CHAPTER The renaissance in psychedelic research: What do preclinical models have 2 to offer Kevin S. Murnane1 Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, Atlanta, GA, United States 1Corresponding author: Tel.: +1-678-547-6290; Fax: +1-678-547-6423, e-mail address: [email protected] Abstract Human research with psychedelics is making groundbreaking discoveries. Psychedelics mod- ify enduring elements of personality and seemingly reduce anxiety, depression, and substance dependence in small but well-designed clinical studies. Psychedelics are advancing through pharmaceutical regulatory systems, and neuroimaging studies have related their extraordinary effects to select brain networks. This field is making significant basic science and translational discoveries, yet preclinical studies have lagged this renaissance in human psychedelic research. Preclinical studies have a lot to offer psychedelic research as they afford tight control of experimental parameters, subjects with documented drug histories, and the capacity to elucidate relevant signaling cascades as well as conduct invasive mechanistic studies of neurochemistry and neural circuits. Safety pharmacology, novel biomarkers, and pharmaco- kinetics can be assessed in disease state models to advance psychedelics toward clinical practice. This chapter documents the current status of psychedelic research, with the thematic argument that new preclinical studies would benefit this field. Keywords Psychedelic, Preclinical, Serotonin, Neuroimaging, Alcoholism, Anxiety, Depression, Substance dependence 1 INTRODUCTION The term psychedelic has come to be associated with a broad class of drugs with diverse chemical, pharmacological, and psychoactive effects. Alternative nomencla- tures have used hallucinogen, entheogen, psychotomimetic and other appellations to Progress in Brain Research, Volume 242, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2018.08.003 25 © 2018 Elsevier B.V. All rights reserved. 26 CHAPTER 2 Preclinical psychedelic research denote specific concepts related to these drugs. Hallucinations are an obvious and profound drug effect that can be produced by these drugs, but as has been noted, this is not an effect that is reliably produced at typical doses (Nichols, 2016), and the term hallucinogen has fallen out of favor. The term psychedelic has been used to denote the idea that these compounds elicit an experience related to the mind, inward reflection, and growth in the boundaries of the mind. The belief is that this term captures a better sense of the core effects of these drugs than other appellations it has replaced. There are many compounds that could potentially fall under the term psychedelic. Cannabinoid agonists (e.g., Δ9-tetrahydrocannabinol), N-methyl- D-aspartate receptor antagonists (e.g., phencyclidine; PCP), muscarinic receptor antagonists (e.g., scopolamine), and substrate-based releasers of monoamines (e.g., 3,4-methylendioxymethampheamine; MDMA or “ecstasy”) all engender psy- choactive effects that could be included in an expansive view of psychedelics. How- ever, the core classes of psychedelics have often been restricted to phenethylamines such as 3,4,5-trimethoxy-phenethylamine (mescaline), tryptamines such as N,N- dimethyl-4-phosphoryloxytryptamine (psilocybin), and ergolines such as lysergic acid diethylamide (LSD). This chapter largely focuses on these core or “classic” psyche- delics, with limited comparisons to other compounds to highlight specific concepts. Psychedelics have been used by humans in traditional indigenous rituals for thousands of years (Meyer and Quenzer, 2005). Mescaline was incorporated into the indigenous religious ceremonies of the native people of North America, and aya- huasca was incorporated into the indigenous religious ceremonies of the native peo- ple of South America (Carhart-Harris and Goodwin, 2017). Modern research with psychedelics largely commenced with the serendipitous discovery of LSD by Albert Hofmann, while he worked on novel analeptics derived from ergot alkaloids for Sandoz Laboratories (now a subsidiary of Novartis). Dr. Hofmann initially synthe- sized LSD in 1938, but discontinued work with the compound for several years as it showed little promise as an analeptic. In 1943, Dr. Hofmann decided to reexamine the effects of LSD, and while carrying out a new synthesis, he was overcome with a series of strange sensations and had to vacate his laboratory and return home. His description of this event illustrates some the core effects of pschedelics, and he wrote, “At home, I lay down and sank into a not unpleasant intoxiceded-like condi- tion, characterized by an extremely