When I first considered initiating a human research

project with N.N-dimethyltryptamine DMT), an endoge-

nous hallucinogen that has also been a drug of abuse, I

was reminded by many professional associates of the pit-

falls involving research with drugs in Schedule I of the

Controlled Substances Act of 1970 (CSA). One leading

authority on hallucinogen structure-activity relationships

remarked to me in half jest that the sole paper he saw com-

ing out of this attempt would be one describing the im-

possibility of such work in the present climate of war

against drug abuse. The psychedelic research community,

especially those whose orientation focuses on the use of

these drugs as catalysts of the psychotherapeutic and/or

creative process. is uniformly pessimistic with regard to

human studies ever proceeding with Schedule I com-

pounds, such as LSD, mescaline. psilocybin or DMT.

The CSA placed all medications and drugs of abuse

into five categories or schedules, depending on their

"medical utility," "abuse potential," and "safety of use

under medical supervision." Schedule I is the most restrictive

category into which bugs with no known medical use,

high abuse potential, and a lack of demonstrated safety

under medical supervision are placed. The CSA also pro-

vided a mechanism for the movement of drugs into and

out of various categories Fm trample, tetrahydrocannabi-

nol (THC) was rescheduled in the 1980s from Schedule

I to Schedule II, after evidence of its efficacy in treating

nausea and vomiting following cancer chemotherapy was

convincingly demonstrated. However, methaqualone's

rescheduling from Schedule III to Schedule I occurred as

a consequence of its widespread abuse.

The placement of hallucinogens into Schedule I was

controversial because studies had clearly demonstrated

their safety under medical supervision (Strassman 1984).

Although their medical therapeutic utility in several patho-

logical conditions had not been irrefutably demonstrated.

their use in research elucidating brain-consciousness issues

was very promising. Nevertheless, further study of their

potential utility for a variety of conditions could not be

conducted after the CSA was passed; consequently. inves-

tigators were required to return their supplies of these

drugs.

The abuse potential of these drugs was clearly high;

it was this characteristic that seems to have been the major

factor in their placement in Schedule I Fortunately, animal

research continued unabated. providing the focal point

for the recent explosion of information about the neuro-

transmitter. serotonin, and its receptor subtypes in the

brain. Then receptors play a role in sleep, aggression.

mood sexuality, and psychosis. as well as the mechanism

of action of the hallucinogens. Schedule I dug research

with animals is significantly easier, and high-purity hal-

lucinogens are available to qualified investigators from

the National Institute on Drug Abuse (NIDA). The pri-

mary hurdles in the case of animal research are those in-

volving Drug Enforcement Agency DEA) requirements

for security of the storage and/or disposal facilities, and

making certain that those who will be handling these drugs

do not have a criminal record.

THE RESEARCH PROPOSAL

For clinical studies with humans, one needs to begin

with a research protocol in which the rationale for hallu-

cinogenic drug administration is described in detail. The

protocol requires a clear statement of why one is interested

in giving hallucinogens to People and what one hopes t

measure or observe. One must be careful not to put the

cart before the horse in this type of work. Psychiatric re-

search workers sometimes spend excessive effort in ap-

plying drugs or other treatments of unknown mechanism

of action to psychiatric disorders of tremendous hetero-

geneity, even within single diagnostic categories.

Furthermore, basic psychophysiological mechanisms art

inferred from research in psychiatrically ill patients before

a clear understanding of the normal physiology of the vari-

able under investigation is known. It is important to sys-

tematically investigate in normal subjects how hormones,

drugs or other factors work before explaining pathophys-

iological states and treating or studying psychiatric pa-

dents.

Similarly, before suggesting that psychedelic drugs

can cure everything from neurosis to hangnails. one is bet-

ter served by first applying current tools of psychophar-

macologic research to shed light on the basic effects

of these drugs, both psychological and biological.

Subsequently, these drugs could be prudently applied to

disorders whose etiology or symptomatology interface

with the known effects of hallucinogens. This approach

seems more likely to provide useful data than a more seat-

of-the-pants approach.

In my case, I approached the task of beginning a new

human psychedelic drug research study from two angles.

The first was from the vantage point of schizophrenia. In

the 1960s and 1970s, DMT had been considered a prime

candidate for the so-called endogenous schizotoxin. One

theory suggested that overproduction of DMT might be

related to the psychotic process seen in schizophrenic dis-

orders (Gillin et al. 1976). Failure to demonstrate differ-

ences in DMT levels in several body fluids between nor-

mals and schizophrenics prompted the discontinuation of

studies either giving DMT or measuring DMT levels.

However, newer data concerning the role of serotonin in

both endogenous and drug-induced hallucinations has pro-

vided a new approach to understanding the etiology of hal-

lucinogenesis (Fischman 1983). At the most basic level,

one might suggest that drugs that could block the hallu-

cinations of DMT might also be antihallucinogenic in pa-

tients with schizophrenia Thus, understanding how DMT

worked in normals had relevance to a major public health

problem.

