This randomised, double-blind, placebo-controlled fMRI study (n=5) investigated the subjective and neural effects of the two enantiomers of the MDMA-like drug MDE in healthy volunteers. Results indicate that (S)-MDE produced elevated mood and right frontal activation associated with entactogenic effects, whereas (R)-MDE induced depressive symptoms and left frontal activation.
In a randomised double-blind trial the subjective, neuropsychological and brain activation effects of the two enantiomers of the MDMA (ecstasy-) like drug N-ethyl-3,4-methylenedioxyamphetamine (MDE) were studied in five normal subjects using functional magnetic resonance imaging (fMRI). (S)-MDE produced elevated mood, impairments in conceptually driven cognition and marked right frontal activation. In contrast, (R)-MDE produced increased depression, enhanced visual feature processing, and activation of visual cortical and left frontal areas. Plasma concentrations were higher for the (R)-enantiomer. The so-called entactogenic effects of MDE are likely to be caused by the (S)-enantiomer, whereas (R)-MDE appears to be responsible for neurotoxic effects.
With the advent of cognitive neuroscience and functional brain imaging, substituted amphetamine derivatives such as MDMA and the closely related N-ethyl-3,4-methylenedioxyamphetamine (MDE) can be studied in humans with a combination of subjective, neuropsychological and brain-imaging measures. Earlier research indicated that these agents produce entactogenic subjective effects (changes in affect, perception and cognitive style) and act on serotonergic and catecholaminergic systems. Animal work has shown enantiomer-specific effects for MDE, with behavioural differences between the (R)- and (S)-forms, but human data on stereoselective effects were lacking. Spitzer and colleagues set out to characterise the enantio-selective effects of (R)-MDE and (S)-MDE in healthy volunteers. The study aimed to compare subjective experience, neuropsychological performance and functional MRI activation during low-level visual and higher-level semantic tasks after a single oral dose of each enantiomer, using a randomised double-blind crossover design. The investigators hypothesised that the two enantiomers would produce dissociable effects on mood, cognition and regional brain activation, reflecting differential actions on serotonergic and dopaminergic systems and on cortical areas such as primary visual cortex and frontal regions.
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Chang, L., Grob, C. S., Ernst, T. et al. · Psychiatry Research (2000)
Nichols, D. E. · Journal of Psychoactive Drugs (1986)
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Doss, M. K., Samaha, J., Barrett, F. S. et al. · Biorxiv (2022)
Five healthy right-handed male physicians without history of psychiatric, neurologic disorders or drug abuse were recruited and gave written informed consent. The study used a randomised double-blind crossover design with at least a two-week washout between sessions. Each subject received a fixed oral dose of 70 mg MDE hydrochloride (59 mg base) of one enantiomer per session; after the washout the other enantiomer was administered. Baseline measures were taken at 09:00 and fMRI measurements occurred about 90 minutes after drug intake. Neuropsychological testing and psychopathometric scales were administered immediately after scanning in a randomised order. Blood samples for enantioselective plasma pharmacokinetics were collected frequently up to 34 hours post-dose; concentrations were measured by an enantioselective HPLC method and pharmacokinetic parameters were derived using a non-compartmental model (TopFit 2.1). Behavioural paradigms outside the scanner included a visual pop-out search task (set sizes 4–16; 96 trials), a computerised modification of the Wisconsin Card Sorting Test (48-card pack; switching cost derived from reaction times), and a semantic priming lexical-decision task with directly associated, indirectly associated, non-associated words and pseudo-words. In-scanner tasks were block-designed semantic and colour similarity decisions using 120 word pairs and 120 coloured-asterisk pairs (40 trials per category), with activation epochs of 21 s (six whole-brain volumes) alternated with controlled rest. Subjects responded by button press and presentation times were subject-controlled up to specified maxima. Imaging data were acquired on a 1.5 Tesla Siemens Magnetom VISION using T2*-weighted echo-planar imaging (38 slices, TR=3.480 s, TE=50 ms, voxel interpolation to 2×2×2 mm in normalisation). Preprocessing and statistical analyses were performed with SPM99 (realignment, coregistration, normalisation, 8 mm FWHM smoothing). A box-car general linear model convolved with the haemodynamic response was used; low-frequency drifts were removed and images globally scaled. Drug-dependent contrasts for semantic and colour tasks were thresholded at voxelwise p<0.001 uncorrected and cluster-level p<0.05 uncorrected. Statistical analyses of behavioural and psychometric data used repeated-measures MANOVA with Newman–Keuls post-hoc tests where appropriate; Wilcoxon tests for paired samples were applied for small-sample comparisons.
