In a double‑blind, placebo‑controlled three‑way crossover study of 18 recreational users, a single 75 mg dose of MDMA impaired immediate and delayed verbal recall during the intoxication phase (1.5–2 h) but produced no residual memory deficits at 25.5–26 h. The withdrawal phase showed increased fatigue and reduced vigour without depression, and methylphenidate 20 mg had no effect on memory or mood.
A range of studies has indicated that users of 3.4-Methylene-dioxymethamphetamine (MDMA, ‘Ecstasy’) display cognitive deficits, particularly memory impairment, as compared to non-drug using controls. Yet it is difficult to determine whether these deficits are caused by MDMA or some other confounding factor, such as polydrug use. The present study was designed to establish the direct relation between MDMA and memory impairment under placebo-controlled conditions. Eighteen recreational MDMA users participated in a double blind, placebo controlled, 3-way crossover design. They were treated with placebo, MDMA 75mg and methylphenidate 20mg. Memory tests were conducted between 1.5-2h (intoxication phase) and between 25.5-26h (withdrawal phase) post dosing. Results showed that a single dose of MDMA caused impairment of immediate and delayed recall on a verbal learning task during the intoxication phase. However, there was no residual memory impairment during the withdrawal phase. Subjects reported more fatigue and less vigour, but no symptoms of depression during the withdrawal phase of MDMA treatment. Methylphenidate did not affect memory or mood at any time of testing. A single dose of MDMA produces transient memory impairment.
Earlier research has reported cognitive deficits, especially verbal memory impairment, in people who use 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). Those between-group and abstinent-user studies have suggested dose-related memory problems and links to serotonergic markers, but interpretation is limited by confounding factors such as unknown dosing, polydrug use, lifestyle differences and the lack of experimental control. Only a few studies attempted to assess memory during intoxication, and those employed quasi-experimental designs (for example assessing users who self-administered MDMA before parties), which left open alternative explanations including sleep loss and uncontrolled substance use. Kuypers and colleagues designed a controlled experiment to test whether a single acute dose of MDMA produces immediate and/or residual memory impairment. The study used a double-blind, placebo-controlled, three-way crossover design in experienced recreational MDMA users, including an active control (methylphenidate) to probe whether any observed effects were likely dopaminergic rather than serotonergic in origin. The primary focus was on verbal memory measured during the intoxication phase (about 1.5 h post-dose) and the withdrawal phase (about 25.5 h post-dose).
Papers in Blossom that reference this study
Ramaekers, J. G., Kuypers, K. P. C., Vollenweider, F. X. · Molecular Psychiatry (2026)
The study employed a double-blind, placebo-controlled, three-way crossover design with counterbalancing. Each participant completed three treatment conditions separated by at least 14 days: placebo, 75 mg oral MDMA (powder dissolved in bitter orange syrup and orange juice), and 20 mg oral methylphenidate (pill). Testing occurred over two consecutive days within each treatment period; drugs/placebo were given on Day 1 and no drug was administered on Day 2. Eighteen healthy recreational MDMA users (nine men, nine women), aged 20–39 years (mean 26.22, SD 5.1), took part. Lifetime MDMA use ranged from less than 30 occasions in 15 participants to 60–120 occasions in three. Inclusion required prior MDMA experience, absence of psychotropic medication, good physical health and BMI between 18 and 28 kg/m2. Exclusion criteria included other substance addiction, pregnancy/lactation, cardiovascular abnormalities, excessive alcohol consumption, hypertension and history of psychiatric or neurological disorders. Medical screening included questionnaires, blood and urine tests and ECG; the protocol was approved by the relevant ethics committee and a licence was obtained for MDMA storage and administration. Before each testing day participants completed a training session and were instructed to abstain from drugs for one week before medical screening through 14 days after final testing, to avoid caffeine and alcohol for 24 h before testing and to obtain normal sleep. On test mornings participants were breath-tested for alcohol, urine-screened for common drugs and women took a pregnancy test. MDMA/methylphenidate concentrations were sampled at 1.5 h post-dose (Day 1) and 25.5 h post-dose (Day 2), with additional clinical chemistry checks 11 days after administration. Cognitive testing concentrated on verbal memory: a computerized verbal word-learning task (five immediate learning trials of 15 monosyllabic words, a 30-minute delayed free recall and a 30-minute recognition test). Other tests included a syntactic reasoning task (working memory and speed), and a computerized digit-symbol substitution task (short-term memory and psychomotor speed). Subjective measures comprised the Groninger Sleep Scale (sleep quality/quantity), the Profile of Mood States (POMS) subscales (Depression, Vigour, Tension, Fatigue, Anger) and the Hamilton Depression Rating Scale (HAM-D). Pharmacokinetic samples were analysed by LC-MS/MS with a quantification limit of 1 ng/mL. For statistical analysis the investigators used GLM univariate repeated measures in SPSS 11.5 with Treatment (3 levels) and Day (2 levels) as within-subject factors; Trial (5 levels) was included for immediate recall. Drug-versus-placebo contrasts were conducted when overall effects were significant. One missing POMS dataset in the placebo condition was imputed using the mean of the other 17 subjects.
