Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects

This study (1994) was one of the first sanctioned studies using psychedelics following their classification as Schedule I substances. Participants received intravenous doses of DMT at 0.05,0.1,0.2, and 0.4 mg/kg. Neuroendocrine, autonomic, and cardiovascular effects were assessed. It was found that DMT can be safely administered to experienced hallucinogen users.

Abstract

“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 β-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.”

Authors: Rick Strassman & Clifford Qualls

Summary

Previous human studies of hallucinogenic drugs’ subjective effects used varied groups of subjects and assessment methods. We present preliminary data from a new rating scale for these effects.

Twelve highly motivated volunteers received two doses of DMT intravenously nonblind, and then four doses of DMT double-blind, saline placebo-controlled, randomized study. They were interviewed and administered the Hallucinogen Rating Scale.

Results: IV DMT effects began almost immediately after administration, peaked at 90 to 120 seconds, and were almost completely resolved by 30 minutes. Hallucinogenic effects were seen after 0.2 and 0.4 mg/kg of dimethyltryptamine fumarate.

SUBfECTS, MATERIALS, AND METHODS

We recruited 12 experienced hallucinogen users and screened them for Axis I disorders, ongoing medical illness, or long-term medication use. The data described in this article are from 11 subjects (one woman and 10 men), of which six had used 3,4-methylenedioxymethamphetamine (MDMA) five or more times.

Witnessed written informed consent was obtained, and intravenous dimethyltryptamine fumarate was administered to all subjects on sepa rate days. The effects of the injection were observed, and conversation focused on the effects of the injection once subjects were able and willing to begin talking. A HRS was given 30 minutes postinfusion, after the single IV line was removed, and a rectal temperature probe was placed 30 minutes be fore drug administration. A saline placebo-controlled, randomized phase was also used.

19 experienced hallucinogen users were interviewed, and 126 individual items were drafted. A one-way analysis of variance (ANOVA) with the factor dose was performed for each question, and only those questions demonstrating a dose-related response were retained for further analysis.

Two methods were used to place HRS items into groups: a clinical mental status method and a perception method.

We obtained six factors using a principal components factor analysis with a variance maximum rotation, and performed a one-way ANOVA with repeated measures to assess the effect of prior MDMA use on subjective responses to DMT.

DMT is a prototypical hallucinogen that was discovered in plants, but later found in lower animals and humans. It has well-characterized neuropharmacologic and behavioral properties.

Hallucinogens can be characterized at multiple levels, including neuroendocrine, cardiovascular, and autonomie. However, the generalizability of animal to human data is more problematic when behavioral effects are addressed.

We studied individuals who had repeatedly used hallucinogens to assess the subjective effects of DMT. We also allowed subjects to use their own words to describe the effects of DMT, and developed a rating scale based on descriptions of the psychological properties of DMT and other hallucinogens from similar experienced users.

This article describes the psychological properties of different doses of DMT, including visual hallucinations, bodily dissociation, and extreme shifts in mood. The effects resolve quickly, and the time course parallels DMT blood levels.

Subjects were overwhelmed at the intensity and speed of onset of this dose of DMT given for the first time nonblind. All subjects described an intense, rapidly developing, and usually transiently anxiety-provoking “rush” throughout their body and “mind.”

All subjects reported seeing visual imagery with their eyes open or closed, and there was little difference between what was “seen” with eyes open or closed. Subjects described concrete, formed, more or less recognizable visual images, including a fantastic bird, a tree of life and knowledge, a ballroom with crystal chandeliers, human and “alien” figures, ducts, DNA double helices, a pulsating diaphragm, a spinning golden disc, tunnels, and stairways.

In these visions, foreground-background distinctions were merged, and hundreds of forms of beautiful women were superimposed onto a pastoral scene.

As their eyes were laid upon the objects and patterns, subjects described a “decomposition” of the external visual perceptual continuity that altered their ability to process normally what they saw.

About half the subjects noted auditory effects, which were usually high-pitched, “whining/whirring,” “chattering,” “crinkling/ crunching,” or at times comical. Some subjects’ auditory acuity seemed enhanced, while others’ auditory stim ulation receded far from awareness.

SOMAESTHESIA

The effects of a fear response were typical of a highly stimulatory “fear response”. Several subjects commented on their “breath catching in the throat” and a sense of constriction and pressure, which often progressed to a sense of detachment or dissociation from the body.

Some male subjects described a sexual effect of the high est dose, including a hot and pleasurable sensation in the genital area.

Subj ects initially were anxious, but quickly settled into the experience. Most described the high dose as exciting, euphoric, and highly positively charged, with different emotional reactions alternating with each other or existing simulta neously.

COGNITION

Subjects found the high dose to be compellingly novel and unusual, if not somewhat disorienting. However, they were able to maintain a watchful, observing ego, and were almost uniformly remark at how qualitatively un changed their thinking processes were.

Subjects were unaware of the experimental setting, and claimed that their experiences were real. However, many others remarked on the similarity between dreams and their experiences at this dose.

Some subjects said the intoxication changed their perspectives on their personal and/or professional lives. They saw clearly how their personal self and conscious ness are just slowed down and less refined versions of’pure consciousness’.

Others found the cognitive effects less sanguine, noting an unpleasant discrepancy between their observation of everyday reality and their apperception of it.

