NIDA Research Monograph 146

Preface (Geraline C. Lin)

Despite a general trend of declining substance abuse by high school seniors and college students in the United States from 1985 to 1991, the most recent (1992) National Institute on Drug Abuse (NIDA) National High School Senior Survey (currently known as Monitoring the Future) has found that annual prevalence of lysergic acid diethylamide (LSD) use has risen for a third consecutive year from 1989 to 1992 among college students and young adults aged 19 to 28. Moreover, from 1991 to 1992, an increase in LSD use by high school seniors comparable to the increase by college students and a trend of increasing annual prevalence of LSD use by 10th and 8th graders (although at a lower rate for the latter) were also observed.

Prompted by these observations and other independent sources indicating an increase in LSD use, the fact that the last comprehensive, indepth review of research in this area by NIDA was conducted well over 10 years ago, and the impressive advances made in and the tremendous research opportunities afforded by molecular biology and other neuroscience disciplines during the past decade, NIDA undertook the present technical review to examine current knowledge on hallucinogen research and to identify research priorities in this area.

The technical review meeting entitled "Hallucinogens: An Update" was held July 13 and 14, 1992, in Bethesda, MD. The objectives of the meeting were: (1) to update current knowledge on hallucinogen research; (2) to identify future preclinical and clinical research needs; (3) to discuss problems and possible solutions associated with hallucinogen research, especially relating to human studies; (4) to explore the potential therapeutic utility, if any, of classical hallucinogens; and (5) to address issues related to substance abuse such as how hallucinogen research can contribute, directly and indirectly, to drug abuse research and help prevent, ameliorate, and resolve problems associated with hallucinogen abuse.

The meeting covered qualitative and quantitative studies in both animals and humans on a wide range of classical hallucinogens, including investigational new drug (IND) clinical studies on N,N-dimethyl- tryptamine (DMT). Presentations addressed behavioral, drug discrimination (DD), and operant conditioning experiments performed

with whole animals as well as electrophysiological and neurochemical studies' exploring receptors, second messenger systems, and structure- function relationships of the 5-hydroxytryptamine, (5-HT 2 ) receptor at the molecular level. It might be noted, as an aside, that progress in serotonin research has been moving at a rapid pace. Since this technical review was held, there have been some changes in serotonin receptor nomenclature. The originally defined 5-HT 2 receptors mentioned in this monograph are now referred to as 5-HT 2A receptors, whereas 5-HT lc receptors are now termed 5-HT 2C receptors. Both receptors, therefore, are considered as members of the same subfamily.

Applications of autoradiography, position emission tomography (PET) scanning, and other imaging techniques for identifying anatomic loci of action also were presented at the review. Other topics addressed structure-activity relationships (SAR) of ergolines, use of molecular graphic models of 5-HT 2 receptors for elucidating the action of hallucinogens (i.e., whether it be agonist, partial agonist, or antagonist), and identifying amino acid residues important in ligand binding. A discussion of the potential psychoheuristic value of hallucinogens also took place. Human studies of hallucinogens have recently resumed. A description of the effects of DMT in humans is provided in this monograph, and a Hallucinogens Rating Scale (or, more accurately, a DMT-like rating scale) is described (Strassman, this volume). Finally, the meeting concluded with a summary highlighting challenges and opportunities and identifying future research needs.

This monograph represents a state-of-the-art information resource concerning classical hallucinogens. It is hoped that this monograph will serve to stimulate further research in this area. Hallucinogen research, in addition to its relevance to hallucinogen abuse due to the unique actions of hallucinogens on human perception, cognition, and behavior, also affords an opportunity to unveil some fundamental brain processes through which these functions are organized and manifested. Therefore, an understanding of the mechanism of the action of hallucinogens not only would allow for opportunities to develop strategies and/or modalities for combating hallucinogen abuse but also would have profound consequences on individual and public health.

The monograph should be valuable to members of the scientific community who are involved in drug abuse research and neuroscience research in general; to those interested in the field of classical hallucinogens, including professionals in mental health, psychiatry,

public health, and education; and to Government agencies with regulatory responsibility, drug enforcement responsibility, or both.

[The volume's fourteen other chapters, on receptor pharmacology, structure-activity relationships, and animal models of hallucinogen action, are omitted, as is the remainder of Strassman's own chapter (its Introduction, Epidemiology, Clinical Issues, Scientific Issues, and Summary sections).]

Rick J. Strassman, "Human Hallucinogenic Drug Research: Regulatory, Clinical, and Scientific Issues" — Regulatory Issues

A detailed account of the process by which an investigational new drug (IND) permit was acquired for DMT has been published (Strassman 1991). This chapter summarizes the salient points.