Verbal learning and recall: Repeated-measures ANOVA on the immediate recall (IR) scores showed a significant Treatment by Day interaction (F(2,34) = 7.58; p = 0.002) and a large Trial effect reflecting learning across the five trials (F(4,68) = 214.86; p < 0.001). Drug–placebo contrasts on Day 1 indicated that MDMA impaired learning: participants recalled fewer words under MDMA than under placebo, with a mean difference summed over five trials of 4.6 words (SE 1.7; p = 0.009). There were no significant drug–placebo differences on Day 2 (withdrawal). Delayed recall (DR) also showed a Treatment by Day interaction (F(2,34) = 4.72; p = 0.016) and a Day main effect (F(1,17) = 5.36; p = 0.033). On Day 1 MDMA reduced delayed recall compared with placebo (F(1,17) = 9.91; p = 0.006), with participants remembering approximately 1.44 words fewer (SE 0.46). Relative recall (a measure of forgetting) showed effects of Day (F(1,17) = 7.30; p = 0.015) and Treatment by Day (F(2,34) = 3.43; p = 0.044); the MDMA–placebo contrast on Day 1 was nearly significant (F(1,17) = 3.5; p = 0.079), suggesting somewhat faster forgetting under MDMA. Recognition scores and recognition reaction times were not affected by Treatment or Day. Syntactic reasoning and digit-symbol: The syntactic reasoning task produced no Treatment effects; only a Day main effect was observed for reaction time of correct responses (F(1,17) = 9.63; p = 0.006), with faster responses on Day 2 (mean 92.01, SE 29.64) than Day 1. The digit-symbol substitution task showed a Day main effect (F(1,17) = 25.87; p = 0.001) with more correct encodings on Day 2 (mean 3.96, SE 0.78), but no Treatment or Treatment by Day effects. Subjective measures: Sleep quantity and quality did not differ by Treatment or Day; average sleep was 7.28 h (SE 0.19). POMS subscales showed Treatment by Day interactions for Fatigue (F(2,34) = 3.56; p = 0.039) and Vigour (F(2,34) = 6.15; p = 0.005). There were no drug–placebo differences on Day 1, but on Day 2 MDMA increased subjective fatigue (F(1,17) = 6.06; p = 0.025) and decreased vigour (F(1,17) = 8.71; p = 0.009) relative to placebo. HAM-D total scores showed a Day main effect (F(1,17) = 5.02; p = 0.039) with higher scores on Day 1 versus Day 2, but no Treatment effects indicating no signs of depression attributable to MDMA in this sample. Pharmacokinetics: Mean plasma MDMA concentration was 113.4 ng/mL (±37.4) at 1.5 h (Day 1) and 11.6 ng/mL (±9.3) at 25.5 h (Day 2). MDA averaged 2.9 ng/mL (±0.9) on Day 1 and 2.1 ng/mL (±1.2) on Day 2. Ritalinic acid concentrations averaged 95.9 ng/mL (±78.4) on Day 1 and 22.9 ng/mL (±7) on Day 2. Methylphenidate produced no detectable effects on memory or mood measures.
