Are Entactogens A New Class of Psychoactive Agents? or How We Came To Work with MDE!

Spring 1993 Vol. 04, No. 1 Remembrance and Renewal

Download this article.

Human research in the field of psychedelic drugs has a long and respected history in Germany and Switzerland. At the Psychiatric Department of the University of Heidelberg, K. BERINGER conducted numerous studies with mescaline. He described them as early as 1927 in his famous monograph on the psychological effects of mescaline in healthy volunteers (Beringer 1927). A few years later, M.G. STRINGARIS, a greek co-worker of Beringer, described the subjective effects of marijuana (Stringaris 1939). In 1943, the famous Swiss chemist A. HOFMANN discovered the psychological effects of LSD in the Sandoz laboratories in Basel and conducted the first self-experiments with the substance. In the 1950’s and 1960’s, H. LEUNER investigated in Gottingen, Germany the utility of LSD and other psychedelics as adjuncts for insight-oriented psychotherapy and gave powerful descriptions of the altered states of consciousness (ASC) produced by these substances (Leuner 1962). About the same time H. HEIMANN worked in Bern, Switzerland with psilocybin and investigated the influence of the substance on cognitive functioning and facial expressions (Heimann 1961). Most of this early research work was done on the basis of the assumption that the psychedelic- induced ASC resembled endogenous psychoses and could be used as models for investigating psychosis-related phenomena. The term model psychosis derives from the very early work of Beringer, done in the Psychiatric Department of the University of Heidelberg. However, Beringer himself and all other scientists who worked with psychedelics pointed out the differences between the two states of mind, and never claimed that psychedelic-induced ASC are identical with endogenous psychoses.

After the criminalization of psychedelics in the USA in the 1960’s and a little later in Europe, human research with these substances was almost completely interrupted in Germany for over 20 years. A. Dittrich, Ch. Scharfetter and co- workers of the Psychiatric University Hospital in Zurich were able to conduct in the 1970’s and 1980’s human studies on ASC induced by a number of different psychedelics and psychological conditions like sensory deprivation and meditation (Dittrich 1985).

In the 1980’s, a group of psychiatrists and psychologists at the Psychiatric Department of the University of Freiburg (L. Hermle, G. Oepen, M. Spitzer, E. Gouzoulis, M. Funfgeld, D. Borchardt, R. Fehrenbach in collaboration with K.A. Kovar from the Pharmaceutical Institute of the University of Tubingen) made efforts to continue the model psychosis research tradition in Germany using modern methodology and newly available technology. Our aim was to study subjective neurobiological effects of psychedelics in healthy volunteers and compare them to findings in patients with endogenous psychoses. It took about two years to get the first permission from the state authorities to conduct a study with mescaline. In this project we gave 12 healthy male volunteers 0.5 grams of mescaline sulfate. We studied the subjective effects, the effects on functional cerebral asymmetry (visual half-field task on a Gerbands 3-channel-tachistoscope with a face/non-face decision task), and the effects on cerebral blood flow (SPECT). The results of this study (Hermle et al 1992), particularly the SPECT- data demonstrating striking similarities to recent PET-findings in acutely ill patients with endogenous psychoses (Cleghorn et al 1989), encouraged us to continue with our investigations.

In the late 1980’s we became aware of the large amount of literature on the amphetamine-derivative 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy ) and some related compounds. MDMA was discussed controversially in the scientific and general press because of its increasing popularity and illegal abuse (Seymour 1986; Beck and Morgan 1986; Beck 1990), its possible neurotoxicity (Price et al 1989; Grob et al 1990) and its putative medical usefulness as an adjunct in insight-oriented psychotherapy (Grinspoon and Bakalar 1986; Greer and Tolbert 1990). MDMA was reported to exert unique psychotropic effects in humans, distinguishing them from the chemically related stimulant amphetamines and from the substituted psychedelic amphetamines like methylenedioxyamphetamine (MDA), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline (Shulgin and Nichols 1978; Shulgin 1986). MDMA was reported to possess antidepressant and anxiolytic properties and to evoke a subtle, well controlled, emotional experience with relaxation, feelings of happiness, increased empathy and a drop in fear responses and defense mechanisms, mostly without distortion of sensory perception and without marked stimulation or mental confusion (Greer and Tolbert 1986, 1990; Peroutka et al 1988). It was hypothesized that MDMA and its similarly acting ethyl-analogon MDE might belong to a novel pharmacological class with a putative therapeutic value as adjuncts in psychotherapy. Drug discrimination experiments and pharmacological studies on the structure-activity relationships of MDMA and related compounds seemed to support the hypothesis of a distinct pharmacological class (Nichols 1986; Nichols and Oberlander 1990). Nichols (1986) proposed that the hypothetical new pharmacological class be designated entactogens , meaning to touch within . However, this view is not generally accepted, and other scientists describe MDMA as just another psychedelic.