I also approached a clinical study of hallucinogens

from the dug abuse perspective. Hallucinogens continue

to be used and abused by people in the United States, par-

ticularly in college-age populations (18-25 years), at about

the same rate now as 20 years ago (Pope et al. 1990). In

spite of the tremendous advances in understanding hallu-

cinogens' effects and pharmacology in lower animals, the

necessary interface of human psychopharmacology and

animal neuropharmacology requires human studies. The

human biology of these compounds has relevance to more

specific treatments for acute adverse effects (e.g.. the bad

trip), understanding the effects of chronic use, and eval-

uating the effects of newly synthesized designer com-

pounds as they appear on the street.

An important element of both of these approaches in-

volved the development of a new rating scale for the ef-

fects of DMT, one that has less pathology-oriented ratings

than previous scales. The Addiction Research Center

Inventory (Haertzen, Hill & Belleville 1963), man or less

the benchmark for assessing subjective effects of drugs

in humans, contains what is known as the LSD Scale.

which is commonly known as the dysphoria scale.

Certainly hallucinogens can produce unpleasant effects.

but they can be distinguished from other drugs by more

than that quality. It seemed important to describe in more

neutral phenomenological terms what actually is observed

in the psychedelic state, particularly for subjects who seek

out these drugs.

Both of these research directions also required basic

dose-response investigations. Is there a relationship be-

tween dose and the effect of DMT, subjectively and bio-

logically? Building on older clinical literature, interviews

with experienced DMT users, and newer animal data, one

might anticipate which experiences and biological effects

would be seen. Dose-response studies could then be ini-

tiated The biological factors I decided to examine involved

hormonal (neuroendocrine) effects of DMT as downstream

markers of effects on central serotonergic neurotransmis-

sion. I also speculated that serotonin receptor activation

would be reflected in effects on basic vegetative variables,

such as core body temperature, blood pressure, heart rate.

and pupillary diameter. Subjective effects would be mea-

sured by the newly designed rating scale. This basic human

research could provide the foundation for more detailed

experimental interventions. Follow-up studies might in-

clude differential effects of DMT in selected patient pop

ulations with presumed abnormalities of serotonergic neu-

rotransmission (e.g., schizophrenia. affective disorders.

posttraumaumatic stress disorder), selective blockade of sub-

types of serotonin receptors to begin assessing receptor

subtypes responsible for specific neuroendocrine and sub-

jective effects, and experiments in which repeated doses

of DMT are administered in an attempt to develop acute

tolerance to the drug.

A research protocol needs to provide an adequate dis-

cussion of background information (i.e.. what is and is not

known about the area to be investigated), hypotheses (find-

ings that one hopes will be derived from the study and how

these data will answer specific questions). a plan of in-

vestigation (what one will do and why), a consideration

of risks and benefits to the subjects involved and how the

risks will be managed (with plans to deal with adverse re-

actions), sample size determination. data management,

references/bibliography, and an informed-consent doc-

ument. Sample size determination and data management

am relatively simple issues, if one has read the literature,

has some idea of the direction and size of expected

changes, and can consult with a qualified biostatistician.

University research offices have copies of U.S. Public

Health Service Form 396, which is used in federal grant

applications. This form contains an outline covering all

the aspects of a research protocol, with clear explanations

of what each area should include. It is the model research

proposal format used by most nonfederal agencies as well.

Most institutional review boards (IRBs),local committees

that review the relevant human-risk issues, like to have

proposals written in a similar format (although generally

in less scientific detail).

In order to decrease the risks involved in this project

my protocol involved using only experienced hallucino-

genic drug users. Administering a drug like DMT to naive

subjects seemed to be a high-risk venture. Level of expe-

rience was determined by an informal interview focusing

on extent of psychedelic drug use as well as negative and

positive effects experienced by prospective subjects.

Special attention was paid to assessing the presence of de

fenses characteristically known to be associated with neg-

ative reactions to hallucinogens, specifically denial and

projection (Barr et al. 1972). Furthermore. experienced

subjects are better able to report on subjective effects and

to compare and contrast their past experiences with DMT

and/or other psychedelics. Finally, from a purely legal

point of view, litigation claiming long-term brain or per-

sonality damage or subsequent problems with drug abuse

would be less sustainable in subjects with extensive past

use of psychedelics.

LOCAL ISSUES

The Institutional Review Board

Once the research protocol has been written (and

hopefully reviewed and critiqued by knowledgeable col-

leagues), it must be reviewed and approved by the local

IRB. This is a requirement for any research involving

human subjects. The function of IRBs is to assure the

safety of participating human subjects and. depending on

the particular IRB, the scientific merit of the study The

latter element almost always is given greater attention by

the scientific review committee of the research site in

which the study will actually take place. The IRB may also

recommend changes in and approves the informed-consent

document that accompanies the protocol. Once approval

by the local IRB and performance site is obtained, the pro-

cess of obtaining federal approval can begin.

Issues with the IRB can be complex if one does not

work within a university/medical school setting. The U.S.

Food and Drug Administration (FDA) has published

guidelines for university- and non university-affiliated

IRBs. This information is available through the FDA's

Office of Health Affairs. Nonuniversity IRBs may be local

or may not be if local ones do not have the requisite ex-

pertise and/or it is a multisite study and the relevant IRB

is at a different site. One can even hire an IRB that may

work with nonuniversity-affiliated investigators. but they

may charge exorbitant fees. If one is interested in creating

an LRB, the requisite composition of an IRB is clearly de

fined in FDA guidelines. However. this is not recom-

mended because it would create an unnecessary bureau-

cratic nightmare, independent of the major goal of receiv-

ing IRB approval. It is preferable to use an IRB that already

exists.

