This randomised, double-blind, placebo-controlled, four-way, cross-over study (n=37) investigated the acute dissociative effects of MDMA (25, 50, and 100 mg), cannabis (THC 21mg/70kg), and cocaine (300 mg) and compared them to data of schizophrenia patients, Special Forces soldiers, and ketamine users. Results indicate that MDMA, cannabis, and (to a lesser extent) cocaine can produce dissociative symptoms that are similar to dissociative pathology.
Introduction
Some drugs of abuse may produce dissociative symptoms, but this aspect has been understudied. We explored the dissociative potential of three recreational drugs (3,4-methylenedioxymethamphetamine (MDMA), cannabis, and cocaine) during intoxication and compared their effects to literature reports of dissociative states in various samples.
Methods
Two placebo-controlled studies were conducted. In Study 1 (N=16), participants received single doses of 25, 50, and 100 mg of MDMA, and placebo. In Study 2 (N=21), cannabis (THC 300 µg/kg), cocaine (HCl 300 mg), and placebo were administered.
Results
Dissociative symptoms as measured with the Clinician-Administered Dissociative States Scale (CADSS) significantly increased under the influence of MDMA and cannabis. To a lesser extent, this was also true for cocaine. Dissociative symptoms following MDMA and cannabis largely exceeded those observed in schizophrenia patients, were comparable with those observed in Special Forces soldiers undergoing survival training, but were lower compared with ketamine-induced dissociation. Cocaine produced dissociative symptoms that were comparable with those observed in schizophrenia patients, but markedly less than those in Special Forces soldiers and ketamine users.
Discussion
Thus, MDMA and cannabis can produce dissociative symptoms that resemble dissociative pathology. The study of drug induced dissociation is important, because it may shed light on the mechanisms involved in dissociative psychopathology.
Papers in Blossom that reference this study
Ramaekers, J. G., Reckweg, J., Mason, N. L. et al. · Neuropsychopharmacology (2024)
Ramaekers, J. G., Hutten, N. P. W., Mason, N. L. et al. · Journal of Psychopharmacology (2020)
Papaseit, E., Torrens, M., Pérez-Mañá, C. et al. · Expert Opinion on Drug Metabolism and Toxicology (2018)
Kuypers, K. P. C., Puxty, D. J., Ramaekers, J. G. et al. · Frontiers in Pharmacology (2017)
Dissociative symptoms encompass a heterogeneous set of experiences ranging from absent-mindedness and excessive daydreaming to severe states such as dissociative amnesia and depersonalization/derealization disorder. These symptoms occur across a range of psychiatric diagnoses and can also appear acutely during intoxication with various drugs. Previous experimental work has shown that subanaesthetic ketamine produces depersonalization and derealization in healthy volunteers, and observational studies have linked regular MDMA and cannabis use with mild depersonalization/derealization experiences, but the dissociative potential of commonly used recreational drugs has been understudied and remains incompletely characterised. Van Heugten-Van Der Kloet and colleagues set out to explore the acute dissociative effects of three recreational drugs—MDMA, cannabis and cocaine—using placebo-controlled experimental designs. The investigators aimed to test whether these substances increase state dissociation during intoxication, whether effects are dose-dependent (for MDMA), and how drug-induced dissociation compares with dissociation reported in clinical and extreme-stress samples (schizophrenia patients, Special Forces soldiers during survival training) and with ketamine intoxication. The study therefore combined experimental drug challenges with comparisons to previously published CADSS (Clinician-Administered Dissociative States Scale) data from other samples to gauge clinical relevance.
