Although psychedelic drugs generally have good safety profiles, a recent systematic review concluded that adverse events in psychedelic trials are poorly defined, not systematically assessed, and likely underreported. In the past year there have been multiple reports of serious adverse events (SAEs), and long-lasting harms to participants in clinical trials of psychedelic-assisted therapy (PAT) have emerged. We draw attention to a unique and overlooked category of risk in PAT stemming from the interactions between therapists and patients receiving high doses of psychedelics. In our view, the understudied therapeutic component of PAT presents the most serious risks. Addressing it requires interdisciplinary approaches by researchers free from conflicts of interests.
adverse effects
Adverse reactions to psychedelic drugs. A review of the literature
The use of naturally occurring and synthetically derived compounds for their “psychedelic” effects has been a part of human culture for thousands of years. The basic pharmacology of the major synthetic psychedelic compounds (primarily lysergic acid diethylamide [LSD]-25) is described and reference is made to their potentially beneficial psychological effects. Adverse reactions, defined as dysphoric and/or maladaptive/dysfunctional responses to the use of these drugs, sometimes require careful clinical judgment in order to diagnose. These reactions can be effectively classified along a temporal continuum. Acute, short-lived reactions are often fairly benign, whereas chronic, unremitting courses carry a poor prognosis. Delayed, intermittent phenomena (“flashbacks”) and LSD-precipitated functional disorders that usually respond to treatment appropriate for the non-psychedelic-precipitated illnesses they resemble, round out this temporal means of classification. The question of organic brain damage as well as permanent changes in personality, attitudes, and creativity in patients and normals who have repeatedly ingested psychedelic drugs is controversial, but tends to point to subtle or nonsignificant changes. Future areas for study of the psychedelics’ pharmacological, psychological, and therapeutic effects are suggested.
A Note on Adverse Effects
While we are talking about the uses of psychedelic drugs, it is appropriate to discuss their dangers. The psychedelic voyage does produce some casualties; the question is how many and how serious they are, what causes them, and how to prevent them. This has been a matter of controversy since the 1960s. Drug users sometimes would not confess that they had any problems, because doubts and regrets were supposed to be a sign of rigidity or repression or some other inadmissible personal problem. Anti-drug crusaders sometimes would not admit that there was such a thing as a good trip or an insight to be derived from psychedelic drugs.
Hallucinogens and Related Compounds
While hallucinogens have a long record of culturally sanctioned and salutary use, dating back thousands of years to pre-historical indigenous communities, their emergence since the 1960s as recreational drugs have led to maladaptive patterns of use and risks to young people. Adverse outcomes can include high levels of acute anxiety, psychotic decompensation that usually though not always resolves, and a chronic disabling condition identified as hallucinogen persisting perception disorder (HPPD). Over the past twenty years additional concerns have been aroused by use of MDMA (aka Ecstasy), which has achieved high levels of popularity among young people as a recreational dance drug. Other new trends among youth include experimentation with the dissociative hallucinogens, ketamine and salvia divinorum. With the re-emergence of approved and methodologically sound clinical investigations of hallucinogens, a better understanding of the full range of effects these highly unusual compounds have will evolve.
Hallucinogen Use Disorders
KEY POINTS
Perceptions among adolescents regarding hallucinogens use are changing. Current trends show there are increasing emergency department presentations from use of these drugs.
Use of novel hallucinogens, such as 25I-NBOMe, is gaining popularity and can have serious medical complications.
Hallucinogen use may result in psychiatric disorders that may occur at time of use or afterward and may cause secondary psychotic, mood, or anxiety disorders. Limited data exist regarding treatment of these psychiatric disorders in adolescents, and evidence is extrapolated from adult studies. Benzodiazepines and behavioral techniques are recommended first-line treatments. Certain antipsychotics may worsen hallucinogen disorders and should be used with caution.