From the outset. I had to explain to the IRB that even

if I received their approval, I could not initiate any studies

until the FDA and the DEA review processes were com-

pleted and their approvals obtained. Local approval was

the necessary first step before I could submit my request

to the federal receive process.

The IRB at the University of New Mexico was most

interested in the nature of the informed-consent document

They requested two things that were somewhat difficult

to address. The first issue was that of Schedule I drug use

in humans. If a drug has no medical use and cannot be used

safely under medical supervision (the criteria for place

ment into Schedule I). how could I justify human research

with it? They requested that I add the phrase "this drug

has no known medical use" to the informed-consent Doc-

ument. I responded by referring to the hundreds of articles

on the human use of LSD and nearly a dozen on DMT be

fore the drugs were scheduled, demonstrating that they

could be used safely under medical supervision, and that

in many ways the Schedule I placement was not a medical

but a legal definition. I asked to be able to state only that

it "had no current medical use," which they agreed to.

Ultimately, I was able to remove even that phrase by ar-

guing that if FDA approval was obtained no current med-

ical use" was no longer true, as I would have demonstrated

its utility as a tool for medical research.

The IRB's second concern was that I describe in the

informed-consent document what the subjects might ex-

perience on the drug. Clearly, one can choose from the

most hellish to the most beatific descriptions of the

psychedelic drug-induced state, with a strong biasing ef-

fect on the subjects. I opted for a balanced description of

effects of the range of symptoms, with a slight emphasis

on pleasurable and interesting effects. I justified this more

sanguine view by summarizing the results of my inter-

views with over 20 essentially normal DMT users, all but

one of whom described their DMT experiences in an ex-

tremely positive light. There also were no published re-

ports of serious psychiatric sequelae (e.g., psychosis last-

ing more than 24 hours) in normals given the drug. I did

suggest the possibility of serious emotional reactions to

the experience induced by DMT, and that in the most ex-

treme case, psychiatric hospitalization was available.

However, I was able to assuage the IRB's concerns slightly

by emphasizing that these were quite experienced hallu-

cinogen users, many of whom have had bad trips that had

been informative and developmentally useful in their abil-

ity to manage subsequent experiences with psychedelics.

The Performance Site Scientific Review Committee

More or less parallel to the IRB process is that of sci-

entific review by the committee that oversees studies in

the research center. My project was to take place in the

General Clinical Research Center (CRC) of the University

of New Mexico Hospital, funded by the National Institutes

of Health to provide beds and nursing as well as laboratory

and statistical support for CRC-approved human research

proposals. Projects are submitted to the CRC Advisory

Committee and need to follow the same general guidelines

as do submissions to the IRB, with a naturally greater em-

phasis on the scientific rationale for the proposed project.

There was less difficulty in obtaining CRC approval than

IRB approval, as the CRC assumed that the IRB would

address the overriding issues of risk and informed consent

The CRC requested an additional Literature review to sup

port my requests for measurements of the hormones I was

interested in evaluating. They also wanted urine drug

screens taken on the morning of every study day. This was

not to disqualify people from participating in the study,

but to be able to assess the effects of a positive urine on

the parameters under scrutiny. Would a less robust pro-

lactin response, for example, be associated with a positive

urine screen for marijuana') The Advisory Committee also

wanted me to impress on subjects the importance of not

taking any other drugs of abuse during the project to keep

the data as clean as possible.

Confidentiality

One of the thorniest issues of the project was that of

anonymity and confidentiality. Admitting to the use of

Schedule I compounds is admitting the commission of a

federal offense and being liable for prosecution. All of the

subjects in this project are professionals, with spouses.

families. reputations, and careers. Therefore. strict

anonymity and confidentiality were required. Several

meetings were held with the Medical Records Department

Legal Counsel for the University Hospital, Admitting

Office, and Head Nurse of the CRC to discuss how to as-

sure strict confidentiality and anonymity. Furthermore, it

is usually required that the signed informed-consent doc-

ument be attached to the subject's medical records, a sit-

uation impossible in this case. The final solution was com-

plex but appears to be working well. A subject coming in

for an admission medical history, physical examination.

and laboratory work (i.e.. blood count and chemistries.

electrocardiogram, thyroid functions. urinalysis) has a

chart made up with his or her real name. This is needed

if at any time in the future the subject happens to visit the

emergency room or clinics, then baseline medical data will

be available for comparison. However, subjects' charts

are not associated with my DMT protocol number. As I

have run several projects through the CRC over the years,

my being their physician of record is not in itself partic-

ularly incriminating. (I just as easily could have had an-

other physician sign these forms; if this were the only pro-

ject I had ever performed at the CRC, having me sign their

papers might be seen as their admitting to the use of illegal

drugs). The subjects' screening psychiatric examination

as well as every admission for the project occurs under a

code name and hospital chart number. Ultimately, the

Medical Records Department allowed me to be the only

person with the code. The more people who have confi-

dential information, the more likely it will be compro-

mised. I was also the sole possessor of the signed in-

formed-consent documents and had to state that clearly

on every admitting form.

