.org/10.3389/fpsyt.2021.727117
Walker, E. R., McGee, R. E., & Druss, B. G. (2015). Mortality in Mental Disorders and Global Disease Burden Implications. JAMA Psychiatry, 72(4). https://doi.org/10.1001/jamapsychiatry.2014.2502
Wieβner, I., Falchi, M., Palhano-Fontes, F., Feilding, A., Ribeiro, S., & Tófoli, L. F. (2023). LSD, madness and healing: Mystical experiences as possible link between psychosis model and therapy model. Psychological Medicine, 53(4). https://doi.org/10.1017/S0033291721002531
Wolfson, P. E., Andries, J., Feduccia, A. A., Jerome, L., Wang, J. B., Williams, E., Carlin, S. C., Sola, E., Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, M. C., & Doblin, R. (2020). MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-75706-1
Yepes-Nuñez, J. J., Urrútia, G., Romero-García, M., & Alonso-Fernández, S. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Revista Espanola de Cardiologia, 74(9). https://doi.org/10.1016/j.recesp.2021.06.016
Yung, A. R., & Lin, A. (2016). Psychotic experiences and their significance. In World Psychiatry (Vol. 15, Issue 2). https://doi.org/10.1002/wps.20328
