The Current Status of Psychedelics in Psychiatry VIEWPOINT

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David Nutt, MD, PhD In the 1950s, the Swiss pharmaceutical company San- ized clinical trials compatible with the US Food and Drug Imperial College doz, which employed the chemist Albert Hofmann, who Administration and European Medicines Agency regis- London, London, discovered lysergic acid diethylamide (LSD) and the simi- tration processes and have been given fast-track status United Kingdom. lar serotonergic psychedelic psilocybin, made these in this field. Many of the trials in other disorders are open- drugs available to the psychiatric research community label designs to gather feasibility and safety data to un- Robin Carhart-Harris, PhD as the products Delysid and Indocybin, respectively. By derpin subsequent double-blind randomized clinical Imperial College the 1960s, these drugs had caused a revolution in brain trials. Once these regulatory-standard trials have been London, London, science and psychiatry because of their widespread use conducted, if the outcomes are positive, then it seems United Kingdom. by researchers and clinicians in many Western coun- plausible that psilocybin will become a licensed medi- tries, especially the US. Before LSD was banned, the US cine for some forms of mental illness when used in an National Institutes of Health funded more than 130 stud- approved treatment model. ies exploring its clinical utility, with positive results in a In the depression trials, the treatment model is be- range of disorders but particularly anxiety, depression, coming standardized as a 4-stage process: assessment, and alcoholism. However, the displacement of LSD into preparation,experience,andintegration.Assessmentde- recreational use and eventual association with the anti- termines if the patient is suitable for psychedelic therapy, Vietnam war movement led to all psychedelics being both from a mental and physical perspective. Currently, banned in the US. This ban became ratified globally un- people with a personal or family history of psychosis and der the 1971 UN Convention on narcotics. Since then, re- bipolar disorder are excluded, as are those with signifi- search funding, drug production, and the study of psy- cant health issues (eg, hypertension) because psychedel- chedelics as clinical agents has been virtually stopped. ics transiently increase blood pressure. Certain medica- Until very recently, no companies would manufacture tions need to be stopped or at least reduced before the medical-grade psychedelics, which made getting regu- treatment, because they can block or attenuate the ef- latory approval for clinical research—especially clinical fect of the psychedelic. Specifically, medicines that block

trials—very difficult and in some countries (eg, Ger- 5-HT2A receptors (eg, amitriptyline, olanzapine, quetiap- many) impossible. ine, risperidone, trazodone) need to be withdrawn, and The past decade has seen a resurrection in human serotonin reuptake inhibitors ideally stopped or, if that is psychedelic drug research, especially involving psilocy- not feasible, tapered down, because they produce sub-

bin. There were 2 drivers to this. The first was the dis- sensitivity of the 5-HT2A receptor. covery by Griffiths et al1 that a single high dose (25 mg) In modern studies,3-5 preparation sessions typi- of psilocybin, given in a psychotherapeutic setting, pro- cally take place the day before the drug administration, duced enduring positive changes in mood and well- the participant is prepared for the experience by at least being in people who do not have depression. The sec- 1 trained therapist, who are often referred to as guides, ond was our series2 of neuroimaging studies in healthy based on the analogy of the psychedelic experience volunteers,whichrevealedthatpsilocybinproducedpro- being a psychological journey. An overview of the dy- found and meaningful alterations in brain function, es- namics and nature of psychedelic experiences is ex- pecially of the default mode network, consistent with an plained, including how it can be challenging for many antidepressant effect. These findings suggested the pos- people, how any such challenges can be best con- sible utility of psilocybin for treating depression and ini- fronted, and how the participant can get the most out tiated the launch of studies in the UK and US that fur- of the experience. During the psychedelic experience, thersupportedanantidepressantoutcomefromasingle, the individual is offered eyeshades and earphones to lis- 25-mg psilocybin dose in people with resistant ten to a music compilation that has been prepared in ad- depression3 and those with anxiety and depression vance (which they can specify) because music seems to symptoms provoked by life-threatening cancer enhance the therapeutic process. For oral psilocybin, the diagnoses.4,5 There have also been open studies show- sessions last 4 to 5 hours. Verbal engagement with the ing efficacy in both alcohol and tobacco dependence.6 therapists is not expected, and most patients go deep Based on these positive findings, at least 2 compa- into their own visions, thoughts, and memories and do nies have been set up to take psilocybin to the clinic by not want to be disturbed. But the guide or guides are pre- Corresponding funding multicenter, dose-finding studies of psilocybin sent, and with permission, they can hold the patient’s Author: David Nutt, in depression, and a search of ClinicalTrials.gov (in April handtoreassurethepersonthatheorsheisbeinglooked MD, PhD, Imperial College London, 2020)revealedthatmorethan30psychedelicdrugtrials after. The next day is the integration session—during Du Cane Road, are registered (mostly with psilocybin, although a few which the same guide or guides talk through the expe- Burlington Danes are with LSD). These include studies in anorexia, obses- rience and help the patient make sense of it. Ideally, a Building, London W12 sive-compulsive disorder, and addictions, as well as de- small number of standard, talk-based psychotherapeu- 0NN, United Kingdom 7,8 (d.nutt@ pression. At least 2 of the depression trials (those of tic sessions are further available for issues that emerged imperial.ac.uk). COMPASS Pathways and Usona Institute) are random- during the psychedelic experience to be processed,