The informed-consent clauses regarding confidential-

ity went through some evolution as the process unfolded.

I had previously run a study giving melotonin, a pineal hor-

mone and an experimental nonscheduled drug, in a clinical

research setting that required FDA approval In that case.

I had stated that the FDA and the manufacturer of mela-

tonin could have access to participants' medical records.

In my first informed-consent document for the DMT ex-

periment, I originally indicated that the FDA, DEA (as also

involved in the regulatory process), and the manufacturer

of DMT (at that time undetermined) might, under extraor-

dinary circumstances. have access to the medical records.

This met with universal alarm. The following was the final

solution to the issue of informed consent if the FDA or

the manufacturer was interested in interviewing subjects

and/or having access to their medical records for scientific

purposes. they would need to go through me, who then

would determine whether or not individuals were indeed

willing to do this. Records theoretically could be subpoe-

naed, but that would be vigorously fought And, as I am

the only one with the key to the code. I would refuse to

divulge the key if this should occur.

State Pharmacy Board Schedule I Permission

The last local issue was getting my state of New

Mexico Schedule I permit, which is necessary before the

DEA will process a Schedule I request This varies from

state to state, and the state board of pharmacy and/or the

local DEA office knows if a state permit is necessary be-

fore applying for DEA approval. This was relatively easy.

I submitted the appropriate form. including an abbreviated

version of the protocol and approval letters from the CRC

and IRB. This permission was granted at the board's next

meeting.

FEDERAL ISSUES

One should never send anything important to any fed-

eral agency by regular mail; always send it by express mail

or with a return receipt requested. Also, always take de-

tailed notes whenever speaking with anyone at any federal

agency. Get names and phone numbers because one rarely

gets the needed person the first time; he or she is often at

the end of a long chain of in-house transfers from exten-

sion to extension. Write down as much as possible from

every conversation. Refer to these phone calls in your mail

correspondence to let the relevant agency know you art

taking notes and to ensure accurate communication.

One will need to deal with at least two federal agen-

cies in the application process: the DEA and the FDA. At

times, their responsibilities overlap in vague and poorly

defined ways. By going through the application process

in a methodical and persistent manner, defects in this two-

tier system became clearer and gradually worked them-

selves out. My overall impression of the process is that

the difficulties I encountered were not due to intentional

malicious roadblocking but uncertainty regarding who had

final authority in a particular matter and what were the

proper channels through which my request should be fun-

neled. This, combined with generic bureaucratic ineffi-

ciency, resulted in a 21-month process from the date of

application to final approval to begin the study. Even so,

with my initial expectations, I was pleased that the process

even went that quickly.

Funding: An Aid to Obtaining Federal Approval

I. submitted a research grant proposal to a nonfederal

granting agency, the Scottish Rite Foundation for

Schizophrenia Research, at approximately the same time

I began the FDA-DEA approval process, which was in the

spring of 1989. I would encourage all potential investi-

gators in this field to consider a similar course. First of all,

one's scientific reasoning is sharpened by the grant review

process. and if the FDA and/or DEA review turns out to

be inordinately long, the feedback obtained from the grant-

ing agencies' review boards may anticipate objections

likely to originate at the federal regulatory level. If such

a grant is approved. this enhances the likelihood of

FDA/DEA taking note of the scientific credibility of the

proposed work. I received a one-year award from the

Scottish Rite Foundation to recruit subjects, develop a way

to measure DMT in blood (the DMT assay), interview sub-

jects who had smoked DMT in the past in order to draft

a DMT rating scale, and pursue FDA-DEA approval. A

second year was approved pending FDA approval. An ap

plication for a NIDA grant was made in June 1989. This

was approved and funding started in May 1990. essentially

at the end of the first year of the Scottish Rite grant The

NIDA grant then took over when the Scottish Rite grant

left off, a fortunate case of good timing. Both these awards

were extremely helpful in prompting the FDA and the

DEA to pay more attention to my request to get started

with the experiments.

The Drug Enforcement Administration:

The Schedule I Permit

DEA approval, although slow, was not particularly

complicated. Then is an application form specifically for

Schedule I drugs DEA Form 225: Application for

Registration Under Controlled Substances Act of 1970)

that is available from Washington or the local DEA branch

This is different from the routine Schedules II-V form that

all medical practitioners use to obtain approval to routinely

prescribe controlled substances (e.g., options, benzodiaz-

epines). There is four-digit code number for all scheduled

drugs that needs to be placed in its respective box on the

form. Not everyone at the DEA knows these numbers. I

did not realize it at the time but the back of the front paper

of form DEA 225 has a List of many scheduled compounds

(including DMT) with their respective drug codes. Should

then be any difficulty in determining the correct drug code

number. one can call the Registration Branch of the DEA

in Washington. I was inadvertently given the National

Drug Code number for DMT by the DEA in Washington

over the telephone. My entire application packet was re-

turned to me a month after I submitted it with a request

for the right number, accompanied by a piece of paper with

all the appropriate numbers for my information. Along

with this properly completed form an abbreviated version

of the protocol needs to be included, along with IRB and

scientific review committee letters of approval. One also

needs to describe the security arrangements for storing and

handling a Schedule I compound. which the pharmacy can

provide on their official stationery.