Kuypers and colleagues interpret their findings as showing that a single 75 mg dose of MDMA produces transient impairments of verbal memory during the acute intoxication phase but not during the withdrawal phase the following day. Specifically, MDMA reduced the total number of words learned across five immediate recall trials and lowered delayed recall after a 30-minute retention interval; recognition memory remained intact. The pattern—reduced immediate and delayed recall with normal recognition—resembles memory deficits reported in previous studies of abstinent MDMA users, which the authors suggest may point to overlapping neuropharmacological mechanisms. The study team argues that the lack of residual memory impairment 25.5 h post-dose indicates a single dose does not produce permanent memory damage. They also note that subjective mood changes during withdrawal were limited to increased fatigue and decreased vigour, with no evidence of depressive symptoms on the HAM-D or POMS. The absence of memory effects after methylphenidate led the investigators to attribute MDMA-induced memory impairment to serotonergic rather than dopaminergic mechanisms. Several possible serotonergic mechanisms are discussed. The authors outline a two-phase pattern of serotonin change reported in animal studies—an acute reversible depletion within the first few hours after MDMA and a later, longer-lasting depletion—and suggest that transient 5HT reductions or receptor-mediated effects might underlie the intoxication-phase memory deficit. They discuss evidence implicating postsynaptic 5HT1A and 5HT2 receptors in hippocampal learning and memory, noting that MDMA increases 5HT release and has some affinity at 5HT2A receptors, which might plausibly impair learning and delayed recall. The investigators acknowledge uncertainty about the exact mechanism and note that manipulations such as tryptophan depletion do not consistently reproduce the same profile of immediate and delayed recall impairment, indicating qualitative differences between experimental serotonin depletion and MDMA effects. They also situate their findings relative to earlier nightclub/quasi-experimental studies, emphasising that those designs were confounded by factors like sleep loss and concomitant substance use. Overall, the authors conclude that acute MDMA causes transient verbal memory impairment during intoxication but that a single dose did not produce measurable residual memory deficits the next day.
MDMA the main psychoactive constituent in the popular recreational party drug Ecstasy, has been frequently associated with cognitive impairments (reviews:.for example showed impairment of (immediate) verbal memory performance in abstinent MDMA users compared to polydrug non-MDMA users. The magnitude of memory impairment was dose related and inversely related to the amount of 5HIAA cerebrospinal fluid. They concluded that memory impairment seen in abstinent users could be due to MDMA's presumed neurotoxicity. Whether MDMA is neurotoxic in humans however is difficult to infer from these studies for two reasons. First, other markers, like decreased transporter density may have more potential to serve as a marker for axonal/structural degeneration. Second, confounding factors may limit interpretation of results from between group designs. A few examples are lifestyle factors that may differ between groups, the dose used that is unknown and the fact that MDMA users are usually polydrug users so damage can be due to other drugs or combinations. To date, only two studies have made an attempt to assess the effects of MDMA on memory during intoxication. Both studies employed quasi-experimental, between subjects designs with multiple test sessions. They assessed mood and cognitive function of regular MDMA users after they self administered MDMA before going to a party. In the first study, MDMA users tended to perform worse on memory tasks during intoxication as compared to normal controls, but this difference did not reach statistical significance. The MDMA group did however show significant impairment of long-term memory, the following day. However, the researchers argued that this effect might not be drug related, as the subjects in the MDMA group had suffered from lack of sleep during the night following MDMA use. In the second studyecstasy users showed marked deficits in memory function after self-administration of MDMA, when compared to normal controls. Yet, results from these studies may suffer from similar interpretational problems as observed in abstinent users.for example noted that the use of alcohol and drugs other than MDMA in both control and experimental groups could not be controlled. The present study was designed to overcome these interpreta-tional problems in quasi-experimental designs. The study is unique in that it is the first to look at the acute and residual effects of a single dose of MDMA (75 mg) on memory functioning in MDMA users in a double blind, placebo-controlled, crossover design. It was hypothesized that memory function would change as a function of serotonin (5HT) availability during intoxication and withdrawal. Methylphenidate (Ritalin), a dopaminergic agent, was used as an active control to see whether the effects of MDMA were mediated by dopamine and/or serotonin.
