Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions, Albert Garcia-Romeu and William A. Richards, 2018

Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions

Albert Garcia-Romeu and William A. Richards
Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA




Humans have used serotonergic hallucinogens (i.e. psychedelics) for spiritual, ceremonial, and recreational purposes for thousands of years, but their administration as part of a structured therapeutic intervention is still a relatively novel practice within Western medical and psychological frameworks. In the mid-20th century, considerable advances were made in developing therapeutic approaches integrating administration of low (psycholytic) and high (psychedelic) doses of serotonergic hallucinogens for treatment of a variety of conditions, often incorporating psychoanalytic concepts prevalent at that time. This work contributed seminal insights regarding how these substances may be employed with efficacy and safety in targeted therapeutic interventions, including the importance of optimizing set (frame of mind) and setting (therapeutic environment). More recently, clinical and pharmacological research has revisited the effects and therapeutic potential of psychedelics utilizing a variety of approaches. The current article provides an overview of past and present models of psychedelic therapy, and discusses important considerations for future interventions incorporating the use of psychedelics in research and clinical practice.

KEYWORDS : Psychedelic therapy; hallucinogens; psilocybin; LSD


Evidence of human hallucinogen use dates back to prehistoric times and spans the globe, with artifacts
suggesting a sacred status of these substances among early civilizations (Guerra-Doce, 2015; Harner, 1973; Rudgley, 1995; Schultes, 1969, 1998; Schultes & Hofmann, 1992; Wasson, 1961; Wasson, Hofmann, & Ruck, 2008). While archaeological findings cannot always elucidate the specific roles of hallucinogenic substances in ancient cultures, traditional uses among extant indigenous populations and syncretic religions provide insights into ritual hallucinogen use for healing, divinatory, spiritual, and sacramental purposes (Jones, 2005; Luna, 2011; Lyttle, 1988; Metzner, 1998). Psilocybin mushrooms, peyote, ayahuasca, and other hallucinogens still maintain a central role in numerous spiritual and religious practices, and have been afforded legal protections, even today, in countries where these substances are otherwise outlawed (Bullis, 1990; De Verges, 1974; Labate, 2012). However, use of hallucinogens in modern medicine has been considerably shorter lived, and fraught with cultural and
legal complications almost since the outset (Bonson, 2018; Carhart-Harris & Goodwin, 2017; Dyck, 2005; Rucker, Iliff & Nutt, 2017; Sessa, 2016). The purpose of the present paper is to provide a brief overview of the ways in which serotonin 2A (5-HT2A) receptor agonist hallucinogens (i.e. psychedelics) have been used for clinical or research purposes as part of targeted therapeutic interventions, highlighting important considerations for working safely and effectively with these substances, and discussing future directions for research and clinical applications of hallucinogens.

Psychopharmacology of hallucinogens
The term hallucinogen is applied broadly to many different naturally occurring and synthetic drugs with
various mechanisms of action and profiles of subjective effects (Garcia-Romeu, Kersgard, & Addy, 2016;
Nichols, 2004). These may include the psychedelics such as lysergic acid diethylamide (LSD), psilocybin,
mescaline, and dimethyltryptamine (DMT), whose primary psychoactive effects are largely mediated by their activity at serotonin, and particularly serotonin 2A (5-HT2A), receptors (Glennon, Titeler, & McKenney, 1984; Nichols, 2016; Vollenweider, Vollenweider-Scherpenhuyzen, B€abler, Vogel, & Hell,
1998); the entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA), which stimulate release
of serotonin, dopamine, and norepinephrine, and inhibit their reuptake (Nichols, 1986; Nichols & Oberlender, 1990); the dissociative anaesthetics that exert their main effects via glutamatergic N-Methyl-
D-Aspartate (NMDA) receptor antagonism (Krystal et al., 1999; Morris & Wallach, 2014); and atypical
hallucinogens such as ibogaine (Popik, Layer, & Skolnick, 1995), the kappa opioid receptor agonist salvinorin A (Addy, 2012; Johnson, MacLean, Reissig, Prisinzano, & Griffiths, 2011), anticholinergic deliriants such as Datura (Forrester, 2006), and cannabinoids (Keeler, Ewing, & Rouse, 1971). The focus of this article is on psychedelic therapy involving administration of 5-HT2A agonist psychedelics, as opposed to other hallucinogens, whose pharmacological and potential therapeutic mechanisms differ sufficiently to distinguish them from the current topic.1