Two placebo-controlled studies were conducted. Study 1 (MDMA) used a double-blind, randomized, four-way, cross-over design in which each participant received single oral doses of placebo, 25 mg, 50 mg and 100 mg MDMA in balanced order, with a minimum 1-week washout between sessions. Treatments were administered in identical-appearing formulations (MDMA dissolved in bitter orange peel syrup mixed with juice; placebo syrup alone). Participants were screened medically, instructed to refrain from drug use and certain substances around test days, and were screened for recent substance use on arrival. The Clinician-Administered Dissociative States Scale (CADSS) self-report items were completed approximately 1.25 h after drug administration (CADSS completed at 18:30 after a 17:15 dose). Study 2 compared single-dose cannabis and cocaine against placebo in a double-blind, placebo-controlled, double-dummy design to control for differing Tmax between routes of administration. Regular cannabis and recreational cocaine users were enrolled and had to meet minimum recent-use criteria (cannabis at least twice per week over the prior three months; cocaine at least five times in the previous year). At T1 subjects received a cocaine HCl capsule (300 mg) or capsule placebo; at T2 (45 min later) subjects inhaled cannabis or cannabis placebo via a standardised vaporiser; at T3 (1 h after T2) subjects received a second cannabis dose (150 mg/kg THC or placebo). The CADSS self-report was completed 3 h 15 min after T1 (i.e., 3.5 h after the cocaine capsule and 1.25 h after the second cannabis administration). The DES (Dissociative Experiences Scale) was administered on a separate training day to assess trait dissociation. The CADSS self-report consists of 19 items (score range 0–76); the DES yields a trait score (reported range 0–100 in the extraction). Outcome measurement and analysis: The primary state outcome was the CADSS total score and its subscores (amnesia, depersonalization, derealization). Internal consistency was estimated with Cronbach's α. CADSS data were analysed with General Linear Model repeated measures analyses, univariate ANOVAs and post-hoc pairwise comparisons. DES–CADSS correlations were examined with Pearson correlations, and comparisons with historical CADSS data from schizophrenia patients, Special Forces soldiers and ketamine-treated volunteers were conducted using independent-samples t-tests. SPSS 18.0 was used for analyses. The extracted text notes that CADSS scores in Study 2 were log-transformed to address right skew and that one outlier (CADSS = 50) was removed from analyses.
Study 1 (MDMA): Repeated-measures ANOVA indicated a significant main effect of MDMA dose on CADSS scores (F(3,45) = 21.27, p < 0.001; partial eta² = 0.59). Post-hoc comparisons showed that the highest MDMA dose (100 mg) produced significantly greater CADSS total scores and greater derealization subscale scores relative to placebo. The 25 mg and 50 mg MDMA conditions did not differ significantly from placebo (p's 0.22–0.72). A negative correlation was observed between duration (years) of prior MDMA use and MDMA-induced CADSS scores (r = −0.28, p = 0.04), indicating reduced state dissociation with longer MDMA use history. No other significant correlations between lifetime use measures and CADSS or DES scores were reported. Study 2 (cannabis and cocaine): After trimming an extreme outlier and log-transforming CADSS to address skew, repeated-measures ANOVA revealed a significant main effect of drug condition (cannabis, cocaine, placebo) on CADSS (F(2,34) = 17.00, p < 0.001; partial eta² = 0.50). Both cannabis and cocaine increased acute dissociation relative to placebo (both p's < 0.05). Cannabis produced significant increases in the CADSS total score and all subscores (amnesia, depersonalization, derealization). Cocaine produced a smaller but statistically significant increase in the CADSS total score, with more modest effects on the separate subscores. Trait dissociation (DES; mean 17.30, SD 11.05) correlated with state CADSS under drug conditions: DES correlated with CADSS for cannabis (r = 0.47, p < 0.05) and cocaine (r = 0.54, p < 0.05), but not with placebo. A Williams test indicated the DES–CADSS correlations did not differ significantly between cannabis and cocaine (t = 1.36, p = 0.19). Comparisons with other samples: The investigators compared their acute dissociation scores with previously published CADSS data from two schizophrenia samples, Special Forces soldiers after survival training, and healthy volunteers intoxicated with ketamine. Single doses of MDMA 100 mg and cannabis produced CADSS scores that significantly exceeded those reported in schizophrenia patients (t's = 2.61–4.00, all p's < 0.01) and were comparable to levels seen in Special Forces soldiers (MDMA: t = 0.52, p = 0.60; cannabis: t = 0.50, p = 0.62). Ketamine intoxication produced substantially higher CADSS scores than MDMA or cannabis (MDMA: t = 7.77; cannabis: t = 8.31; both p's < 0.01). Cocaine-induced CADSS scores were comparable to those in schizophrenia patients (t = 2.03, p = 0.05; t = 1.21, p = 0.23) but significantly lower than scores in Special Forces soldiers (t = 2.30, p = 0.02) and ketamine users (t = 12.28, p < 0.01). The extracted text reports example group CADSS means for comparison: Special Forces soldiers ~11.6 and ketamine users ~40.
