Psychedelics : Where we are now, why we got here, what we must do
Sean J. Belouin, Jack E. Henningfield
Neuropharmacology, 2018, 142, 7e19
a b s t r a c t
The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its
promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies.
Keywords : Abuse potential, Addiction, Controlled substances act, LSD, Mental health disorders, Psychedelic drug research
1. Introduction . . . . . . . . . 8
1.1. The modern rise of psychedelic drug research and clinical application . . . . . . . . . 8
1.2. The US Controlled Substances Act and the fall of psychedelic drug research . . . . . . . . 9
1.3. Twenty-first century psychedelic drug research and development: a new era . . . .. . . . . 10
2. Public health need . . .. . . . 11
3. Summary of major mental health challenges facing the United States . . .. . . . . 12
3.1. Cumulative behavioral healthcare and societal costs . . . . . . . . 13
3.2. Stigmatizing scientific medical problem solving . . . . . . . . . 13
4. Evolving to address a critical national healthcare need . . . . . . . . 14
5. Operationalizing forward . . . . . . . . . 15
5.1. Research in new and emerging areas can be appropriately guided with the convening of a research summit . . . . . . 15
5.2. Funding research . . . . . . . . 15
6. Summary . . . . . . . . . . . . 15
Disclaimer . . . . . . . . . . 16
Conflicts of interest . . . .. . . . 16
Acknowledgments of funding and grants . . . . . . . 16
References . . . .. . . . . . 16
The history of psychedelic substance use, modern research efforts, and their potential clinical applications addressing current treatment resistant mental health disorders evolved through an intriguing and complexly interwoven story linking ancient cultures, modern discovery, pop cultural movements, national and international politics, and well-intentioned laws with unintended consequences. In the context of this history, this commentary discusses the 21st century resurgence of psychedelic drug assisted psychotherapeutic research, the challenges imposed by the United States Controlled Substance Act (US CSA), and the potential for development of medicinal products for the treatment of persisting mental health disorders.
The unrelenting persistence of behavioral disorders, for which those who are afflicted and refractory to current evidenced based therapies, reveal a powerful incentivizing force for advancing new medicinally assisted psychotherapeutic treatments. On the other hand, we enter the 21st century humbled by the daunting challenge of developing medicines for central nervous system (CNS) disorders in response to the failure of so many seemingly promising medicines that emerged from years of clinical trials, billions of US dollars invested, with benefit to risk profiles which at the time, were acceptable to regulatory agencies in the US and globally (Hyman, 2012; Pangalos et al., 2007; Pankevich et al., 2014). With
these considerations in mind, the present commentary is not postured as advocacy for a simple or certain solution to the challenges posed by mental health disorders or “brain diseases.” Nonetheless, it suggests that pressing public health challenges involving behavioral disorders may be addressed in part by recent advances in neuropharmacology, on the effects, mechanisms of action, and potential clinical applications of psychedelic drugs discussed in this special issue of Neuropharmacology. Together, these advances support our conclusion that increased scientific investigation of psychedelic substances for potential clinical application merits serious consideration among the many other efforts that are vigorously being pursued to address mental health illnesses that continue to be so pervasive in the United States and globally.
The purpose of this commentary is to provide a brief historical context for psychedelic drug research, its modern rise, fall, reemergence, and the importance of finding pathways through the complex legal, policy, and social barriers, to effectively research the battery of potential medicinal applications that may lead to US and international regulatory approval where they may find their place in service to humanity. This story is multifaceted and a thorough elucidation goes far beyond the scope of any commentary, however, the authors have endeavored to provide key references for readers interested in pursuing these diverse issues for further inquiry. We recognized the opinions of researchers, clinicians, policy makers,
regulatory agencies, research funders, those views that span culturally across society, and ultimately the legislative halls that govern this nation and those of others. All vary widely, and all merit consideration. The following is our perspective.
1.1. The modern rise of psychedelic drug research and clinical application
Plants and plant-derived substances known to produce psychedelic effects have been used for millennia for their apparent healing powers, in rituals, and for pleasure (Hofmann, 1980; Multidisciplinary Association for Psychedelic Studies, 2007; Nichols, 2004; Strassman, 1995). These have included certain
mushrooms, herbs such as nutmeg, anticholinergic plant derivatives, cannabis, and numerous other substances used in medicine, as well as prototypic substances of abuse and dependence such as alcohol, opioids, stimulants and tobacco. Although the apparent reasons for early use must be surmised in the context of archeological investigations and historical records, the reasons and occasions for use included ceremonial, medicinal, and what today might be termed in relation to modern western culture, recreational use. This history is intriguing and has been recounted elsewhere (Bastiaans, 1983; Hofmann, 1980; Merlin, 2003; Multidisciplinary Association for Psychedelic Studies, 2007; Siegel, 1989; University of Maryland, 2013a, b).