Therapeutic Guidelines: Dangers and Contraindications in Therapeutic Applications of Hallucinogens
INTRODUCTION There are widespread beliefs about the dangers of hallucinogenic drugs and frequent media reports attributing fatalities to hallucinogens. This media bias was typical in the early 1970s when much attention was focused on supposed chromosome damage and birth defects in children born to mothers who had taken LSD (lysergic acid diethylamide) during pregnancy. Later on, negative results of better-controlled, rigorous investigations (Muneer 1978) refuted the earlier alarmist concerns, but these received very little attention in the media. The controversial nature of the U.S. drug policy and its influence on government-sponsored research of illicit drugs has recently drawn media attention due to investigational flaws of highly publicized research claiming harmful effects (Jennings 2003).
The Adverse Effects of Hallucinogens From Intramural Perspective
Very recently, after a long-lasting, worldwide moratorium on research of hallucinogenic agents, a good number of advanced countries have been revising their position, and start to approve testing the physiological and therapeutic effects of hallucinogens in human subjects. The purpose of this article is to review safety information available in the literature on hallucinogen use, and sort out those data from the reported complications of their abuse. Because of prohibitory regulations of the last 35 years, there are difficulties in achieving this kind of evaluation. Our approach has to be broad, and at times retrospective, in contrast to the well-controlled, focused, prospective design of the premarketing trials of legal drugs. The article summarizes the analyses in anticipation of supportive regulatory changes for the use of hallucinogens in well controlled studies and strictly supervised clinical trials.
Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naïve healthy volunteers
3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a recreational drug reported to produce a different psychological profile than that of classic hallucinogens and stimulants. It has, therefore, been tentatively classified into a novel pharmacological class termed entactogens. This double-blind placebo-controlled study examined the effects of a typical recreational dose of MDMA (1.7 mg/kg) in 13 MDMA-naı̈ve healthy volunteers. MDMA produced an affective state of enhanced mood, well-being, and increased emotional sensitiveness, little anxiety, but no hallucinations or panic reactions. Mild depersonalization and derealization phenomena occurred together with moderate thought disorder, first signs of loss of body control, and alterations in the meaning of percepts. Subjects also displayed changes in the sense of space and time, heightened sensory awareness, and increased psychomotor drive. MDMA did not impair selective attention as measured by the Stroop test. MDMA increased blood pressure moderately, with the exception of one subject who showed a transient hypertensive reaction. This severe increase in blood pressure indicates that the hypertensive effects of MDMA, even at recreational doses, should not be underestimated, particularly in subjects with latent cardiovascular problems. Most frequent acute somatic complaints during the MDMA challenge were jaw clenching, lack of appetite, impaired gait, and restless legs. Adverse sequelae during the following 24 hours included lack of energy and appetite, feelings of restlessness, insomnia, jaw clenching, occasional difficulty concentrating, and brooding. The present findings are consistent with the hypothesis that MDMA produces a different psychological profile than classic hallucinogens or psychostimulants.
Transient reinforcing effects of phenylisopropylamine andindolealkylamine hallucinogens in rhesus monkeys
Relatively few studies have assessed the reinforcing effects of hallucinogenic compounds, and no such studies have attempted to engender contingent responding for these compounds in animals with behavioral histories that include experience with serotonergically mediated reinforcing effects. The objectives of the present study were to investigate the capacity of several hallucinogenic compounds to maintain self-administration behavior in rhesus monkeys with a previous history of 3,4-methylenedioxymethamphetamine (MDMA) self-administration, and to compare these effects across a range of doses of drugs from two structural classes (indolealkylamines and phenylisopropylamines). The results indicate that no compound generated reliable responding and that no subject ever self-administered 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) at rates above those engendered by contingent saline. However, 3 out of 4 subjects did respond at rates between 0.75 and 3.0 responses/s in one or more sessions where N,N-dimethyltryptamine (DMT), mescaline or psilocybin were available. During some of these sessions in which self-administration was maintained, animals earned a majority of all available infusions and appeared intoxicated by the end of the session. This pattern of transient self-administration may indicate that these compounds have weak reinforcing effects, or mixed reinforcing and aversive effects.