Many subjects referred to an “other intelligence” present within the hallucinatory state, which was usually described as “supra-intelligent” but “emotionally detached”. Others had a clear view of “alien beings”

VOLITION

Almost every subject found the high dose to cause a complete loss of control, and felt completely helpless, unable to function either physically or psychologically in a normal manner.

Subjects were not able to control the progression of the effects during the earliest stages, and described being “forced” to attend to certain aspects of the experience, by the “otherintelligences”.

INTENSITY

Many subjects described a wavelike pattern of intensity lev els with this dose of DMT, including those with expe rience smoking DMT. They were prepared to “lose control” after having been in that state previously, and their confidence in the research team grew.

0.2-MG/KG DOSE

This was the threshold dose for hallucinogenic effects. It was less frightening than the 0.4-mg/kg dose, but still generated enough perceptual and affective responses to be interesting, novel, and pleasurable.

0.1-MG/KG DOSE

This dose was least enjoyed by subjects, who felt more somaesthetic sensations of excitation and the “drive to dis charge” than perceptual or affective changes.

0.05-MG/KG DOSE

Several subjects mistook this dose for placebo, and one former heroin user likened it to “soft cotton batting”.

Subjects were fairly consistent in their reaction to DMT; those who spoke early did so after receiving all doses, and those who preferred silence did so after receiving all doses.

Seventy-five of 126 questions demonstrated a significant effect of dose, and five of the six clusters discriminated between placebo and the lowest dose of DMT. Two clusters, Intensity and Cognition, discriminated among all doses.

Three of six principal components factors discriminated between placebo and 0.05 mg/kg of dimethyltryptamine fumarate, whereas two factors discriminated among all five doses.

A two-way repeated measures ANOVA with repeated factor dose and class variable MDMA history showed no effect of degree of prior MDMA exposure on either set of item groupings, across all doses.

Human studies of hallucinogens used many approaches, but the effects were always dependent on the subject’s psychological state and the physical environment in which the session occurred.

Clinical observations by skilled clinicians were among the first attempts to describe a general pattern of hallucinogens’ effects in humans. However, it was difficult to transfer these observations from one research center to another.

A parallel course of research applied previously vali dated psychological instruments to the hallucinogenic drug state and quantified effects of these drugs on relatively well-characterized psychological functions.

Three rating scales were used most frequently to quantify the psychological properties of hallucinogens: the Linton-Langs questionnaire, the Abramson et al question naire, and the Addiction Research Center Inventory (ARCI). The Linton-Langs questionnaire was developed in 1962 and was modified based on experimental data.

The Abramson etal questionnaire,35 developed in 1955, was administered to volunteer “non-psychotic” adults and was used to assess their response to LSD. Only five of 47 questions could distinguish between “high dose” LSD and placebo.

The most commonly used rating scale for drug effects is the ARCI, a 550-item, true-false test, developed in 1958. It was used to assess the effects of detoxified opiate addicts serving prison terms for violations of narcotics laws, as well as several other psychoactive drugs.

Our study differed from previous studies in that our sample found hallucinogens highly desirable, and we believe the clustering of symptoms, as reflected by items on the HRS, provides a clinically useful manner of capturing some of the subtleties of DMT’s effects.

In a double-blind, placebo-controlled, randomized design, 11 experienced hallucinogen users reported subjective effects of multiple doses of the short-acting, endogenous hallucinogen, DMT. A new instrument, the HRS, was proposed to quantify DMT’s effects.

The effects of DMT were nearly instantaneous in on set, paralleling blood levels of DMT, described in the preceding article. Subjects experienced intensely colored, rapidly moving visual images, a physical rush, and alternate and sometimes simultaneous experiences of fear, anxiety, eu phoria, and calm.

Lower doses of dimethyltryptamine fumarate were not hallucinogenic, and produced primarily somaesthetic and emotional responses. The lowest dose had mildly mood elevating and calming properties, likened by one subject to IV heroin.

We chose to study DMT in this initial attempt to be gin a careful characterization of hallucinogen effects in humans. However, there are few data directly comparing human responses to DMT with other hallucinogens, particularly in the same individual(s).

IV DMT has a rapid onset and peak effects, and an extremely short duration of action, compared to IV LSD, which takes 20 to 30 minutes to reach peak brain levels and then promptly follows by a slower clearance of drug.

Hallucinogen binding and localization of 5-HT receptor sites in human central tissue has been studied. 5-HT2 receptors are found in cortical areas, mammillary bodies, claustrum, amygdala, caudate, putamen, nucleus accumbens, and hippocampus.

Lower doses of DMT are nonhallucinogenic, but clearly psychoactive, and may reflect the relative contributions of several 5-HT receptor subtypes.

Older human data were limited by lack of specificity of modifying agents used and lack of careful characterization of “psychological effects” being modulated.

More selective and better characterized serotonergic agonists, with binding profiles overlapping those of the classic hallucinogens, have been administered to humans, but have not produced classic “hallucinogenic” or “psy chedelic” symptoms.

The HRS could be used to characterize stimulant, dissociative, or less classical hallucinogenic drugs, as well as “nonhallucinogenic” serotonergic probes. Selective blockade of relevant receptors and noting effects on functions quantified by the HRS could help relate hypothetical neurotransmission disorders with subjective symptoms in psychiatric conditions.

Our data do not suggest that moderate prior MDMA use has a negative effect on human serotonergic function, but additional studies with control subjects with no history of drug abuse are necessary for a more rigorous assessment.