Document distributed under permission of Rick Strassman MD

I. Neuroendocrine, Autonomic, and Cardiovascular Effects

Rick J. Strassman, MD, Clifford R. Qualls, PhD

BACKGROUND: To begin applying basic neuropharmacological hypotheses of hallucinogenic drug actions to humans, we generated dose-response data for intravenously administered dimethyltryptamine fumarate's (DMT) neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users.

METHODS: Dimethyltryptamine, an endogenous mammalian hallucinogen and drug of abuse, was administered intravenously at 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users, in a double-blind, saline placebo-controlled, randomized design. Treatments were separated by at least 1 week.

RESULTS: Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration, and were negligible at 30 minutes. Dimethyltryptamine dose dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of ß-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Threshold doses for significant effects relative to placebo were also hallucinogenic (0.2 mg/kg and higher). Subjects with five or more exposures to 3, 4-methylenedioxymethamphetamine demonstrated less robust pupil diameter effects than those with two or fewer exposures.

CONCLUSIONS: Dimethyltryptamine can be administered safely to experienced hallucinogen users and dose-response data generated for several measures hypothesized under serotonergic modulatory control. Additional studies characterizing the specific mechanisms mediating DMT's biological effects may prove useful in psychopharmacological investigations of drug-induced and endogenous alterations in brain function.

(Arch Gen Psychiatry. 1994; 51:85-97)

Hallucinogenic drugs reliably induce a unique constellation of subjective effects in humans. They elicit perceptual illusions and hallucinations, primarily visual but often auditory. Mood effects range from euphoria to panic to bland indifference. Somatic effects include dissociation, relaxation, or tension.1 'Classic' hallucinogens include phenethylamines (eg, mescaline), indolealkylamines (eg, psilocybin and dimethyltryptamine [DMT]), and the lysergamides (eg, lysergic acid diethylamide [LSD]).2

These unique compounds were the focus of intensive clinical research in the 1950s and 1960s. The discovery of LSD may arguably have been as important to the development of a 'biological' psychiatry as was the contemporaneous discovery of chlorpromazine. Hallucinogens' use in clinical research was associated with acceptable risks when subjects, both psychiatric patients and normal controls, were carefully screened, prepared, and followed-up.3 Clinical research with hallucinogens, however, became increasingly difficult with their widespread abuse by young adults. Highly publicized 'adverse reactions' to hallucinogens, primarily LSD,4 resulted in their placement into the restrictive schedule I of the Controlled Substances Act. Human studies with these drugs effectively ended in the mid-1970s despite legal restrictions and severe penalties for manufacture, possession, and distribution of hallucinogens, their use among college students has held relatively steady over the past 20 years.5

Basic research into the mechanisms of action of hallucinogens continued, however, and contributed to recent advances in serotonin (5-HT) receptor pharmacology.6 Recent behavioral, in vivo, and ligand binding data suggest agonist or partial agonis effects at the 5-HT2, 5-HT1A, and 5-HT1C receptors.7-10 Dopaminergic11 and noradrenergic12 effects have been described but not studied recently.

Hallucinogenic drugs have diffuse and relatively well documented biological effects, presumably related to their serotoninergic properties. Growth hormone (GH), prolactin, ß-endorphin, corticotrophin, and cortisol levels are all affected by serotoneric stimuli.13 Consistent with the presumed serotonergic properties of the classic hallucinogens, levels of several of these hormones increase with their administration. For example, human prolactin blood levels rise in response to dimethyltryptamine14 and rat plasma corticoid levels are stimulated by LSD.15 Cardiovascular variables, core temperature, and papillary diameter also are affected by serotonergic hallucinogens. Examples of these effects include DMT's hypertensive and mydriatic,16 LDS's pyretogenic and mydriatic, 17, 18 and psilocybin's hypertensive and tachycardic19 properties.

Dimenthyltryptamine is a short-acting hallucinogen, first discovered in hallucinogenic Amazonian snuffs.20 It was later synthesized and determined to be active by parenteral (intramuscular [IM] administration only.16 Its discovery in human body fluids prompted a flurry of investigations into its possible biosynthesis in man and its role as a putative endogenous psychotogen.21 difficulties distinguished peripheral levels of DMT between normal controls and patients with endogenous psychoses led to a loss of interest in the function of this hallucinogenic tryptamine.22

It has been impossible to test in humans hypotheses of hallucinogen mechanisms of action developed from basic research. Systematic psychopharmacological investigations are the necessary interface bridging recent neuropharmacological findings to human effects. Dose-response investigations applying current psychiatric research methods to assess hallucinogens' effects can generate data providing the bases for more experimental studies, such as selective blockade with receptor sub-type antagonists.

Several properties recommend DMT as an appropriate drug with which to renew such investigations. Its short duration minimizes prolonged dysphoric reactions in the potentially stressful environment of a modern clinical research center. The lack of a widespread 'folklore' concerning its effects provides less bias and expectations from subjects. Finally, DMT's role in human brain function has yet to be explicated in normal and pathological states. That is, understanding effects and mechanisms of action of DMT may shed light on the etiology and treatment of endogenous hallucinatory conditions.
We have performed a dose-response study of the neuroendocrine, cardiovascular, autonomic, and subjective effects of dimethyltryptamine fumarate using a double-blind, placebo-controlled, randomized design. This article focuses on biological data generated by this study.

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RESULTS

The major findings of this study are the following: (1) Intravenous dimethyltryptamine fumarate was fully hallucinogenic in doses of 0.2 and 0.4 mg/kg. Effects were felt nearly instantaneously, peaked within 2 minutes after injection, and resolved within 20 to 30 minutes. The time course of DMT blood levels matched the march of subjective effects. (2) Multiple biological variables rose dose dependently in response to DMT. The time course of elevations in blood levels of pro-opiomelanocortin (POMC) peptides (corticotrophin and ß-endorphin), HR, blood pressure, and pupil diameter paralleled subjective effects and DMT blood concentrations. Elevations of prolactin and cortisol blood levels lagged 5 to 10 minutes behind these changes. Core temperature and GH effects did not begin until the first set of perturbations had almost resolved (15 to 30 minutes) and may not have peaked by 60 minutes after DMT administration.

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