Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers

This double-blind study (n=9) of the psychological effects of (s)-ketamine and DMT found the positive effects of DMT, and the negative effects of ketamine most resemble those symptoms of schizophrenia.

Abstract

“Introduction: Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. 

Methods: Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT_2A agonist DMT and the glutamate N-methyl-d-aspartate (NMDA) antagonist (S)-ketamine. 

Results: Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine. 

Discussion: The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT_2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT_2A agonist state may be a better model for psychoses of the paranoid type.”

Authors: Euphrosyne Gouzoulis-Mayfrank, Karsten Heekeren, A. Neukirch, M. Stoll, C. Stock, M. Obradovic, K.-A. Kovar

Summary

Introduction

Subjects in hallucinogenic drug states exhibit phenomena which resemble symptoms of schizophrenia or schizophrenia spectrum disorders. However, some authors argued that subjects in hallucinogenic drug states are more differ- ent from patients with schizophrenia than alike.

In a double-blind, crossover study, 15 healthy volunteers were given two doses of serotonin 5-HT2A agonist DMT and glutamate N-methyl-d-aspartate (NMDA) antagonist (S)-ketamine. The psychological effects were similar for both drugs, but DMT induced more positive symptoms of schizophrenia and ketamine induced more negative symptoms of schizophrenia.

The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model, but rather that the two classes of drugs tend to model different aspects or types of schizophrenia.

Research interest in hallucinogens has been again on the rise since the beginning of the 90s, with several studies using both serotonergic substances and the PCP-like drug ketamine. However, the psychological effects of ketamine have not been directly compared to the effects of a serotonergic hallucinogen in an experimental within-subject design.

We compared the psychological effects in humans of the 5-HT2A agonist hallucinogen DMT and the NMDA antagonist hallucinogen S-ketamine in a randomized, double-blind, cross-over design. We hypothesized that neither drug state was an overall better model of psychosis.

Subjects

Fifteen healthy volunteers were included in the study. All had a medical history, a standardized psychiatric interview, a physical examination, ECG and a routine laboratory testing, and no subject had been under medication or subject to excessive caffeine intake and/or stressful life events in the four weeks prior to the study.

The study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee at the Medical Faculty of the University of Technology Aachen.

Drugs

DMT was synthesized in Germany and prepared as a solution for intravenous use by Wülfing Pharma. Ketamine was purchased from the hospital pharmacy. In a previous open study with six subjects, we determined the appropriate dosages for DMT and (S)-ketamine. In the double-blind study, we decided not to give the same fixed doses to every subject, but rather to titrate the doses within the defined ranges.

We started with a dose of DMT that was on the maximum of the dose range of the low dose and the minimum of the dose range of the high dose. The second dose was higher or lower than the first one depending on the intensity of effects.

We started the second dose with the lowest possible bolus of 0.15mg/kg and continued with the lowest infusion rate of 0.01125mg/kgmin. If the first dose caused intense effects, we started the second dose with the highest possible bolus of 0.3mg/kg and continued with the highest infusion rate of 0.02mg/kgmin.

Study Design and Experimental Procedures

Subjects participated in two experiments with DMT and (S)-ketamine in a double-blind, cross-over design and pseudo-randomized order. They were lying comfortably in a bed with their head and upper trunk elevated and were administered a low and high dose of one of the two substances.

Drugs were administered intravenously by an automatic infusion pump between 10:00 and 11:30 a.m. and again between 1:30 and 3:00 p.m. Cardiovascular parameters were monitored automatically throughout the experiment, and psychological effects were assessed within 10 to 30 minutes of stopping the drug infusion. Subjects were served a light standardized meal at 0:30 p.m. and remained in the hospital under medical supervision for at least two hours after termination of the second drug dose. They were interviewed on possible delayed effects, psychological well-being and substance use.

Self-assessment Inventories

The Hallucinogen Rating Scale HRS consists of 99 items rated on a scale of 0 to 4. High scores indicate stronger deviation from the normal state.

The APZ-OAV questionnaire measures experiences in hallucinogenic drug induced and other similar altered states of consciousness. It includes 66 items and is divided into three subscales: OSE (Oceanic boundlessness), AIA (Angst vor der Ich-Auflösung) and VUS (Visionary restructuralization).

Clinician Ratings

We used three psychiatric scales for the assessment of schizophrenia-like psychotic symptoms: the SANS, alogia, avolition-apathy, anhedonia-asociality, and attention.

The Schizophrenia Prediction Instrument-Adult Version (SPI-A) consists of 49 items and is used to evaluate subtle, subclinical subjective symptoms, complaints and perceptional alterations occurring in prodromal stages of psychosis.

We selected the most suitable single items from the psychometric scales to assess motor and behavioral phenomena that resemble catatonic symptoms of psychosis: motor interference, motor blockages, Ifelt like a marionette, Ifelt as though Iwere paralyzed.