So, we decided to study the subjective and some neurobiological effects of an entactogen in healthy volunteers and to try to characterize these substances. We chose to study the effects of MDE, which is much less neurotoxic in animal studies than MDMA (Schmidt 1987; Ricaurte et al 1987; Gibb et al 1990) and was not restricted in Germany until January, 1992. MDE was synthesized at the Institute of Pharmaceutics, University of Tubingen and was administered in a single 140 mg oral dose. We conducted two series of studies with MDE. Almost all volunteers were, like in the mescaline study, colleagues with a scientific interest in the substance who did not receive any payment for their participation. The studies were conducted in a randomized, double-blind, placebo- controlled, cross-over design, i.e. every volunteer took part in one active and one placebo experiment. In the first series we studied the subjective, neuroendocrine and cardiovascular effects, and in the second series the subjective and sleep-EEG effects of MDE. Studies of the neuroendocrine and sleep-EEG effects of centrally acting drugs can contribute to the pharmacologic characterization of these substances.

Eight healthy men participated in the first series of experiments. They received MDE at noon and stayed for the entire period of the experiment on a bed in a single sound-isolated room of the endocrinology laboratory of our Department. They were observed by a video camera with a monitor located in the neighboring laboratory unit. The intravenous catheter for taking blood samples and the sphygmomanometer and ECG rate meter for registration of heart rate were connected to long tubes that passed through an opening in the wall into the adjacent laboratory. The taking of blood samples for the determination of cortisol (C), prolactin (PRL) and growth hormone (GH) and the registration of cardiovascular parameters were performed in the laboratory room every 20 minutes for a period of three hours. All volunteers participated in a series of psychometric tests, which were performed before ingestion of MDE, and at 2, 5, and 24 hours after ingestion of the drug, as well as 7 days after the trial. The psychometric tests we used were: Manic-State Rating Scale (Beigel et al 1971), state anxiety inventory STAI-X1 (Laux et al 1981), Depression Scale (von Zerssen 1986), scale for vegetative lability B-L (von Zerssen 1986), parts of the FPI revised (Fahrenberg et al 1984), and the questionnaire for the assessment of altered states of consciousness APZ (Dittrich 1985).

Another six volunteers participated in the second series of experiments. They spent four nights in the sleep laboratory: one adaptation night and one consecutive night on 140 mg MDE or placebo and two to six weeks later another adaptation night and one consecutive night on placebo or 140 mg MDE. The drugs were administered at 11:00 pm just before lights were switched off. Sleep EEG recordings were performed between 11:00 pm and 7:00 am using standard procedures. Those volunteers also participated in a series of psychometric tests which were conducted before ingestion of the drug, in the next morning, at 24 hours and at 7 days after the trial. Pharmacokinetics and drug metabolism were investigated in urine samples of the subjects in the Institute of Pharmaceutics, University of Tubingen. Evaluation of the pharmacokinetics and metabolism data is still in progress.

The data on subjective effects of MDE are difficult to interpret because they are very heterogeneous: however, they are indicative of the close relation of MDE to both psychedelics and stimulants (Hermle et al, in press). All volunteers displayed amphetamine-like effects with increased drive and desire to speak. Several subjects described their feelings in a way similar to the anecdotal reports about entactogenic effects: relaxation, reduction of anxiety, feelings of self- acceptance and peacefulness. But, in addition, they described depersonalization/derealization experiences, and disturbances of visual and time perception. One of the six subjects experienced a dysphoric state with anxiet y and motor agitation, and another subject experienced a psychotic state with hallucinations and delusional ideation for the duration of three hours (Gouzoulis et al, 1993).