After several months of phone calls, inquiring as to

the status of my application, I learned it had been sent to

the regional DEA office in Denver. From them, it was sent

to the local DEA office in Albuquerque. The local DEA

agent assigned to my case then came wt to the University

of New Mexico a couple of times. She inspected the se-

curity system in the pharmacy (and found some weak-

nesses in the system that required correction), instructed

that a special freezer with its own lock be purchased that

was to be placed in the controlled-substances vault in the

pharmacy (which was already kept locked and guarded

24 hours a day), interviewed me and the manager of the

pharmacy, and requested the names, addresses, social se-

curity numbers, and phone numbers of all the people who

would have access to the DMT and/or have keys to the

freezer(several laboratory personnel and pharmacists, pri-

marily; I do not have a key to the freezer). She then ran

security checks on me and all those whose names were

provided to check for any criminal records. After being

satisfied with the security checks, locked freezer, and im-

provements in the security system, she described to me

the consequences of poor record keeping and unexpected

lasses of drug supplies She wrote an approval letter to the

DEA office in Washington. After a month or two of keep

ing track of this letter. I encountered another unexpected

difficulty.

My project required laboratory-grade DMT for the

assay, which I could purchase from Sigma Chemical with-

out difficulty once I received my Schedule I order forms.

This form of DMT did not need to meet the many require-

ments necessary for human administration. It could be

taken off the shelf of a chemical supply house and used

directly for laboratory or animal work. The project also

required getting permission to obtain and possess clinical-

grade DMT for human administration. This form of DMT

needs to be certified by the FDA as safe for human use.

However, the DEA had no recent experience processing

a request for administering a Schedule I drug to humans

and had difficulty in differentiating the two requests. They

were reluctant to let me order laboratory-grade DMT until

I had received FDA permission to go ahead with the

human study. However, FDA approval for this could not

occur until I found a source for, and established the safety

of, a clinical-grade DMT. I asked the FDA for their help

in interfacing with the DEA's pharmacist, and finally suc-

ceeded in getting the DEA to distinguish between the two

requests. Soon thereafter I was issued my Schedule I per-

mit. with order blanks. and could order DMT from Sigma

Chemical for the laboratory. Once I received FDA ap-

proval to begin human administration of DMT (from, at

that point, an unknown source) I was to notify the DEA

of this but no additional paperwork was required.

The Food and Drug Administration:

The Investigational New Drug Application

and the Drug Master File

The application process with the FDA involved two

steps. Usually, if a drug is used for a purely experimental

study. an Investigational New Drug (LND) application

needs to be submitted. This was quite simple in the case

of my previous melatonin study in 1985. At that time, I

worked with Sigma F 8r D, a division of Sigma Chemical.

who had a Drug Master File (DMF) for melatonin on file

at the FDA After I spoke with and wrote to Sigma they

authorized the FDA to access their DMF on melatonin on

my behalf The FDA looked at the manufacturing data,

chemical purity tests. and other information on melatonin

in the DMF and then gave me permission to order the

melatonin. After the pharmacy prepared it in a solution

appropriate for injection. I tested the sterility and pyre-

genicity (ability to cause fever), sent in this information,

and shortly thereafter received permission to proceed with

the study.

Since 1985, and particularly since the early 1970s,

when a group at the National Institute of Mental Health

(NIMH) received permission to give DMT to humans, reg-

ulations have become much stricter at the FDA. particu-

larly regarding injectable drugs. DMF requirements are

more elaborate and require a full pedigree of the compound

(i.e., statements regarding the source and purity of all pre-

cursors, assessment of purity and identification of con-

taminants in all intermediary synthetic compounds, and

more documentation regarding the composition and char-

acteristics of the final product that would ultimately be

given to subjects). Therefore. when I submitted my IND

application for DMT, I again believed that Sigma F 8r D

would be able to provide the drug and that the process

would be analogously simple. I spoke with and wrote to

Sigma F 8r D, who agreed to set up a DMF for their DMT.

I sent in my IND application forms, along with copies of

the IRB and scientific committee approvals. a copy of the

informed-consent document and a brief description of the

study hoping that the FDA would accept Sigma F Br D's

information.

The forms used to apply for an IND are FDA 1571

and 1572, each of which is two pages long. Form 1571

contains an interesting clause that might be of use when

trying to study drugs that have been previously investi-

gated This clause, which can be checked as part of an ap

plication procedure, is a "request for reinstatement of an

IND that is withdrawn, inactivated, terminated or discon-

tinued" DMT had been studied by a group of investigators

at NIMH in the 1970s (Giltin et al. 1976) and another

group in Chicago had used the NIMH IND for a series of

their own studies somewhat later (Meltzer et al. 1980). I

thought that I might be able to use information from the

old IND to speed the approval process for my own appli-

cation.