Results

Twelve out of fifteen subjects completed the experiment with DMT and ketamine, and ten out of fifteen completed the experiment with S-ketamine. One subject abstained from the second experiment because of unpleasant aftereffects. Nine subjects completed both experiments with both doses of DMTand (S)-ketamine, and their plasma levels decreased rapidly after termination of the infusion.

The day after the experiments, 10 out of 13 subjects who received DMT and 4 out of 11 subjects who received (S)-ketamine reported tiredness and headache, one subject reported nausea, and one subject reported mild orthostatic complaints.

Psychometric Scores

There were no significant effects of substance or dose on somaesthesia, volition, intensity, affect or perception. There were no significant interactions substance x dose.

The APZ-OAV scale revealed no significant main effects of substance or dose, but a marginal effect of dose for OSE. There were no significant interactions substance x dose for VUS.

SAPS (Scale for the Assessment of Positive Symptoms): Significant main effects of substance and dose were found for positive symptoms, positive formal thought disorder, inappropriate affect, hallucinations, delusions, and bizarre behavior.

The SANS revealed that higher doses of S-ketamine resulted in higher scores for negative symptoms, including affective blunting, alogia, avolition-apathy and attention. There was also a stronger increase of effects with the higher S-ketamine dose compared to the higher DMT dose.

The SPI-A (Schizophrenia Prediction Instrument) showed significant main effects of dose for all six subscales except for overstrain, and a significant interaction of substance x dose for body perception disturbances.

The effects of substance on catatonia-like items were significant for motor interference, motor blockages, feel like paralyzed, and stayed frozen in an unnatural position. The effect of dose was also significant for motor blockages.

High DMT plasma levels were associated with more pronounced positive symptoms, global alteration of consciousness, and body perception disturbances. High S-ketamine plasma levels were associated with more pronounced negative symptoms, subjective cognitive impediments, and body perception disturbances.

The effects of substance on the SAPS positive formal thought disorder, SANS global score, SANS emotional blunting, SPI-A cognitive impediments, SPI-A body perception disturbances and SPI-A motor blockages were significant.

Summary of Subjective Descriptions of the Drug States and Observations of the Researcher

Both DMT and S-ketamine were dose-dependently perceived as strong to extremely strong alterations of mind, with limited to no possibility for the subject to have an influence on what was happening.

DMT State

Effects of both DMT doses included vivid alterations of visual, auditory and tactile perception, illusions and abnormal somatic sensations. Paranoid ideation was reported by four subjects at the high dose, and increased energy and drive were observed in five subjects.

(S)-Ketaminestate

After the action of (S)-ketamine faded, all subjects reported feeling more or less remote, isolated from others and emotionally blunted, and two subjects reported feeling like an automaton running automatically without personal will. Most subjects reported dream-like alterations of visual perception, but only one reported visual hallucinations at the high dose. All but one subject found the experience more or less unpleasant.

Discussion

Two doses of DMT and S-ketamine were administered intravenously to healthy volunteers and the psychological effects were studied. All subjects tolerated the procedures and no serious delayed adverse effects were observed.

Both hallucinogens caused dose-dependent, powerful alterations of perception, affect and cognition. The psychological effects were less pronounced than the clinical effects, but the global intensity of the hallucinogenic effects was similar.

The psychological profiles of DMT and OAV were different, with OAV showing more positive symptoms of schizophrenia, and DMT showing more visual phenomena. However, correlational analyses failed to demonstrate significant associations between the scores on these scales.

After (S)-ketamine, phenomena that resemble negative symptoms of schizophreniawere clearly more pronounced, including emotional deficits, cognitive problems, and difficulties with concentration and short-term memory. The psychometric data alone do not allow us to securely distinguish between negative/cognitive symptoms and sedative effects, and some of the (S)-ketamine phenomena could be viewed as sedation. However, the subjective descriptions of the (S)-ketamine state suggest that the subjects felt blunted, isolated and without energy and motivation, and less sedated.

We used a double-blind experimental design to compare the psychological effects of a serotonergic and antiglutamatergic hallucinogen. However, due to methodological limitations, we cannot draw firm conclusions on the effects of certain doses of the drugs. We decided to omit the placebo condition from our study due to practical considerations, and because a third experimental day would have been critical for the recruitment of volunteers, and because placebo controlled hallucinogen experiments have their own methodological problems.

Most of the subjects were psychiatric staff, and most had some previous experiences with hallucinogenic drugs. Therefore, it would be unrealistic to plan studies with larger samples, and volunteers would have their own biases. We did not perform drug screens on the days of the experiments, and this may have influenced the results. However, it is unlikely that these factors will account for the differences between the two hallucinogens.

Although methodological caveats have to be taken into account, the data from the present study support the hypothesis that the two models portray different aspects of psychoses of the schizophrenia spectrum.

Conclusion

The LSD-type model of schizophrenia may refer to paranoid-hallucinatory psychoses and brief psychotic disorders, while the PCP-type model may refer to the undifferentiated and possibly also to the catatonic subtypes of schizophrenia.