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insights to be further integrated, and guidance given on how best generally been greater than those of current treatments,3-5 to cultivate positive cognitive and lifestyle changes. although confirmation biases may be inflating these. Retention In all of the treatment studies conducted so far, the psyche- rates are excellent, and few adverse effects have been reported. delic is given just once or twice over a few weeks with psychothera- Head-to-head comparative efficacy studies with current treat- peutic input (which, in the case of addictions, can be a standard 10- ments are necessary to fully gauge how promising psilocybin week to 20-week abstinence-based program). In this regard, therapy is in comparison with current treatments. In this vein, our psychedelic treatments are being considered as a new paradigm in research team will report the results of our psilocybin vs escitalo- psychiatric medicine—that of drug-facilitated psychotherapy. pram comparison in major depression later this year. Why might psychedelics work in such a wide range of disorders? Perhaps the major challenge is how to scale the treatment We suggest this may be because these conditions are all internalizing up. The current model is time and therapist intensive, and even disorders.Indepression,patientscontinuallyruminateabouttheirfail- though only a couple doses of medicine are required, this is cur- ings, reiterate thoughts of guilt, and engage in self-critical inner nar- rently costly because of the many regulatory challenges associ- ratives. In addiction, drug craving drives behavior that is specific, nar- ated with psychedelics still being scheduled as very dangerous, row, and rigid; individuals with addiction ruminate on the drug, illegal drugs under the UN Conventions and all Western govern- including where to get it, how to pay for it, etc. In obsessive- ments’ drug laws. Another issue is how to provide enough compulsivedisorderandanorexia,thereisexcessiveruminationabout psychedelic-trained therapists and ensure good practice through threats to the person, from contamination or the effects of eating or structuring, manualizing, monitoring, and delivering quality train- overeating,respectively.Neuroimagingstudiesrevealthatpsychedel- ing and practice. Several of the centers currently researching psy- ics probably work by disrupting brain systems and circuits that en- chedelic therapy are offering training under the supervision of code these repetitive thoughts and behaviors. The psychedelic expe- more experienced therapists; for example, Kings College in Lon- rience opens a therapeutic window that disrupts entrenched thinking don, in the UK, has successfully piloted group training of potential and allows insight, which with psychotherapeutic support can lead to therapists, some of whom also received psilocybin as part of this a recalibration of one’s spectrum of associations.9 course (though self-experience is not required). If this form of So far, the published trials of psychedelic therapy have therapy does become more widely used, more formal training of yielded promising tolerability and efficacy data. Effect sizes have large numbers of therapists will be required.

ARTICLE INFORMATION Natl Acad SciUSA. 2012;109(6):2138-2143. 6. Rucker JJH, Iliff J, Nutt DJ. Psychiatry & the Published Online: July 29, 2020. doi:10.1073/pnas.1119598109 psychedelic drugs: past, present & future. doi:10.1001/jamapsychiatry.2020.2171 3. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Neuropharmacology. 2017. Conflict of Interest Disclosures: Dr Nutt reported Psilocybin with psychological support for 7. ClinicalTrials.gov. A study of psilocybin for major grants and personal fees from COMPASS Pathways treatment-resistant depression: an open-label depressive disorder (MDD). Published March 7, during the conduct of the study. Dr Carhart-Harris feasibility study. Lancet Psychiatry. 2016;3(7):619- 2019. Accessed July 1, 2020. https://clinicaltrials. reported serving as a scientific advisor to COMPASS 627. doi:10.1016/S2215-0366(16)30065-7 gov/ct2/show/NCT03866174 Pathways, Usona Institute, Entheon Biomedical, 4. Ross S, Bossis A, Guss J, et al. Rapid and 8. ClinicalTrials.gov. Psilocybin vs escitalopram for Synthesis, and Mindleap. sustained symptom reduction following psilocybin major depressive disorder: comparative treatment for anxiety and depression in patients mechanisms (Psilodep-RCT). Published February REFERENCES with life-threatening cancer: a randomized 12, 2018. Accessed July 1, 2020. https:// 1. Griffiths RR, Richards WA, McCann U, Jesse R. controlled trial. J Psychopharmacol. 2016;30(12): clinicaltrials.gov/ct2/show/NCT03429075 Psilocybin can occasion mystical-type experiences 1165-1180. doi:10.1177/0269881116675512 9. Carhart-Harris RL, Nutt DJ. Serotonin and brain having substantial and sustained personal meaning 5. Griffiths RR, Johnson MW, Carducci MA, et al. function: a tale of two receptors. J Psychopharmacol. and spiritual significance. Psychopharmacology (Berl). Psilocybin produces substantial and sustained 2017;31(9):1091-1120. doi:10.1177/0269881117725915 2006;187(3):268-283. doi:10.1007/s00213-006- decreases in depression and anxiety in patients 0457-5 with life-threatening cancer: a randomized 2. Carhart-Harris RL, Erritzoe D, Williams T, et al. double-blind trial. J Psychopharmacol. 2016;30(12): Neural correlates of the psychedelic state as 1181-1197. doi:10.1177/0269881116675513 determined by fMRI studies with psilocybin. Proc

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