Documents sent to the FDA enter via the Documents

Room. and from there letters are routed to the appropriate

division. In the four years since my melatonin IND was

issued, a new division has been formed for Pilot Drug

Evaluation. to which my DMT IND application was re-

ferred a week or two after its arrival in Washington. The

FDA then sent me a standard form letter acknowledging

receipt of the application. the name of the drug for which

the application was made, and the IND number. It was

signed by the responsible Consumer Safety Officer (CSO)

with a phone number and routing address. (Never fail to

write the IND number on the top of any future correspon-

dence with the FDA. Without it, letters will languish for-

ever in the Documents Room awaiting someone who has

the time to figure out what the IND number is and, by de-

fault. where it needs to go,) This letter stated that unless

I heard from the FDA within 30 days of the date stamped

on the top of the form letter (generally 10-15 days after

sending the application)I could proceed with the study.

This is standard procedure for the FDA on receipt of any

IND application.

At this point, it is necessary to begin intensive tele-

phone contact with the review section staff. I began calling

as soon as I received the name of my project manager

(PM). Of course, the main problem with the IND appli-

cation was that I had no source of drug, and the FDA could

not grant me permission to begin a study without the DMT.

It was therefore on "Hold" (an official FDA term) from

the outset However. I needed to begin finding out who

could make the drug, and what information I would need

to send to the FDA concerning the compound. Within a

couple of months, I received a detailed teeter from the FDA

requesting the necessary information regarding preparation

of the bulk drug, and the characteristics of the clinical form

of the drug that I actually planned to administer.

The two primary contacts one first works with on the

section staff art the CSO (or PM) and the chemist. The

FDA has two charges in a case like this: the first is to as-

sure the safety of human subjects, and the second is to give

some scientific guidance to optimize the chances that the

experiments with humans will provide valid and valuable

data. A chemist is involved because no drug company

makes Schedule I drugs for human use anymore. My re-

quest was linked to the finding of a sourer for the actual

drug; the chemist needed to help me with this process.

Even if a drug company was making the drug, the FDA

chemist would still be involved in assessing and examining

the DMF to assure that the drug was safe for human use.

Safety in this context means assuring that the dug is in

a high state of purity (99+96) and contains no toxic im-

purities. The chemist must evaluate the manufacturing pro-

cess and analytical data (the chemical pedigree) for the

drug in order to certify these requirements. The PM, on

the other hand. interfaces with the scientific staff at the

FDA regarding scientific matters.

I was aided in the area of scientific concern by virtue

of having received IRB and CRC input and approval I also

was fortunate to have received the Scottish Rite and then

NIDA funding for the project The review processes in-

volved in these grants sharpened the science of the project

and funding from outside agencies greatly enhanced my

credibility.

The Search for Clinical-Grade Dimethyltryptamine

Acquiring the DMT for the study was a complex pro-

cess, and atone point in time I began to fear that the whole

project would come to a dead end because satisfactory

DMT could not be obtained. When a drug has been made

for human use, be it by a pharmaceutical company or a pri-

vate concern, the FDA has a DMF on it, containing de-

tailed information regarding synthesis of the drug and its

pedigree. Drug companies have large chemistry labora-

tories that provide this information to the FDA, and they

are familiar with the process of setting up a DMF for any

particular compound The DMF also contains information

regarding animal and human toxicity data when relevant

Fortunately, in the past, DMT had been given in numerous

animal studies and nearly a dozen human studies.

Therefore, the toxicity issue did rot concern this particular

drug.

My IND application was complicated by the fact that

it was necessary to establish a DMF for the DMT. in ad-

dition to acquiring permission to give the drug for an ex-

perimental purpose. If a study was designed to use a drug

currently in use (e.g., morphine) for research on a nonindi-

cated use (e.g., to control high blood pressure in an emer-

gency setting), a drug company could simply authorize

the FDA to access their DMF on the researcher's behalf.

However, no DMF existed for DMT. One hope I held out

was that l might acquire DMT from some sourer, and if

it were not pure enough. I could purify it to the required

level. However, at a very early stage in the negotiations

it was clear that this was not satisfactory to the FDA. The

pedigree and detailed synthetic information had to be pro-

vided.

With the aid of the FDA chemist, I was able to track

down (in the Federal Archives Building) the old IND for

DMT that was used at NIMH in the 1970s. Recall that I

was hoping to reactivate an expired IND. using data ac-

quired by NIMH researchers. However, the information

in that IND was wholly inadequate for current FDA re-

quirements: there was no DMF in their IND. The IND file

said that Aldrich Chemical in Chicago had made the DMT

for the NIMH study. I contacted Aldrich. but they had

never compiled a DMF for the drug not did they distributed

the compound anymore. The NIMH group, whom I sub

sequently contacted, no longer had either their IM) record!

or any information regarding the drug.

Sigma F & D, as described previously, was willing

to supply the FDA with as much information as it had

available regarding their DMT in order to set up a DME

on the compound. However, they did not actually man-

ufacture the drug; a source in Europe supplied it to them

The European source was unwilling to provide detailed

information regarding their synthesis of the drug.

Therefore, Sigma F & D was ruled out as a source of DM?

that could set up a valid DMF.

NIDA has made scheduled drugs available for animal

studies. and has in fact supplied investigators with a non-

hallucinogenic LSD analogue for human positron-emis-

sion tomography studies (Wong et al. 1987). However.