Pharmacokinetics: Both enantiomers were measurable in plasma and had comparable times to maximum concentration and elimination half-lives, but plasma concentrations of the (R)-enantiomer were significantly larger due to higher clearance of the (S)-enantiomer. Subjective measures: The two enantiomers produced markedly different subjective profiles. On the Actual Subjective Mental State Scale (BfS) there was a significant difference with (R)-MDE producing depressive mood and (S)-MDE producing manic/elevated mood (P<0.05, Wilcoxon). The Depression Scale (DS) showed a numerical increase under (R)-MDE and a decrease under (S)-MDE but this contrast did not reach significance (P=0.22). Somatic complaints (BL) trended higher after (R)-MDE and lower after (S)-MDE (P≈0.07). Scores on the Altered States of Consciousness OAV instrument showed a large and significant difference on the 'oceanic boundlessness' scale ((S)-MDE: 86.1; (R)-MDE: 3.9; P<0.05), with (S)-MDE producing pronounced entactogenic-type experiences. Neuropsychology: In the visual pop-out search task a repeated-measures MANOVA found a main effect of drug (F(2,38)=9.16; P<0.001). Post-hoc tests showed a significant decrease in visual search time under (R)-MDE compared with pre-drug (P=0.001) and compared with (S)-MDE (P=0.001). The small increase in search time after (S)-MDE versus baseline was not significant. For WCST switching costs there was a main effect of drug (F(2,42)=5.45; P<0.01). Switching costs increased significantly after (S)-MDE relative to baseline (P<0.05) and relative to (R)-MDE (P<0.01); the decrease in switching costs under (R)-MDE versus baseline was not significant. Semantic priming showed a trend for the indirectly related condition (P=0.067): (S)-MDE produced a 38% decrease in reaction time while (R)-MDE produced a 5% increase, suggesting greater availability of remote associations with (S)-MDE. fMRI: Direct contrasts between enantiomers revealed distinct activation patterns. During the semantic judgement task (R)-MDE significantly activated right visual cortical areas and left frontal regions, whereas (S)-MDE produced right frontal and bilateral temporoparietal activation. In the colour discrimination task (R)-MDE again increased occipital visual activation; (S)-MDE produced no increased activation in visual regions. Imaging statistics were reported at voxelwise p<0.001 uncorrected with cluster-level p<0.05 uncorrected. No severe hallucinatory visual phenomena were reported by subjects at the doses used.
Spitzer and colleagues interpret the pattern of results as evidence for stereoselective pharmacological effects of MDE in humans. They propose that (R)-MDE facilitates bottom-up visual information processing, as reflected by occipital activation and faster parallel visual search, and that this effect is accompanied by depressive subjective changes and activation of left frontal areas that correlated with numerically lower switching costs. The authors link these observations to psychological models in which negative mood narrows attentional scope and promotes systematic processing. They also note that although (R)-MDE activated visual cortex, subjects did not report prominent visual hallucinations at the administered dose; higher doses or experimental paradigms with sensory stimulation might be required to evoke hallucinatory phenomena. In contrast, the (S)-enantiomer produced entactogenic subjective effects (elevated mood, talkativeness), increased switching costs on the WCST and right frontal and temporoparietal activation, which the investigators relate to reduced context-driven conceptual control and greater availability of remote associations. On this basis the authors suggest that the entactogenic properties of racemic MDE (and by extension MDMA-like effects) are likely mediated by the (S)-enantiomer. With respect to neurotoxicity, the discussion highlights three converging observations that make (R)-MDE a candidate mediator of deleterious effects reported after repeated substituted-amphetamine use: preferential activation of visual cortical regions with dense serotonergic projections, engagement of cortical areas implicated in cognitive functions known to be impaired in heavy users, and substantially higher plasma concentrations of the (R)-enantiomer under the dosing regimen used. The investigators therefore recommend that any future therapeutic applications consider using the (S)-enantiomer alone. The authors acknowledge dose-dependency as an important consideration (higher doses might yield different sensory phenomena) and argue that repetition effects do not explain their findings because the order of enantiomer administration was balanced across subjects. They conclude that stereo-specific drug-challenge studies combining experiential, behavioural, neuropsychological and functional imaging methods are a valuable approach for probing the neurobiology of psychoactive drugs and suggest further work along these lines.