The modern era of research and potential clinical development of such substances for treating mental and behavioral disorders was launched by the discovery of a new chemical entity, lysergic acid diethyl amide (LSD) as discussed in the preface and elsewhere in this special issue (Hofmann, 1980; University of Maryland, 2013a). Although discovered in 1938, its potentially powerful effects to alter mood and cognition were not realized until the self-experiment by its inventor, Albert Hofmann, a Sandoz pharmaceutical company chemist, in 1943 on a day that later came to be renowned internationally as Bicycle Day (Tables 1 and 2). Following several years of active research, the first European clinical study was published in 1947; and in 1949, two American psychiatrists, Max Rinkel and Nick Bercel personally brought Sandoz’s LSD into the US to begin testing it. Importantly, it was the Federal Food, Drug, and Cosmetic Act (Federal FD&C Act) of 1938 that permitted Sandoz to distribute LSD samples, under the brand name Delysid for investigational research. These samples were given to experts who were believed to have the necessary training and experience to administer such drugs to patients, thereby further evaluating their potential clinical benefits and safety risks (Bonson, 2017). It was heralded in the medical literature and popular press with great promise for the treatment of a variety of serious mental health disorders including anxiety, depression, schizophrenia, war time stress reactions, alcoholism and other substance use disorders (Hofmann, 1980). Its clinically documented favorable safety profile, potency, and its ability to produce powerful and occasionally enduring beneficial psychological effects, led many prominent leaders in the behavioral science field along with the pharmaceutical industry to view LSD, and possibly related chemical entities, as potential breakthroughs in many areas of mental illness, including various forms of drug addiction.
The promise of LSD, psilocybin, mescaline and other psychedelic substances as tools in psychiatric investigation and their potential for medicinal application was pursued vigorously by many leading researchers in psychiatry and the emerging fields of neuropharmacology and neuropsychopharmacology (Abramson et al., 1955; Freedman, 1968, 1986, 1992; Grinspoon and Bakalar, 1979; Multidisciplinary Association for Psychedelic Studies, 2007; Nichols, 2004; Nutt et al., 2013; Siegel and West, 1975). This area of pharmaceutical research exploration coincided simultaneously with the rapid advancement of research on medicines to treat anxiety, depression and psychosis during the 1950s, which were also essential in the development of the modern fields of psychopharmacology and neuropharmacology (Ban, 2006, 2007; Lopez-Munoz et al., 2011; Stolerman, 2010).
The apparent benefits of medicines for such diverse and formerly all too often intractable disorders certainly fueled the hope for LSD and possibly other psychedelics, which were initially referred to the more general term of psychotomimetics, for their ability to produce transient psychotic like states, and equally psychotherapeutic for their ability to relieve such states. Research funding came by way of pharmaceutical companies, institutions such as the US National Institute of Mental Health (NIMH), and importantly, though controversially, from military and intelligence agencies (Kamienski, 2016; Lee and Shlain, 1992; Multidisciplinary Association for Psychedelic Studies, 2007) which appeared to have interests not only in clinical application but possibly as tools for espionage and warfare.
By the early 1960s, research on psychotherapeutic agents including psychedelics contributed to the emergence of new research societies such as the American College of Neuropsychopharmacology, the American Psychological Association’s Psychopharmacology and Substance Abuse Division 28, the Behavioral Pharmacology Society, and many others. Even though there was this extensive growing body of clinical research on hallucinogens, especially with LSD, which at the time was being distributed in the US for investigational purposes, there was still no federal legal requirement in the Federal FD&C Act of 1938 requiring pharmaceutical manufacturers to demonstrate proof of clinical efficacy through adequate and well controlled clinical trials. It was on October 10th, 1962, in response to the thalidomide tragedy where children were born with serious birth defects from mothers consuming the drug thalidomide for morning sickness, that the Kefauver-Harris Drug Amendments to the Federal FD&C Act, known officially as the “Drug Amendments of 1962” was signed into public law (Chhabra et al., 2005; Meadows, 2006). This crucial legislation significantly strengthened the FDA’s regulatory controls on the experimentation of new chemical entities in humans.
For any new drug substance, pharmaceutical companies were now required to submit as part of their New Drug Application (NDA) adequate and well-controlled studies, demonstrating their drug was both safe and effective for the clinical indication(s) the company was seeking to market. Additionally, there would be the requirement for informed consent of patients before their participation in any clinical trials; adverse drug reaction reports were now going to be required by the FDA; good manufacturing practices would be formalized; and lastly, prescription drug advertising would be transferred from the Federal Trade Commission to the FDA. As a crucial component of the Kefauver-Harris Drug Amendments, the Drug Efficacy Study Implementation (DESI) was initiated, and in 1966, the FDA contracted with the National Academy of Sciences National Research Council to undertake an evaluation of all drugs approved between 1938 and 1962 for clinical efficacy. It would take almost 20 years, 1984, to evaluate and issue final regulatory actions on 3443 marketed drug products, totaling more than 16,000 therapeutic efficacy claims. Of those 3443 drug products, 2225 were found to be effective, 1051 were found ineffective, and 167 were still pending more research. The 1051 ineffective drug products were designated DESI drugs, and with the passage of the Omnibus Budget Reconciliation Act of 1981, reimbursement for DESI drugs was prohibited by Medicaid programs as well as under Medicare Part B (Chhabra et al., 2005; Meadows, 2006; Navarro, 2009).