The cardiovascular effects of MDE with moderate, long-lasting rises in blood pressure and heart rate underline its sympathomimetic properties (Gouzoulis et al, in press). The neuroendocrine studies revealed elevations of plasma C and PRL and a trend towards decrease of GH secretion. The effects of C and PRL are similar to the effects of the chemically related amphetamines. However, the GH data might be indicative of distinct pharmacological mechanisms supporting the hypothesis of a novel psychoactive substance class (Gouzoulis et al, in press).

In the sleep laboratory study MDE caused a clear-cut deterioration of objectively evaluated sleep. After a normal sleep onset latency and sleep duration of 30-90 minutes, all subjects awoke and stayed awake for at least 150 minutes. One subject did not fall asleep again at all. Three subjects with the relatively long sleep time of 4-4.5 hours after again falling asleep, showed a sleep architecture with cyclic stage shifts from one non-REM stage to another and a remarkable amount of slow wave sleep (SWS). These subjects caught up with SWS, which was shifted from the first to the second half of the night. There was a trend towards increase of sleep stage 4 during the second part of the night after MDE compared to placebo. REM sleep was completely suppressed and did not occur in any volunteer after again falling asleep. Our data demonstrate to a large extent the similarity of the sleep EEG effects of MDE to the well documented effects of 10 mg and higher doses of d-amphetamine in respect to onset and duration of action, decrease of total sleep time and suppression of REM sleep. But, in contrast to amphetamines, MDE allowed a cyclic sleep pattern to appear in three subjects after again falling asleep 2.5-3.5 hours after their initial awakening, i.e. 3.5-4.5 hours after drug intake. This sleep pattern appeared while MDE was still pharmacologically active in terms of REM sleep suppression. A cyclic alternative of light sleep and deep sleep, and a shift of SWS from the first to the second half of the night were observed in those three volunteers who slept 4 -4.5 hours in the second part of the night. This finding might indeed indicate a unique effect pattern of MDE on sleep. However, the interpretation of these data, as well as the data on GH secretion, must be viewed with caution because of the limited number of subjects and the lack of statistical significances (Gouzoulis et al, 1992).

In conclusion, it is still not possible to securely position MDE and MDMA within the range of chemically related stimulant amphetamines and psychedelics. Our personal opinion is that the entactogens really do exert unique psychological effects in humans. However, these entactogenic effects are only one part of the spectrum of actions of MDMA and MDE in humans. Further investigations, particularly direct comparative investigations with amphetamine and psychedelics, are needed in order to better understand the mechanism of action of MDMA and related compounds. At present, we are designing comparative studies with entactogens, stimulants, and psychedelics, and hope that we will soon get permission to conduct these studies. These investigations will include studies of the subjective, neurophysiological, neurometabolic, and neuroendocrine effects of the drugs. With these studies, we hope that we can give more definitive answers to the questions about MDMA and related compounds.


Beck, J (1990): The Public Health Implications of MDMA Use. In SJ Peroutka (ed.), Ecstasy: The Clinical Pharmacological and Neurotoxicological Effects of the Drug MDMA. Norwell, MA: Kluwer Academic Publishers, pp 77-103.

Beck J, Morgan PA (1986): Designer Drug confusion: A focus on MDMA. J. Drug educ 1:287-303.

Beigel A, Murphy DL, Bunnery WE (1971). Tha manic-state rating scale. Arch Gen Psychiatry 25:256-262.

Beringer K (1927). Der Meskalinrausch. Berlin, Springer.

Cleghorn JM, Garnett ES, Nahmias C et al (1989). Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiatry Research 28:119-133.

Dittrich A (1985) Atiologie-unabhangige Strukturen verabderter Wachbewu tseinszustande. Enke, Stuttgart.

Fahrenberg J, Selg H,Hampel R (1984) Das Freiburger Pesonlichkeitsinventar FPI-R. Horgreve, Gottingen.

Gibb JW, Stone D, Johnson M, Hanson GR (1990). Neurochemical effects of MDMA. In SJ Peroutka (ed.), Ecstasy: The Clinical Pharmacological and Neurotoxicological Effects of the Drug MDMA. Norwell, MA: Kluwer Academic Publishers, pp 133-150.