stimulanted imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kalei- doscopic play of colors” (Hofmann, 1959). As can be gleamed from Dr. Hofmann’s account, the interoceptive effects of psychedelics include elements of reflective lucid dream-like states and changes in sensation and perception, but not necessarily frank hallucinations (Kraehenmann, 2017). Despite the inherent difficulty in defining and describing such amorphous effects, extensive research has led to the development of validated questionnaires, such as the Hallucinogen Rating Scale (Tancer and Johanson, 2003) and the Dimensions of Altered States of Consciousness Scale and Mystical Experience Questionnaire (Liechti et al., 2017), to objectively 1 Introduction 27 measure the subjective effects of the psychedelics. Psychedelic-like effects on these measures include changes in somathesia (changes in the body such as feeling physically detached), affect (changes in emotions such anxiousness or closeness to others), cognition (changes in thoughts such as new insights or feelings of insanity), perception (changes in somatosensory, auditory, and visual detection and/or processing), volition (changes in attention and self-control), self (e.g., ego dissolution and oceanic boundlessness), and mystical-type experiences. Following this initial report of LSD, it was clear that such drugs could elicit pow- erful psychoactive effects, spurring great interest in their research. Over the next three decades, additional naturally occurring psychedelics were identified and new compounds synthesized, and hundreds of studies were completed. His discovery ushered in an era of intense LSD research, with nearly 1000 articles appearing in the medical literature by 1961 (Dyck, 2005; Grinspoon and Bakalar, 1986). This research was largely divided into two distinct areas. One body of research examined the psychedelics as a model for acute psychosis (Gouzoulis-Mayfrank et al., 1998). Although perhaps somewhat of an oversimplification, a general conclusion that can be drawn from this literature is that there is some overlap in the symptoms of acute psychosis and high dose administration of psychedelics, yet there are distinct differences between psychedelic effects and the nosological entity known as schizo- phrenia (Hollister, 1962). The occurrence of psychotic symptoms related to LSD, psilocybin, and ayahuasca in controlled and ritual settings is rare and can be further minimized by psychiatric screening and collecting family histories before adminis- tration of these drugs (Dos Santos et al., 2017). As this literature has been extensively discussed elsewhere (Gouzoulis-Mayfrank et al., 1998) and represents a distinct branch of psychedelic research, it will not be a major topic of this chapter. Another body of research examined the use of psychedelics as an adjunct to psychotherapy. Between 1950 and the mid-1960s over 1000 clinical trials were completed, several dozen books were published, and six international conferences were held providing data on approximately 40,000 patients that had undergone these “psychedelic” therapy sessions (Grinspoon and Bakalar, 1986; Riedlinger and Riedlinger, 1994). These approaches were primarily used in the treatment of alcoholism, depression, anxiety, neuroses, compulsive behavior, and psychosomatic disorders. Although advocates strongly argued that this was both safe and effective, the conclusions that can be garnered from these studies are limited due to the anecdotal nature of much of the work, lack of appropriate experimental control, and antiquated methodologies. However, it seems reasonable to hold that these compounds have shown the potential for therapeutic value. Unfortunately, the anti-establishment movement of the 1960s found commune with the use of psychedelics, and LSD became increasingly associ- ated with student riots, antiwar demonstrations, and the counterculture (Dyck, 2005). Perhaps most troublingly, many of the leaders of the movement proposed the use of these compounds for a variety of non-medical purposes and in the absence of medical supervision. This led the government to tightly regulate the availability of the psyche- delics and subsequently place many into the most restrictive level of the Controlled 28 CHAPTER 2 Preclinical psychedelic research Substances Act (i.e., Schedule 1). Despite their great promise for advancing clinical care and elucidating our understanding of neurobiology and psychiatry, human re- search with the psychedelics largely terminated by the 1970s. In the context of this chapter, it is important to note that important basic science studies continued through the 1970s and 1980s, as will be