The study design was, double blind, placebo controlled, 3-way crossover with balancing of the treatments. Testing took place on two consecutive days, in three separate testing periods, with a minimum washout period of 14 days inbetween. On the first day of each period, participants received either 75 mg of MDMA, 20 mg of methylphenidate or placebo. MDMA powder was dissolved in 25 ml bitter orange peel syrup and mixed with 200 ml orange juice; and methylphenidate was administered as a pill. All treatments were identical in appearance. Participants received, on each first day, a solution and a pill in order to blind them and the researcher for the treatment. The second day was identical to the first day with the exception that no drugs or placebo were given.
Eighteen healthy subjects, nine male and nine female, aged 20 to 39 years (mean SD: 26.22 (5.1)) participated in the study. They all had used MDMA prior to onset of the study. Lifetime use of MDMA varied from light (Ͻ30 times) in 15 subjects to heavy (between 60-120 times) in three subjects. They were recruited by means of advertisements in local newspapers and the snowball technique. Potential candidates first underwent a telephonic screening. They were questioned about their drug use and medical condition and were given information about the study. They were sent a detailed brochure with information about the study procedure and two questionnaires for medical history and detailed history of drug use. Inclusion criteria were experience with MDMA use, free from psychotropic medication, good physical health, absence of major medical endocrine and neurological conditions, normal weight (BMI 18-28 kg/m 2 ). Exclusion criteria were history of drug abuse (other than MDMA) or addiction, pregnancy or lactation, cardiovascular abnormalities (assessed by a standard 12 lead ECG), excessive drinking (Ͼ20 alcoholic consumptions), hypertension (diastolic Ͼ 100; systolic Ͼ 170), history of psychiatric or neurological disorders. A medical doctor checked the completed list, and upon approval, they were invited for a medical examination. Blood and urine samples were taken for examination and they underwent an electrocardiogram (ECG) measurement. When they were found medically sound, they were contacted for participation. They were given a brochure with information about the study and a number of rules they had to obey during the period of the study and signed an informed consent to prove they read the information and agreed to it. They were paid upon completion of the testing periods for their participation. The study was performed in accordance with the 1975 declaration of Helsinki, adjusted inand was approved by the Medical Ethics Committee of the Academic Hospital of Maastricht and the University of Maastricht. A permit for obtaining, storing and administering MDMA was obtained from the Dutch drug enforcement administration.
Prior to testing days, participants were familiarized with the tests on a training day. Participants were requested to abstain from any drug use 1 week prior to the medical examination until 14 days after the last testing day. They were asked not to use any caffeinated or alcoholic beverages 24 h prior to testing and to get a normal night's sleep. Participants were screened for alcohol use in breath and for recent drug use in urine (THC, opiates, cocaine, amphetamines, methamphetamines) upon arrival at the testing facilities at 9.00 AM. Women were given a pregnancy test. When the results of all of the tests were negative, subjects proceeded with a light breakfast and were given a sleeping questionnaire to assess sleep complaints. One hour later subjects received drugs or placebo. One hour and a half after drug intake a blood sample was taken to determine the MDMA/MDA or ritalinic acid concentrations in blood plasma. Following blood sampling, subjects proceeded with the memory tests during the intoxication phase. Similar study procedures were followed when the subjects returned to the laboratory the following day to assess memory performance during withdrawal, i.e., between 25.5-26 h post dosing. An additional blood sample was taken every 11th day after drug administration to control for renal and liver functioning.
In the verbal word-learning taskparticipants were shown subsequently 15 monosyllabic words in the centre of a computer screen; each word was shown for 2 s. Their task was to repeat every word aloud upon appearance and recall as many as possible at the end of the trial. This procedure was repeated five times. The total number of correct recalled words over five trials yielded the immediate recall score (IR), a measure of learning or working memory. After a 30-minute delay filled with other tasks, the subject was again asked to recall as many words as possible from the list shown previously. The number of correctly recalled words represented the delayed recall score (DR). The DR score was also transformed into a percentage of the highest IR score in the learning trials ((IR-DR)/IR) to yield relative recall scores, a measure of forgetting or memory decay. Finally, after a 30-minute delay, the subject was shown a series of 30 words on the computer display, comprising of the original set and 15 new words in random order. Their task was to indicate which words were part of the original list. The number of correct recognitions and the average speed (ms) of correct recognitions were recorded as the recognition score (a measure of long-term memory) and the recognition time (a measure of speed of retrieval from long-term memory), RS and RT, respectively. Parallel versions of the verbal word-learning task were used in each test replication to prevent learning effects over time.