NIDA's DMT that was on the shelf was relatively old and

did not have the pedigree and required synthetic informa-

tion that the FDA required.

However. NIDA has a contract with the Research

Triangle Institute (RTI) in Research Triangle Park, North

Carolina. RTI provided the THC for the marijuana/THC

protocols in the 1970s that investigated the effects of these

drugs on nausea and vomiting induced by cancer

chemotherapy. However, when I contacted RTI on NIDA's

referral, they initially claimed they could not make drugs

for human use because of liability concerns, but I was told

by NIDA that not one suit has ever been brought against

NIDA for the marijuana/THC study. Although NIDA ex-

pressed their general concern about the lack of any reliable

sourer of high-quality drugs of abuse for human studies,

they stated that research with DMT was not of sufficient

priority for them to pay RTI to make the drug to the spec-

ifications required by the FDA, even if RTI did agree to

make it Therefore, I would have to pay for the preparation

These discussions with RTI and NIDA took place before

my grant from NIDA was approved and funded. After

some negotiating, RTI agreed to prepare high-quality

DMT and send me the information necessary to set up my

own DMF for the drug. They estimated the cost of such

a synthesis, including the record keeping, to be "in the

thousands." which was quite out of the range of my ability

to pay. Thus, RTI and NIDA were also effectively ruled

out as sources for clinical-grade DMT.

Next I tried NIMH, which has a Chemical Synthesis

Program to make obscure research drugs for investigators.

Again. their contract stipulated that their drugs, even if

prepared to the most exacting specifications. could not be

used in humans. However, the director of this program

stated that he was considering changing the wording of

their contact when it was up for renewal to be able to pro-

vide drugs for human studies. This might be a sourer of

such drugs for future investigators and should be pursued.

but NIMH also had to be ruled out as a source of DMT for

my own study.

I then asked a colleague with experience in synthesis

of hallucinogens within a university setting if he would

consider making the DMT for my project. He declined,

referring to the difficulties involved in acquiring a man-

ufacturer's license through the DEA to distribute sched-

uled drugs. I approached another colleague with similar

experience within a university setting. He had been keep

ing abreast of my futile search and was swan that I had

about exhausted all possible avenues. He finally agreed

to consider making DMT to FDA specifications at cost.

and thereby considerably less than the RTI quote.

However, manufacturer's licensing procedures are much

stricter than regulations concerning individual laborato-

ties' research use and he wanted assurance that making

the drug for me would not break any DEA regulations.

After some effort I found a division within the DEA, the

Office of Drug Research Registration, that regulates reg-

istration issues for researchers. They informed me of the

"coincidental activities" clause within their regulations

that allows registered researchers to prepare snail batches

of scheduled substances for collaborative research efforts

rather than the sale-for-profit context of a manufacturer-

purchaser relationship.

At this point, when asked whether or not this would

be a satisfactory arrangement from the FDA's point of

view the FDA chemist referred me to a physician on the

drug abuse staff in the FDA's Pilot Drug Division. He be-

lieved such an arrangement would be satisfactory. He also

quickly became my most important, responsive, and re-

liable liaison within the FDA.

My colleague who agreed to manufacture the DMT

and I then submitted brief amendments to each of our DEA

applications that would justify the preparation and pos-

session of adequate amounts of DMT for a collaborative

research effort. We needed to provide the DEA with the

reason for requesting this amendment, the amount of DMT

involved, and a statement to the effect that this was a re-

search, not a fiduciary, relationship. A tremendous number

of phone calls was required to keep this amendment mov-

ing through the maze of sections at the DEA. One major

delay was the DEA's request that the FDA approve this

amendment. The FDA did not believe this was necessary,

although the DEA would not proceed pasta certain point

until they received, in writing, FDA approval of this

amendment. I do not know where the truth actually lies

n this case, although the FDA complied with the DEA's

request.

DEA approval was thus obtained for my colleague to

produce DMT. Several months later, I received eight grams

of DMT-fumarate (a form of DMT that RDA has approved

for human use) and ail the supporting documentation of

the synthesis and analysis of this material necessary to set

up a DMF in support of my IND. The University of New

Mexico Hospital Inpatient Pharmacy then prepared a

dosage form of the DMT suitable for injection into hu-

mans. This was a sterile nonirritating solution that was dis-

tributed into 50 sterile vials.

Finding out how many samples to subject to quality

control was difficult Guidelines at the FDA generally refer

to pharmaceutical companies' massive lots of a drug. After

some discussion with the Pilot Drug Division and several

other divisions within the FDA. it was agreed that I would

use two vials each for the four tests necessary on the clin-

ical form of the drug. The following were the four tests:

(1) Content Uniformity -- Is the measured concentration

in the vials actually that calculated? (2) Purity -- Is the

drug pure and/or free of potentially toxic chemical con-

taminants? (3) Sterility -- Are there bacteria, yeast or

other pathogens in the solution of DMT? (4) Pyrogenicity

-- Are there fever-producing bacterial fragments in the

solution? A fifth and related test is that of Stability -- Are

purity and content uniformity maintained over time? The

rigorousness of these criteria was in part determined by

the fact that the drug was going to be injected, not given

orally. If the drug were to be given orally, some of these

requirements would have been relaxed

Purity and content uniformity can be performed on the

same vials. The University of New Mexico Hospital

Toxicology Laboratory agreed to perform these tests using

equipment already available for measuring levels of abused

drugs in clinical samples (e.g., blood, urine). Most toxi-

cology laboratories have the requisite gas chromatography.