Both enantiomers of MDE could be detected in the plasma samples taken, and pharmakokinetic data revealed comparable times of maximum activity and half lives for both. Owing to the significantly increased clearance for the (S)-enantiomer, plasma levels of the (R)enantiomer were significantly larger (Table). The (R)-and the (S)-enantiomers of MDE led to markedly different subjective-behavioural, brain imaging, and neuropsychological effects. Subjective behavioural effects as indicated by self-rating scales are summarised in Fig.. When comparing drug induced alternations from baseline of both enantiomers against each other, the (R)-MDE led to numerically increased scores on a depression scale (DS) whereas the (S)-enantiomer decreased depressiveness and dysphoria (P=0.22; Wilcoxon test). With respect to subjective mental states (BfS) the difference between (R)-MDE causing depressive, and (S)-MDE causing manic mood was significant (PϽ0.05; Wilcoxon test). In the BL scale there was a trend towards more somatic symptoms of dysphoria under (R)-MDE while the (S)enantiomer led to decreases in somatic complaints (PϽ0.07; Wilcoxon test). The OAV questionnaire revealed significant differences for the scale of 'oceanic boundlessness' ((S)-MDE: 86.1; (R)-MDE: 3.9, PϽ0.05, Wilcoxon test for paired samples). Taken together, the (S)-enantiomer produced the entactogenic subjective effects of increased talkativeness, openness, and elevated mood whereas the (R)-enantiomer mainly caused dysphoria and somatic complaints. Functional MRI data were assessed by comparing the effects of the two enantiomers directly against each other (Fig.and Table). During the semantic judgement task, (R)-MDE caused significant activation of right visual and left frontal areas. In contrast, the (S)-enantiomer caused right frontal and bilateral temporoparietal activation. In the colour discrimination task, no increased activation was seen under (S)-MDE, whereas under (R)-MDE the same occipital visual areas as during the semantic task became more active (data not shown). Neuropsychological data on low-level visual processes and on switching costs in the WCST are summarised in Fig.. A MANOVA for repeated measures on reaction times for pop-out search revealed a significant main effect of the factor drug (F(2,38)=9.16; PϽ0.001). Newman-Keuls post-hoc analyses demonstrated that the decrease of visual search time under (R)-MDE was significant when compared with pre-drug (P=0.001) as well as the (S)-enantiomer (P=0.001). The slight increase in scanning times after application of the (S)-enantiomer compared with pre-drug was not significant (PϾ0.10) (Fig.). For switching costs in the WCST a MANOVA for repeated measures showed a significant main effect of drug (F(2,42)=5.45, PϽ0.01). Post-hoc analyses a C max , maximum concentration; T max , corresponding time to maximum plasma concentration; T 1/2 , elimination half life; AUC, area under the curve; Total Cl, total clearance; P, level of significance (non-parametric Wilcoxon tests for paired samples). revealed that switching costs were significantly increased by the (S)-enantiomer when compared with baseline (PϽ0.05) and with the (R)-enantiomer (PϽ0.01). The decrease of mean switching costs under application of the (R)-enantiomer was not significant when compared with baseline (PϾ0.05) (Fig.). To assess the effects of the two MDE enantiomers on semantic processing, reaction times for the three conditions (associated, indirectly associated and non-associated) obtained in the pre-drug session were compared with the corresponding reaction times under (R)-and (S)-MDE. Only in the indirectly related condition was a trend for differential effects found (P=0.067) in that there was a 38% decrease in reaction time under the (S)-enantiomer, and a 5% increase under (R)-MDE, indicative of a tendency towards a larger degree of activation of remote associations under the influence of (S)-MDE.
