## Psychedelics

David E. Nichols

Pharmacological Review, 2016, 68, 264–355

http://dx.doi.org/10.1124/pr.115.011478

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .266
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . 266
A. Historical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 268
B. What Are Psychedelics? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . 268
C. Psychedelics Can Engender Ecstatic States with Persistent Positive Personality Change  271
II. Safety of Psychedelics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 273
A. General Issues of Safety and Mental Health in Psychedelic Users. . . . . . . . . . . . . . . . . . . 275
B. Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
C. Hallucinogen Persisting Perception Disorder . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . 277
D. N-(2-methoxybenzyl)-2,5-dimethoxy-4-substituted phenethylamines (NBOMe) Compounds . 278
III. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 279
A. Evidence for Agonist or Partial Agonist Action at Serotonin 5-Hydroxytryptamine 2A Receptors . 280
B. Production of Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
C. Functional Selectivity at the Serotonin 5-Hydroxytryptamine 2A Receptor . . . . . . .  . . . 283
D. Role of Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
E. A Role for g-Aminobutyric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . 295
F. Possible Role of Other Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 295
IV. Where Is the Serotonin 5-Hydroxytryptamine 2A Receptor Expressed? . . . . . . .  . . . . . 299
A. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Cortex . . . . . . . . . . . . . 300
B. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Thalamus and Reticular Nucleus .  301
C. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in Primary Visual Cortex V1 .  302
D. Effects of Psychedelics on Raphe Cell Firing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
E. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Ventral Tegmental Area  302
F. Effect of Psychedelics on the Locus Coeruleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . 303
G. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Amygdala . .  . . . . . . . . 304
H. A Role for the Claustrum? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 305
V. Effects on Visual Perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
VI. Effects on Sleep. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . 309
VII. Effects on Time Perception. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . .. . . . . . . . 309
VIII. Use of Animal Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . 311
A. Rat Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . 312
1. Drug Discrimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
2. Effects on Locomotor Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . .  . 315
3. Prepulse Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . .. . . 315
B. Mouse Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
1. Head Twitch Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . 316

2. Drug Discrimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..  . . . . . . 317
3. Effects on Locomotor Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . 318
C. Rabbit Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . 319
D. Zebrafish Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
E. Drosophila melanogaster. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
F. Monkey Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 322
IX. Potential Therapeutic Value for Psychedelics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
A. Alleviation of Anxiety and Depression in Life-Threatening Illness. . . . . . . . . . . . . . . .  . . 323
B. Possible Use in Depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . 326
C. Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
D. Treatment of Alcoholism or Nicotine Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 329
E. Cluster Headaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . 329
F. Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

G. Cognitive Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 330
H. Creativity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 331
I. 3,4-Methylenedioxymethamphetamine in Post-Traumatic Stress Disorder . . . . . . . . . . . 332
J. Use as Ocular Hypotensives for Glaucoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 332
K. Tissue Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
L. Effects on Immune Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . 334
M. Effects on Cell Differentiation and Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
X. Models of Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 336
XI. Use as Tools to Study Brain Function and Connectivity. . . . . . . . . . . . . . . . . . .. . . . . . . . 337
XII. Conclusion and Outlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

Abstract —Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter
perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodentmodelshave been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network.

### I. Introduction

I was delighted when the editors invitedme to write a review on “psychedelics,” perhaps a watershed moment, representing a shift in opinion that has been developing for more than 3 decades with respect to research and understanding of psychedelics. When I began my graduate studies in 1969, it was politically correct in scientific circles to refer to these substances only as psychotomimetics, a negative term suggesting that they fostered a mental state resembling psychosis (Hoffer, 1967). Later, as it was realized that these compounds did not provide very realistic models of psychosis or mental illness, it became more correct to refer to them as hallucinogens, again a pejorative term suggesting that they principally produce hallucinations. Yet that is not what they do in most users at ordinary doses, so this term likewise is not particularly descriptive or useful, although it is still widely used and seems to remain the preferred name for these substances in most scientific writing. In addition, the term hallucinogen is often used as a rather broad category to include all kinds of psychoactive molecules, including cannabinoids, “ecstasy,” dissociative agents, and others.