There were several reasons DMT, rather than longer-acting, more popular hallucinogens, was chosen for a research proposal. First, it is a very short-acting hallucinogen, with peak effects obtained within 2 to 5 minutes after intramuscular (IM) injection (Sai-Halasz et al. 1958).

This attribute is an advantage in the potentially anxiety-provoking environment provided by a modem clinical research center, where a renewal of human studies with hallucinogens must take place. That is, no

matter how troubled a subject's experience on DMT might be, it would be short-lived and relatively manageable.

Second, DMT is an endogenous hallucinogen whose existence in the human nervous system has never been adequately explicated (Gillin et al. 1976). Thus, an investigation into the mechanisms of action and effects of DMT might shed some light on endogenous hallucinatory states.

Along this line of reasoning, antidotes to DMT might show efficacy as treatments of disorders with hallucinations such as schizophrenia. The importance of the 5-HT 2 receptor subtype in the mechanism of action of the novel antipsychotic drugs clozapine (Meltzer and Nash 1991) and ritanserin (Gelders et al. 1986) bespeaks the relevance of this approach. Finally, DMT abuse is not a widespread phenomenon. Thus, beginning human hallucinogen research with DMT would not cause the intense public scrutiny that might result from knowledge that LSD once again was being used in humans.

In order to use a drug in humans for either nonindicated purposes or a purpose with no currently established use, it is necessary to apply to the Food and Drug Administration (FDA) for an IND permit. However, for a Schedule I hallucinogen, none of which has been used in humans for many years, there is the additional problem of locating an acceptable source of the compound. A Drug Master File for the compound must be established for the FDA to determine basic safety and manufacturing data concerning any drug for human use. This file contains manufacturing and quality control data for the drug to which FDA may refer. FDA also is charged with concurrently establishing whether the proposed course of study will yield worthwhile data.

The proposed study was to establish normative dose-response data for DMT in a group of experienced hallucinogen users in a double-blind, randomized, placebo-controlled study design.

Experienced hallucinogen users were chosen for three reasons: experienced subjects would be less likely to panic than naive subjects in response to the sudden onset and intensely hallucinogenic effects of a short-acting drug such as DMT; experienced subjects would be more capable of carefully describing the effects of DMT than would subjects with no experience with these compounds; and liability for the subsequent development of substance abuse and/or other psychiatric pathology would be less sustainable in subjects with a prior history of use of these drugs.

The literature on the biological and psychological effects on humans and animals of hallucinogens in general and DMT in particular was reviewed, primarily from the perspective of recent advances in 5-HT neuropharm¬ acology and psychopharmacology. Several hypotheses were then generated regarding what variables would be affected by DMT, what the interpretation of these effects would be, and subsequent experiments that would help prove or disprove these interpretations. The variables of interest were easily observable and verifiable. They included several neuroendocrine functions, cardiovascular effects, autonomic effects (pupil diameter and core temperature), and rating scale scores.

The first step in the application process for use of DMT was to submit a protocol to the Human Research Review Committee of the University of New Mexico School of Medicine's Institutional Review Board (IRB).

The IRB is responsible for the protection of human subjects involved in any clinical research. Although the IRB is concerned primarily with risk- to-benefit ratios, it also may offer suggestions regarding the scientific quality of the proposed study. This latter function usually is subsumed by the Scientific Advisory Committee of the General Clinical Research Center (GCRC) of the University of New Mexico Medical School, where the actual study was to take place.

The IRB places great emphasis on the nature of the informed consent document and, at first, was inclined to have this document state that DMT "had no known medical use," one of the criteria for placement into Schedule I. However, the suggestion was made that, if FDA approval were subsequently obtained, this would not be the case, as DMT would have been approved as a medically useful compound (i.e., as a probe of human serotonergic psychopharmacology and neuroendocrinology). The IRB accepted this reasoning and did not insist on including this phrase, which would have unnecessarily alarmed the subjects who were already approaching the study with some trepidation. The IRB also wanted a statement in the informed consent document regarding what effects subjects might experience while under the influence of DMT.

Interviews had previously been conducted with 19 experienced DMT free-base smokers in order to draft a new rating scale for this study (see below). Thus, a relatively balanced account of the subjective effects of DMT could be provided without going into too much detail. The subjects interviewed spoke most frequently of positively charged effects, so these predominated in the infoimed consent. However, panic, fear, confusion, and other unpleasant experiences also were listed as possible

outcomes. Prolonged ( > 24 hour) reactions to hallucinogenic drugs do occur in carefully controlled settings, although such reactions never have been reported for DMT. However, their overall incidence is quite low. The informed consent document, then, included a statement concerning the fact that subjects might experience prolonged adverse responses to the drug and that psychiatric hospitalization was available.