The investigators conclude that MDMA and cannabis can elicit acute dissociative symptoms during intoxication, with cannabis producing significant increases across depersonalization, derealization and amnesia subscales and MDMA primarily elevating derealization. Overall magnitudes of dissociation following MDMA (at 100 mg) and cannabis were comparable to each other and, in these experimental samples, exceeded CADSS scores reported in schizophrenia patients and matched dissociation levels observed in Special Forces soldiers undergoing survival training; however, ketamine produced substantially larger dissociative effects than either MDMA or cannabis. Cocaine produced only a modest increase in CADSS total scores and yielded dissociation levels similar to those reported in schizophrenia patients but lower than those in Special Forces soldiers and ketamine users. The authors note a dose-dependent effect for MDMA (only 100 mg increased CADSS) and report an inverse relationship between prior MDMA exposure and drug-induced CADSS scores, suggesting tolerance or reduced sensitivity in more experienced users. Trait dissociation (DES) was moderately associated with state dissociation under cannabis and cocaine but not under MDMA; the absolute DES scores in the sample were relatively low (mean 17.3), and the extracted text does not clearly report the precise DES cut-off value referenced. The investigators therefore do not claim direct causality between drug-induced state dissociation and trait dissociative pathology given the non-clinical nature of their sample. Several limitations are acknowledged that restrict generalisability: relatively small sample sizes in the current and comparison datasets, enrolment of participants with prior drug use (which may attenuate acute responses and thus underestimate effects in novice users), and use of only the 19 self-report items of the CADSS rather than the full instrument including observer-rated items, complicating direct comparison with some historical datasets. The authors recommend mechanistic studies comparing drugs with differing hypnotic, psychotomimetic and stimulant profiles to clarify neuropharmacological drivers of drug-induced dissociation and to explain why some substances produce stronger dissociative effects than others.
Statistical analyses were performed using SPSS 18.0 software. Cronbach's α values were used to estimate internal consistency of the measures. Pearson product-moment correlations between baseline and state measures were calculated. CADSS data were analyzed using General Linear Model (GLM) repeated measures analyses, univariate analyses (ANOVA), and post-hoc pairwise comparisons. Using independent samples ttests, we compared our data with findings from several previous studiesthat explored the prevalence of acute dissociative symptoms in a variety of groups.