This review will focus exclusively on the so-called classic serotonergic hallucinogens (psychedelics), which are substances that exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors, as discussed later. The discussion will not consider cannabinoids, dissociatives such as ketamine, salvinorin A (a specific opioid k agonist), or entactogens such as 3,4-methylenedioxymethamphetamine (MDMA). In certain contexts, all of these and some related agents have been swept into the catchall category “hallucinogens.” Although they all can produce profound changes in consciousness, they have a different mechanism of action and will not be discussed unless there is a specific reason to do so.

The name psychedelics for these substances was coined by Humphrey Osmond in 1957, connoting that they have a mind-manifesting capability, revealing useful or beneficial properties of the mind (Osmond, 1957). This name has been popular among the lay public for more than 5 decades, but it has generally been frowned upon by the scientific community because it implies that these substances have useful properties.

The notion that psychedelics can have beneficial effects has thus far not been embraced in most medical or scientific circles; indeed, federal funding agencies (e.g., the National Institutes of Health National Institute on Drug Abuse and the National Institute of Mental Health) have no mission to support research on potentially useful properties of psychedelics. Yet this term has remained popular with the public and even appears to be gaining popularity. As I intend to show in this discussion, however, the idea that psychedelics may have useful properties is not at all farfetched, and very recent clinical studies have reinforced the belief by many that psychedelics are well worth studying from a number of different perspectives. Indeed, one of the most striking developments in this field has been the initiation and successful completion of a variety of clinical studies of psychedelics in the past 15 years, most of which have been targeted to specific medical indications. As will be discussed later, the results have been, in the main, remarkably positive. It should be kept in mind that the relative dearth of research on psychedelics in the past half century did not result from a lack of scientific interest, but rather occurred as a consequence of political forces that manifested principally in the United States in the 1960s and 1970s (Grinspoon and Bakalar, 1979). Use of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and marijuana by so-called hippies who demonstrated against the Vietnam War during the 1960s created great consternation among authorities and legislative bodies, both at the federal and state levels. Antiwar attitudes and rejection of conventional social norms by adolescents and college students were often perceived by the mainstream culture to be a consequence of drug use; hence, these substances were often believed to be “perverting” the minds of our youth. Furthermore, the outspoken Harvard University professor and firebrand Timothy Leary encouraged young people to “turn on, tune in, and drop out,” essentially coaching them to take drugs, discover their true selves, and abandon convention. Such
messages did not playwellwith the mainstreamculture, all while the mass media fanned the flames of public hysteria with greatly exaggerated reports of drug-induced insanity, chromosomal damage, attempts to fly, and so forth.

Strict laws were quickly passed. After the passage of the Controlled Substances Act of 1970, LSD and other psychedelics known at the time were placed into the most restrictive category of drugs, Schedule 1. This classification made them virtually impossible to study clinically and effectively ended any significant research into the pharmacology and medical value of psychedelics for more than 3 decades.

Nevertheless, there can be no doubt that psychedelics played a substantial role in defining the youth culture of the 1960s and 1970s, with books and essays too numerous to cite being written on this topic. It is believed that more than 30 million people have used LSD, psilocybin, or mescaline (Krebs and Johansen, 2013). One suspects that had LSD never been discovered, the world might look very different today than it does now, for better or worse, depending on one’s perspective.

Despite the recreational use of psychedelics, a quote from a book by Grinspoon and Bakalar (1979 Pg 192) needs to be kept in mind:

Many people remember vaguely that LSD and other psychedelic drugs were once used experimentally in psychiatry, but few realize how much and how long they were used. This was not a quickly rejected and forgotten fad. Between 1950 and the mid-1960s there were more than a thousand clinical papers discussing 40,000 patients, several dozen books, and six international conferences on psychedelic drug therapy. It aroused the interest of many psychiatrists who were in no sense cultural rebels or especially radical in their attitudes.”

One very important scientific consequence of the discovery of LSD also is often overlooked. The powerful
psychologic effect of LSD was accidently discovered in 1943 (Hofmann, 1979a), followed only a decade later in 1953 by the detection of serotonin in the mammalian brain (Twarog and Page, 1953). The presence of the tryptamine moiety within LSD was also quickly seen to be the scaffold for the chemical structure of serotonin (Fig. 1).

(…)

pr.115.011478