Gouzoulis E,Steigner A, Ensslin M, Kovar K-A, Hermle L (1992). Sleep-EEG effects of 3,4-Methylenedioxyethylamphetamine (MDE; ) in healthy volunteers. Biol Psychiatry 32:1108-1117.

Gouzoulis E, Bardeleben UV, Rupp A, Kovar K-A, Hermle L (in press). Neuroendocrine and cardiovascular effects of MDE in healthy volunteers. Neuropsychopharmacology.

Greer, G and Tolbert, R (1986): Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs 18:319-327.

Greer, G and Tolbert, R (1990): The therapeutic use of MDMA. In S.J. Peroutka (Ed.), Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Norwell, MA: Kluwer Academic Publishers, pp. 21-35.

Grinspoon, L and Bakalar, JB (1986): Can drugs be used to enhance the psychotherapeutic process? Amer J Psychotherapy 40:393-404.

Grob, C, Bravo, G and Walsh, R (1990): Second thoughts on 3,4-methylenedioxymethamphetamine (MDMA) neurotoxicity. Arch Gen Psychiatry 47:288-289.

Heimann H (1961). Ausdrucksphanomenologie der Modellpsychosen (Psilocybin). Psychia Neurol 141: 69-100.

Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach RA, Spitzer m (1992). Mescaline-induced psychopathological, neuropsychological and neurometabolic effects in normal subjects. Experimental psychosis as a tool for psychiatric research. Biol Psychiatry 32:976-991.

Hermle L, Spitzer M, Borcahrdt D, Kovar K-A, Gouzoulis E (in press). Psychological effects of MDE in normal subjects. Are entactogens a new class of psychoactive agents? Neuropsychopharmacology.

Laux L, Glanzmann P, Schafner P, Speielberger CD (1981). Das State-Trait-Angstinventar (STAI). Beltz, Weinheim.

Leuner HC (1962). Die experimenelle Psychose. Ihre Psychopharmakologie, Phanomenologie und Dynamik in Bezishung zur Person. Springer, Berlin.

Nichols, DE (1986). Differences between the mechanism of action of MDMA, MBDB, and the classi hallucinogens. Identification of a new therapeutic class: Entactogens. J. Psychoactive Drugs 18:305-313.

Nichols, DE and Oberlender, R (1990): Structure-activity relationships of MDMA and related compounds: A new class of psychoactive agents? In S.J. Peroutka (Ed.), Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Norwell, MA: Kluwer Academic Publishers, pp 105-131.

Peroutka SJ, Newman H, Harris H (1988): Subjective Effects of 3,4-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology 1:273-277.

Price, LH, Ricaurte, GA, Krystal, JH and Heninger, GR: Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine (MDMA) users. Arch Gen Psychiatry 46:20-22, 1989.

Ricaurte, GA, Finnegan KF, Nichols DE, DeLanney LE, Erwin I, Langston JW (1987). MDE, a novel analogue of MDMA, produces long-lasting depletion of serotonin in rat brain. Eur J Pharmacol 137: 265-268.

Schmidt CJ (1987). Acute administration of methylenedioxymethamphetamine: comparison with the neurochemical effects of its N-desmethyl and N-ethyl analogs. Eur J Pharmacol 136: 81-88.

Shulgin AT, Nichols DE (1978): Characterization of three new psychotomimetics. In Stillman RC, Willette RE (eds), The Psychopharmacology of Hallucinogens. Pergamom Press, New York, pp 74-83.

Shulgin AT (1986): The background and chemistry of MDMA. J Psychoactive Drugs 18:291-304.

Stringaris MG (1986). Die Haschisch-Sucht. Springer, Berlin.

Zerssen D von (1986). Clinical Self-Rating-Scales (CSRS) of the Munich Psyhciatric System (PSYCHIS Monchen). In: Sartorius N, Bau TA (eds), Assessment of Depression, Berlin.

Present addresses of the authors: Euphrosyne Gouzoulis, M.D. Department of Psychiatry, Medical Faculty of the RWTH, Pauwelsstrasse 30, D-51– Aachen, Germany. Leopold Hermle, M.D. Department of Psychiatry, Christophsbad, Faurndauerstrasse 16, D-7320 Goppingen, Germany.