The present study demonstrated differential effects on various measures assessing alterations of psychopathology, neuropsychological performance and brain activation patterns after ingestion of (R)-and (S)-MDE. Within this framework of our experimental neuropsychological data, combined with the subjective-behavioural observations, the differential effects of (R)-and (S)-MDE on brain activation in fMRI are interpreted as follows. The (R)-enantiomer of MDE activates visual areas, thereby facilitating bottom-up driven information processing, as indicated by facilitating parallel visual search. The activation of left frontal areas was paralleled by numerically decreased switching costs and lower priming effects. From the experimental psychology of affective states it is known that bad mood is associated with 'tightening' and focusing of thought processes whereas good mood is concomitant with 'loosening' of thought processes and increased associations. During cognitive tasks, people in bad mood prefer systematic strategies and show improvement in tasks requiring assiduity and discipline whereas people in good mood prefer heuristic problem-solving strategies and are better at creative tasks. Depression and anxiety, i.e. the main subjective components of (R)-MDE driven experiential changes, promote bottom-up information processing and thereby facilitate automatic feature detection and, in general, scrutiny to environmental signals under the influence of possible incipient danger to the organism. Moreover, under the (R)-enantiomer subjects are more depressed and better at performing the WCST. Although the above mentioned animal data suggest that the hallucinogenic activity of MDE is caused by its (R)-enantiomer, our subjects did not report prominent positive visual non-object bound phenomena such as hallucinations or severe illusory experiences. As both the semantic and the colour task caused increased activation of visual occipital areas under the (R)-enantiomer, we may tentatively conclude that our data do not rule out, but are compatible with, the view that higher doses of (R)-MDE may cause hallucinatory effects in humans by the activation of visual areas. This argument of dosedependency still holds even with respect to previous studies that applicated hallucinogens in sufficiently high doses. Most of these studies that failed to observe sensory phenomena were so-called resting studies that did not use sensory stimulation that might have been necessary to induce the expected sensory alternations or hallucinations. The effects of the (S)-enantiomer are in contrast to the effects of (R)-MDE, producing subjective experiences of elevated mood, a decrease in concept-driven thought processes (as indicated by increased set shifting costs) and some evidence for increased availability of remote associations. This is in line with the activation of right frontal areas that have been found to harbour remote associations in a number of experimental behavioural and neuropsychological studies. The finding of a decrease of WCST performance under (S)-enantiomer and an increase of performance under the (R)-enantiomer is consistent with the view of a dynamic balance between two synergistic decision making systems in the frontal lobes: context-dependent in the left hemisphere and context-invariant in the right. Thus, the increase in right dorsolateral prefrontal functioning under application of the (S)-enantiomer results in a decreased ability to consider contextual cues and to switch between conceptual affordances. (S)-MDE does not cause activation in the visual system in either (semantic and colour) task, and has no effect upon parallel visual search. Given its positive emotional effect and its influences on cognition, this agent may be responsible for the entactogenic component of the effect of the racemic mixture that is illegally used. An alternative interpretation of our data, i.e. (R)-MDE has fewer psychotropic effects than the (S)-MDE and, additionally, that enhancements in neuropsychological performance under the (R)-enantiomer are possibly due to repetition effects, is unlikely for the following reasons. The increase of depressiveness after ingestion of (R)-MDE was approximately as pronounced as the decrease in depressive mood after (S)-MDE. Secondly, contrasts of neural activity of both enantiomers against each other's data could distinctly demonstrate that there exist objective patterns of different brain activations after ingestion of (S)-and (R)-MDE. Finally, repetition effects can be ruled out because the sequence of drug application was balanced over sessions. On the first study day, the (R)-MDE was applicated in three subjects ((S)-MDE: two subjects), and consequently in two subjects on the second study day ((S)-MDE: three subjects). With respect to the neurotoxic effects of substituted amphetamines, our data favour the (R)-enantiomer as a possible candidate for the following reasons. This enantiomer acts upon visual cortical areas into which the 5-HT system preferentially projects. This is in line with a previous single-photon emission computed tomography study demonstrating 5-HT related effects to be prominent in the visual cortex of abstinent MDMA users. In addition, the (R)-enantiomer affects cortical areas relevant for carrying out those cognitive functions that have been found to be impaired after excessive abuse of MDMA, possibly by causing 5-HT depletion after increased activity of these regions. Finally, the approximately three-fold plasma concentrations of (R)-MDE alone would render this enantiomer as the likely candidate for any neurotoxic effects. Together with the differential psychological effects of the agent, this suggests that any future medical applications of MDE within the framework of psychotherapeutic interventions should make use of the (S)-enantiomer only. In conclusion, our results link the pharmacological study of psychoactive agents and neuromodulatory systems with the neuropsychology of specific cognitive functions, and with brain activation by cognitively defined paradigms. They fit within the general framework provided by a large number of animal and human data from these fields. Given the wide use of illegal drugs and their potential for biological approaches to the understanding of psychological and psychopathological phenomena, this approach of stereo-specific drug challenge in human subjects, in conjunction with experiential, behavioural, neuropsychological and functional imaging methods, should be further carried on to study the unique features of the human mind.
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