mass spectrometry or high-performance liquid chromatog-

raphy equipment necessary for such work Any clinical mi-

crobiology laboratory can perform the necessary sterility

testing for aerobic and anaerobic bacteria, yeasts/fungi, and

actinomyces (similar to tuberculosis). The fact that DMT

is a Schedule I drug and the results were to be used to de-

termine safety for human administration dissuaded the

University of New Mexico Hospital Microbiology

Laboratory from conducting these tests. However, the New

Mexico State Laboratory's Environmental Microbiology

Section agreed to provide this service. Pyrogenicity is usu-

ally determined by injecting a rabbit with a predetermined

amount of drug and then measuring its temperature,

However, DMT raises body temperature in rabbits (as do

all hallucinogens) by a pharmacological mechanism, in-

dependent of pyrogen presence. Another test, the limulus

amebocyte lysate (LAL) test, can be performed in a test

tube and is also FDA approved. Two laboratories with LAL

expertise refused to handle a Schedule I drug, a third agreed

(Scientific Associates of St. Louis). It is important to make

certain that a quantitative result and raw data for the LAL

test are obtained. A simple presence or absence result is

not adequate.

Stability testing can occur concurrently with the study

and samples will be submitted far purity and concentration

checks one and two months after preparation of the drug

solution, and at three-month intervals as long as de study

is proceeding. The pharmacy, as well, needed to prepare

a report describing their preparation of the clinical form

of the DMT. Finally, my colleague had to prepare a large

file on the drug's preparation, its pedigree, the qualifica-

tions of those who made it, and several tests as to its purity

and identity.

I organized all of these reports, wrote a cover letter

to the FDA addressing each issue brought up in their letter

notifying me that the IND was on hold, and mailed it As

the study was on hold, the FDA was required to respond

within 30 days of receiving my letter. A letter with the ac-

companying data is called, in these cases. an amendment

to the IND. I received written approval to proceed within

two weeks of submitting this amendment. I began the

study accordingly.

At the time of this writing, the study is nearly half

completed. This particular phase of my work with DMT

will end in early 1992. Hopefully, the remaining DMT can

be used in future studies of its effects in humans. These

future studies will require CRC. IRB, and FDA approvals.

Because there is an existing supply of DMT, which I am

able to administer safely, I do not anticipate major

problems in beginning other studies.

CONCLUSIONS AND

FUTURE DIRECTIONS

A question that comes to mind while reviewing this

process is, What if the drug has been made by a pharma-

ceutical company (e.g., LSD by Sandoz)? Does Sandoz

have the information to set up a DMF? Would they test

whatever remaining available drug exists for the FDA?

Would the expiration date on their lots of LSD have

passed. thus voiding their use? I do not know, but using

a drug company's compound would certainly bypass de

difficulties I encountered in finding an approved manu-

facturer of the drug. not to mention all the chemistry, tox-

icology, bacteriology, pyrogen testing, and clinical for-

mulation work.

What can one learn from this, at times, Kafkaesque

process? First, with perseverance. it is possible to acquire

permission to conduct human research with a hallucino-

gen; in this case, DMT. Second personal contact primarily

by phone and carefully followed-up mailings are the best

ways to help the process keep moving forward. Such con-

tact is required, especially to convince the FDA, DEA, and

at times NIDA, to speak with one another on the n-

searcher's behalf. Third, a simple. scientifically well-reas-

soned approach with in-house approval is essential. and

outside funding is very important. Fourth, a close collab-

orative relationship with someone who can manufacture

hallucinogens may be necessary. Drug companies, if they

do make the drug, might be inclined; however. it is better

to have a first-class medicinal chemist with a university

affiliation. Again, outside funding and the possibility that

the project might dead-end without my colleague's assis-

tance were very important factors in persuading him to

take on this daunting task.

For researchers interested in studying the use of hal-

lucinogens to enhance the psychotherapeutic of creative

process, I believe that using the same approach, tedious

and plodding as it is, might be similarly applied. There

have been well-validated advances in psychotherapy

and cognitive science research in the past 20 years.

Standardized treatment protocols and testing procedures

are effective in teasing apart salient issues in psychopatho-

logical states. Carefully blending the relationship between

the effects of hallucinogens on cognitive, emotional, and

interpersonal variables with the processes involved in stan-

dardized psychotherapy techniques (or creative problem

solving) could be combined in attempting to use these

compounds for such purposes.

ACKNOWLEDGMENTS

I would like to express my gratitude to Margaret

Brophy, E Ivy Carrol, Daniel X. Freedman, Bernhardt

Funk, J. Stephen Kennedy, Betty Lee, Corinne Moody,

David Nichols, Dottie Pease, Juanita Ross, Alexander

Shulgin, Marion Strassman, Robert Walsh, and Curds

Wright for advice and help along the way.

REFERENCES

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