In the syntactic reasoning taskparticipants were shown subsequently 32 sentences in the centre of a computer screen describing the order of two letters, each followed by a letterpair (AB or BA). Half of the letterpairs showed the same order as in the preceding sentence, and half of the pairs the opposite. Sentence difficulty varied within the series, from simple active sentences, as given above, to more complicated sentences involving passives, negatives or both; e.g., 'B is not followed by A'. Participants had to decide, as quickly as possible, by means of pressing a yes or no button whether the letter pair matched the descriptive sentence. The number of correctly categorized items can be considered as a measure of working memory and reaction time of correct answers as a measure of speed of working memory.
The digit symbol substitution taskused here was a computerised version of the paper and pencil task from the WAIS. It assesses short-term memory and psychomotor performance. Participants were shown an encoding scheme which linked numbers of 1 to 9 to nine different symbols. The same row of symbols was shown at the bottom of the screen as response buttons. In the centre of the screen, digits appeared. The task of the subject was to choose the correct symbol that was linked to the digit by means of moving the cursor to the correct symbol in the bottom row and clicking on it. The number of digits correctly encoded within 3 min was the performance measure. Subjective measures Three subjective measurements were taken: i.e., the Groninger Sleep Scale (GSS), the Profile of Mood States (POMS) and the Hamilton Depression Rating Scale (HAM-D). The GSS assesses sleep quality and quantity (hours of sleep). It consists of 15 dichotomous questions about sleep complaints and an open question concerning the duration of sleep. The POMS is a self-assessment mood questionnaire with 32 visual analogue scales representing five mood states; that is Depression, Vigour, Tension, Fatigue and Anger. On both ends of each scale there are words reflecting opposite moods. The participant had to indicate in how far these items were representing his mood. Pharmacokinetics Blood samples were collected in 5 mL glass tubes containing sodium fluoride and potassium oxalate. After centrifugation at 4000 g for 10 min, the resultant plasma was transferred to a clean tube and frozen at Ϫ20 °C until LC-MS/MS analysis. The limit of quantification for MDMA, MDA, and ritalinic acid was 1 ng/mL.
All statistical analyses were conducted by means of SPSS 11.5 for Windows. Each objective parameter was analysed using GLM univariate repeated measures procedures with Treatment (3 levels) and Day of testing (2 levels) as main within subject factors. In case of the immediate recall scores, Trial (5 levels) was added as an additional factor. Separate contrast (drug vs placebo) tests were conducted in case of a significant overall effect of Treatment or Treatment by Day.
In the Placebo condition, one subject completed only 50% of the POMS questionnaire on 2 consecutive days. Missing values were replaced by the mean of scores of the other 17 subjects in the same condition.
Verbal word-learning task ANOVA revealed significant main effects of Treatment by Day (F 2,34 ϭ 7.58; p ϭ 0.002) and Trial (F 4,68 ϭ 214.86; p Ͻ 0.001) on immediate recall scores. The latter effect reflects the overall increase in the number of words recalled over five subsequent learning trials (see Fig.). The former effect was further analysed by means of separate drug placebo contrasts on each Day of testing. These revealed a significant difference between MDMA and placebo (p ϭ 0.009) on Day 1. During MDMA intoxication subjects learned less words as compared to placebo (see Fig.). The mean (SE) difference from placebo summed over five trials was 4.6 (1.7) words. There were no differences between drugs and placebo on Day 2 of testing during withdrawal. Delayed recall scores revealed significant main effects of Day (F 1,17 ϭ 5.36; p ϭ 0.033) and Treatment by Day (F 2,34 ϭ 4.72; p ϭ 0.016). Subjects generally remembered less during delayed recall on Day 2 (mean (SE): 0.83 (0.36)) as compared to Day 1. Separate drug-placebo contrasts revealed a significant difference between MDMA and placebo (F 1,17 ϭ 9.91; p ϭ 0.006) on Day 1 but no differences between drugs and placebo on Day 2. While under influence of MDMA participants remembered approximately 1.44 (SE 0.46) words less during delayed recall, compared to placebo. Relative recall scores analysis showed main effects of Day (F 1,17 ϭ 7.30; p ϭ 0.015) and Treatment by Day (F 2,34 ϭ 3.43; p ϭ 0.044). Treatment contrasts revealed a nearly significant difference between MDMA and placebo (F 1,17 ϭ 3.5; p ϭ 0.079) on Day 1 but no differences between drugs and placebo on Day 2. Recognition scores were not affected by Treatment, Day or their interaction.