The present study demonstrates that MDMA and cannabis can induce dissociative symptoms. Cannabis significantly increased subjective ratings of depersonalization, derealization, and amnesia during intoxication. MDMA primarily increased feelings of derealization. The magnitude of total dissociation following cannabis and MDMA, however, was comparable. On the other hand, cocaine only mildly increased the total CADSS score when compared with placebo. CADDS ratings were negatively correlated to MDMA use history, indicating that MDMA induced dissociative symptoms were less in more experienced users. The effects of MDMA on dissociative symptoms were also shown to be dose dependent. MDMA 100 mg significantly increased dissociative symptoms, whereas MDMA 25 and 50 mg did not. We compared our results with the data of schizophrenia patients, Special Forces soldiers, and ketamine users. Total CADSS In contrast, total CADSS scores reported in Special Forces soldiers (i.e., 11.6) and in ketamine users (i.e., 40) have been found to be elevated and much more indicative of a dissociative state. A comparison between their CADSS data and the current data revealed that dissociative symptoms following cannabis and MDMA largely exceeded those observed in schizophrenia patients and were comparable with those observed in Special Forces soldiers, yet lower relative to ketamine induced dissociation. Cocaine produced dissociative symptoms that were similar to those observed in schizophrenia patients, but they were well below the dissociative levels found in Special Forces soldiers and ketamine users. Thus, MDMA and cannabis, but not cocaine, can produce severe dissociative symptoms that resemble dissociative pathology. We measured trait dissociation in participants of Study 2 with the DES. Mean DES scores were relatively low (i.e., 17.3) and well below the cut-off score430 that is thought to be indicative of a dissociative disorder. These data suggest that our participants had not developed dissociative pathology despite their regular drug use history. A correlational analysis between DES and CADSS scores revealed a moderate but significant association between cannabis and cocaine induced CADSS scores and DES. The absolute increments in CADSS following cocaine, however, were generally small, and the association between DES and CADSS scores did not exist for MDMA, even though this drug did produce severe dissociative symptoms. Our results, then, fail to provide strong evidence for any direct causality between drug-induced state dissociation and trait dissociation. This was to be expected because the current sample did not include any participants with a psychiatric background. All in all, our findings demonstrate that stimulant drugs such as MDMA and, to a lesser extent, cocaine may produce dissociative effects, a finding that is at odds with the idea that only sleep producing manipulations may increase dissociation levels (Van der. Clearly, the psychostimulant MDMA produced acute dissociative symptoms that were similar to those obtained with cannabis, a sedative and sleep promoting drug. Therefore, our data are much more in line with the chemical model of dissociation that poses that drug-induced dissociation occurs due to detachment from reality and not necessarily because of the sleep-promoting properties of the drugs involved. Research showing that dissociative disorders and substance abuse disorders are often co-occurring is consistent with the current finding that dissociative states can be drug-induced. Relatedly, in clinical practice, dual diagnoses patients are known to pose serious treatment challenges due to drug abuse, increased risk of suicidal and violent behaviors, and overall poorer functioning. According to the chemical dissociation hypothesis, individuals suffering from a traumatic past may use illicit drugs to blunt traumatic feelings, when dissociative pathology is not effective any longer to defend against intrusions of traumatic memories. Alternatively, the use of drugs like cannabis may elicit dissociative symptoms such as depersonalization. Our studies were subject to a number of limitations that restrict the generalizability of the current findings to clinical groups. First, our data set as well the historical datasets consisted of relatively small samples, which due to chance fluctuations may limit the reliability of our findings. Second, participants in our studies had a history of drug use, which may have mitigated their response to acute drug challenges. The present results may therefore underestimate druginduced dissociative responses in novice drug users. Third,used the full version of the CADSS (including observerrated items), whereas we only used the 19 self-report items. This hampers a fine grained comparison and given our reliance on a relatively small sample, the differences with the Bremner et al.'s (1998) study should not be over interpreted. In sum, our findings show that MDMA, cannabis, and cocaine all induce acute dissociative symptoms. Dissociative symptoms were most prominent after MDMA and cannabis and similar to pathological symptomatology. Future studies might want to include mechanistic designs to further distinguish the neuropharmacology of druginduced dissociative states that might clarify why some substances have stronger dissociative properties than others. Thus, studies that compare drugs with regard to their dissociative potential might clarify the physiological drivers of these symptoms, especially when the drugs differ in a systematic way in terms of their hypnotic, psychotomimetic, and stimulant properties., Special Forces soldiers during survival training, and healthy men during ketamine intoxication. Displayed are SEM bars and significant differences between the groups (*p o 0.05, **p o 0.001). 001812-98-08036) awarded to DHK, EU grant (Number: TREN-05-FP6TR-So7.61320-518404) awarded to JR, and a ZONMw grant (Number: 31160206) awarded to JR and RJV. There are no conflicts of interest.
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