Finally, the IRB was told that local approval was necessary before applying for Federal permission to begin this study. Once Federal permission was acquired, the principal investigator (PI) would notify the IRB and begin, and not before.

The issues of confidentiality and anonymity also were of concern, since admitting to the use of Schedule I drugs is a crime, and a relatively high- functioning group was expected to volunteer for the study based on the socioeconomic status of the initial interviewees. Meetings with the university hospital counsel, directors of medical records and hospital admissions, GCRC head nurse, and administrative assistants led to a coding scheme by which subjects' confidentiality and anonymity were maintained, with only the PI having the key to the code.

The next step was presenting the protocol to the GCRC Scientific Advisory Committee for a thorough scientific critique. Issues of informed consent and ethical review were not taken up, except in a general way, as these concerns were the purview of the IRB.

After approval from both university committees charged with scientific and ethical issues. State Pharmacy Board approval was necessary to obtain and use a Schedule I drug. The protocol and the appropriate approvals had previously been submitted to the Drug Enforcement Administration (DEA) in Washington, DC, but approval had not yet been received. However, the State Pharmacy Board approved the protocol after it was explained that Federal DEA approval could not be received until State approval was obtained and that the project could not begin until all the requisite Federal permits were in hand.

The Federal approval process required simultaneous interaction with the FDA and the DEA. The applications for a Schedule I permit for DMT were sent to DEA, and the IND application was sent to FDA at the same time. Nearly 2 years were required to keep both of these processes on track until they were finally approved.

The application process to the DEA was complicated by requests for DMT for two separate reasons, possibly from two different sources, and of two different grades. DMT was required for the development of a laboratory assay for DMT in human blood and could be purchased from one of several chemical supply houses. However, laboratory grade DMT could not be used for human studies, even if it were purified to FDA standards. Thus, an additional source of pharmaceutical quality DMT was necessary for human administration. DEA was reluctant to approve the Schedule I application to possess laboratory grade DMT until the IND was received from the FDA. FDA could not decide whether to approve the IND request until pharmaceutical quality DMT was on hand and its appropriateness for human use could be confirmed. FDA finally wrote a brief letter to DEA saying that the science of the study was reasonable and that human studies of DMT would not begin until the FDA had deemed it safe to begin, but that DEA could approve the Schedule I permit to obtain laboratory grade DMT (so assay development could begin) and pharmaceutical grade DMT (to which the appropriate quality control procedures could be applied).

The next major effort involved finding a source of DMT approved by the FDA. The FDA required a pedigree of the DMT if it were to be administered parenterally, the only way DMT alone is active. The pedigree is a description of all precursors, intermediates, and impurities in these compounds, en route to the final synthesis of the DMT. A detailed chemical analysis of the final product also is required. Additionally, the manufacturer must provide FDA with details concerning the manufacturing and cleanup procedures to assure FDA that "good manufacturing procedures (GMP)" were followed. The National Institute on Drug Abuse (NIDA) had some DMT "on the shelf," as did Sigma Chemical (from which the laboratory grade DMT was purchased). Either sample could be purified to > 99 percent purity, but FDA would not accept DMT without a pedigree. Neither NIDA nor Sigma had the pedigree information. Several other possible sources also proved to be either legally or economically unfeasible.

Finally, the DEA determined that regulations allow the synthesis of small batches of Schedule I drugs by previously licensed research laboratories if the drug was for research rather than fiduciary puiposes. The "coincidental activities" clause frees synthesizers of small batches of scheduled drugs from the much more rigorous and costly security arrangements required for manufacturers with primarily commercial interests. A colleague with a Schedule I permit for DMT then agreed to

make a small batch of DMT for this study and to provide the requisite documentation, a collaboration with which FDA was satisfied in principle.

The DMT was formulated for intravenous (IV) administration by the inpatient pharmacy of the University of New Mexico Hospital. The DMT then had to be put through the quality control steps required by FDA. Since pharmaceutical companies work with much larger lots of drugs than this small batch, it took some creative problem solving to determine the number of vials of injectable DMT that needed to be tested for pyrogenicity, sterility, and content uniformity. The last issue concerns both the concentration of representative samples of the product being within 5 to 10 percent of the hypothetical value (in this case 40 milligrams per milliliter [mg/ml]) and the maintenance of this concentration over time.

Satisfied with the quality of the DMT for human use and the scientific rigor of the study, FDA gave approval to begin. DEA was notified at this time. Amendments to this protocol, if not substantive, were discussed and approved by telephone. More substantial amendments, such as combining DMT with another drug, required both written and telephone consultation as well as formally requesting the manufacturer of the additional drug to provide written authorization for FDA to access its Drug Master File and IND information. DEA was sent copies of all changes to the original DMT protocol.