Except for a main effect of Day (F 1,17 ϭ 9.63; p ϭ 0.006) on reaction time of correctly categorized items, there were no significant main effects of Treatment, Day or Treatment by Day on the variables of the syntactic reasoning task Transient memory impairment after acute dose of 75 mg MDMA 635 (see Table). Subjects appeared to react faster on Day 2 (92.01; SE 29.64) compared to Day 1.
Apart from a significant main effect of Day (F 1,17 ϭ 25.87; p ϭ 0.001), there were no significant effects of Treatment or Treatment by Day on number of correctly encoded digits (see Table). Subjects encoded on average more digits correctly on Day 2 (3.96, SE 0.78) compared to Day 1.
There were no significant main effects of Treatment, Day or Treatment by Day on Sleep Quantity or Quality scores. Subjects slept on average 7.28 h (SE 0.19) and had an average score of 2.28 (SE 0.39) on the sleep complaints questionnaire. There were no significant main effects of Treatment or Day on the five subscales of the POMS. There were however significant interaction effects of Treatment by Day on two subscales measuring fatigue (F 2,34 ϭ 3.56; p ϭ 0.039) and vigour (F 2,34 ϭ 6.15; p ϭ 0.005). Drug-placebo contrasts on Day 1 revealed no significant differences between MDMA, methylphenidate and placebo. On Day 2 however MDMA increased subjective feelings of fatigue (F 1,17 ϭ 6.06; p ϭ 0.025) and decreased vigour (F 1,17 ϭ 8.71; p ϭ 0.009) relative to placebo. There were no significant effects of Treatment or Treatment by Day on the total score of the Hamilton-D. Analysis of Hamilton-D scores did reveal a significant main effect of Day (F 1,17 ϭ 5.02; p ϭ 0.039) indicating that scores were higher on Day 1 as compared to Day 2.
Plasma concentrations of MDMA, MDA and ritalinic acid were determined 1.5 h (Day 1) and 25.5 h (Day 2) post-drug. Concentrations of MDMA were on average 113.4 ng/ml (Ϯ37.4) and 11.6 ng/ml (Ϯ9.3), respectively on Day 1 and Day 2. Concentrations of MDA were on average 2.9 ng/ml (Ϯ0.9) and 2.1 ng/ml (Ϯ1.2), respectively on Day 1 and Day 2. Concentrations of ritalinic acid were on average 95.9 ng/ml (Ϯ78.4) and 22.9 ng/ml (Ϯ7), respectively on Day 1 and Day 2.
A single dose of MDMA impaired memory during the intoxication phase. This impairment was no longer visible the day after, during the withdrawal phase. In the intoxication phase, working memory, as assessed by the number of words recalled in the immediate recall trials of the word-learning task, was impaired. Subjects showed a normal learning curve over the five trials, that is, every trial they could recall more words compared to the previous trial, but in total, they learned fewer words following MDMA as compared to placebo. In addition, the delayed recall trial was also affected after MDMA. Subjects recalled fewer words after a delay of 30 min compared to placebo. An almost significant reduction of the relative recall score furthermore demonstrated that this effect was not only attributable to a lesser amount of words learned in the immediate recall trials but also to a faster forgetting rate. This pattern of impairment of immediate and delayed recall is similar to the pattern of memory deficits shown in abstinent users of MDMA. The similarity in memory impairment observed in abstinent MDMA users and that during acute MDMA intoxication strengthen the notion that these phenomena may share a common source or neuro-pharmacological brain structure. Verbal memory was not impaired in the withdrawal phase of MDMA. Both immediate and delayed recall scores showed no deviations from performance in the placebo condition. Subjects learned a comparable number of words and produced the same learning curve as in the placebo condition. They also recalled a comparable number of words after a 30-minute delay and had normal forgetting rates as shown by the relative recall score that was the same in the placebo condition. These findings show that one single dose does not cause permanent memory damage. It has been noted before that memory impairment during withdrawal may be secondary to the development of depressive symptoms during the mid-week.were the first to describe symptoms of depression in subjects between 2 to 5 days following the use of MDMA. In the present study mood assessments were also included in the study protocol. On Day 2, during withdrawal, subjects appeared to be less vigorous and more fatigued as compared to placebo. However, there were no signs of depression following MDMA treatment, as measured by the HAM-D or the Profile of mood Transient memory impairment after acute dose of 75 mg MDMA 637and Parrot and Lasky (1998) may