A special issue of Neuropharmacology (2017) provides insightful commentary regarding the historical perspective of psychedelic drug research including: their potential for treating psychiatric disorders; the challenges facing researchers due to regulatory controls and the limitations of attaining Schedule 1 drugs for research; and a summary of recent data suggesting potential treatment applications for several non-psychotic psychopathology.
The recent research of the 60 year old anesthetic ketamine, which causes dissociative symptoms and has been widely abused as a “club drug”, provides a useful precedent. The unexpected findings regarding ketamine as viable and thus far an impressive treatment for refractory depression and suicidality have created a new target for novel approaches to treating mental illness.
At present, there is limited but ongoing research regarding the efficacy and safety of LSD, psilocybin and MDMA (Ecstasy) as potential agents or adjunctive treatment modalities for interpersonal disorders and specific, non psychotic psychiatric disease. The commentary by Rucker, et al, provides insight into the hope and challenges that lie ahead in researching these controversial drugs for therapeutic purposes.
A Look at Psychedelic Drugs
The public’s first perceptions of LSD and psilocybin occurred in the late 1960s when stories of college students jumping to their death from tall buildings because they believed they could fly, left indelible images of our nation’s consciousness.
Lysergic acid diethylamide (LSD) was first synthesized in 1938 and its psychoactive effects were discovered in 1943. It was supplied by Sandoz Labs for experimental use in the 1940s through the 1960s. LSD is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness and perception after oral doses as low as 20μg.
The early research revealed its structural resemblance to serotonin that led to a groundbreaking hypothesis and eventual discovery that central serotonin plays a key role in mood regulation. At the time, and under controlled clinical settings, LSD seemed to be safe and non-addictive, with a very low incidence of adverse events. As a result, it was hailed as a breakthrough for its potential in treating mental illness in the1950s and early 1960s. In those days, hallucinogenic drugs were used by some psychiatrists to treat what was then called ‘psychoneurotic’ disorders. The therapeutic effect was thought to be attained by reducing strongly fixed, maladaptive beliefs and thinking, thus reducing anxious and neurotic patterns of behavior, when administered in supportive therapeutic settings.
As a result of the growing abuse of LSD being used as a recreational drug, and the dramatic, well publicized deaths of scores of young people during their “acid trips”, LSD and similar drugs were placed in Schedule 1 of the Controlled Substances Act.
Despite the legal and practical obstacles— renewed interest and research in the 1990s and early 2000 revealed additional understanding of the brain mechanisms involved in the action of these drugs. At present, pathways to accelerate clinical research for investigating the therapeutic potential for psychedelic drug development is gaining support by the accumulated research and increased public support.
The current evidence suggests that hallucinogenic effects from these drugs may be provoked by increasing cortical excitability via thalamocortical interactions. The authors assert that these findings provide a new level of understanding into the role of the 5- HT2A-receptor during altered states of consciousness.
Since 2006, there have been several small pilot studies and some randomized controlled trials using psychedelics (primarily psilocybin) for various non-psychotic, psychiatric disorders. The results provided initial evidence of safety and efficacy. Moreover, the limited evidence suggests that psychedelic drug assisted psychotherapy may emerge as a viable treatment modality for several types of mental illness including depression, anxiety, post-traumatic stress disorder, and substance use disorders for persons who do not respond to current evidence-based therapies, in addition to advancing our understanding of the brain and its functional properties and capacity.
Why Does This Matter?
The increasing prevalence of mental illness, addictive disease, suicidality and mortality demand that we push forward as scientists to find better treatments. The recent discovery and the unprecedented success associated with the off label use of ketamine for treatment resistant depression has provided a whole new target for scientific inquiry and a blank canvas for new and creative neuroscientific innovation. Of the psychedelic drugs, MDMA trials for PTSD appear to have promise for safe and effective use compared to existing standards of treatment. Others, not so much. So, we press on.
Rucker JJH, Iliff J, Nutt DJ. Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacology. 2017 Dec 25. pii: S0028-3908(17)30638-X. doi: 10.1016/j.neuropharm.2017.12.040. [Epub ahead of print]