be related to the fact that the latter conducted their quasi-controlled studies in nightclubs. Many subjects in these nightclub studies were polydrug users who attested to the use of combinations of MDMA with alcohol, cannabis or cocaineor suffered from lack of sleep when tested the day after. It can thus, not be excluded that depressive symptoms reported in these nightclub studies may have been confounded by such factors as polydrug use or sleep deprivation. Methylphenidate did not affect memory performance. This finding indicates that MDMA-induced memory impairment is related to the drugs' serotonergic, but not its dopaminergic mechanism of action.previously also found this absence of effects of methylphenidate on verbal memory. Sleep deprived subjects, which were administered 20 mg of methylphenidate, performed equally well compared to a sleep deprived control group on a verbal memory task. Apparently, methylphenidate does not seem to play a role in verbal memory, at least not at the dose that was used byand the present study. Thus, memory impairment, observed after administration of MDMA is likely to be caused by manipulation of the serotonergic system. The exact mechanism underlying memory impairment following acute MDMA administration is presently unknown. There are several candidate explanations, one of which is 5HT depletion. From animal studies, it is known that administration of MDMA causes two serotonin depletion phases. Single doses of MDMA diminish tryptophan hydroxylase, responsible for serotonin synthesis, and increase release of 5HT at the same time. The net result of these two processes is lowered serotonin concentrations during the first 3 to 6 h post-drug. This is the first depletion phase, also known as the acute or reversible phase. Hereafter a gradual recovery of serotonin levels takes place, followed by a second depletion phase (neurotoxic or long-term phase) 24 h to 1 week post-drug. Perhaps these fluctuations in serotonin concentrations can account for the results of the present study. That is, depleted serotonin levels may account for the impairment in memory seen 1.5 h after MDMA administration. The absence of memory impairment 25.5 h post-drug may have resulted from a normalization of 5HT levels following the first depletion phase. Still, it should be noted that tryptophan depletion has generally failed to affect working memory as measured in immediate word recall tasks.What seems typical however to MDMA induced memory deficits is a reduction in both immediate and delayed word recall. This impairment pattern was shown in the present study during acute MDMA intoxication and in previous studies assessing memory in abstinent MDMA users. The qualitative differences between memory impairments observed after MDMA intoxication and tryptophan depletion raises the question whether MDMA exerts its detrimental effect on 638 Transient memory impairment after acute dose of 75 mg MDMAshowed that stimulation of postsynaptic 5HT 1a receptors in the hippocampus produced dose-related short-and long-term (recognition) memory impairment in humans. In addition, PET studies have shown a negative correlation between memory function and 5HT 1A receptor agonists binding in the hippocampus. It is also known that 5HT 1a receptors possess very high binding affinities for 5HT. Thus, an increment in 5HT release following acute MDMA administration may indirectly stimulate postsynaptic 5HT 1a receptors.have shown that 5HT 2a receptor binding was associated with memory impairment in abstinent MDMA users. It is clear from animal studies that 5HT 2 receptors mediate learning and memory processes, although it is not completely clear whether 5HT 2 receptor drugs achieve their facilitating and impairing effects through agonism, antagonism or inverse agonism. Still, there appears to be some consensus that 5HT 2A/2C blockade improves learning whereas 5HT 2 receptor agonists such as mCPP have been shown to decrease learning and memory in rats. The same mechanism might be responsible for the decrement in learning and delayed recall in the present experiment, as it has been previously demonstrated that MDMA possesses a moderate affinity for activating the 5HT 2A receptor. In conclusion, data from the present study showed that a single dose of MDMA causes memory impairment during intoxication. It was demonstrated that subjects recalled fewer words during immediate and delayed recall of a word-learning task while under the influence of MDMA. Yet, memory impairment was also transient and no longer present the following day.
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