This review (2014) examines both the negative and positive aspects of using MDMA for psychotherapy, with specific regard to its neurohormonal profile, the effects of serotonergic depletion, and neurotoxicity of repeated usage. The most critical issues are related to the release of difficult feelings and memories and the lack of control thereof due to heightened environmental sensitivity, as well as the risk that negative mood states predominating the phase of neurochemical recovery amongst certain individuals.
Introduction
MDMA has properties that may make it attractive for psychotherapy, although many of its effects are potentially problematic. These contrasting effects will be critically reviewed in order to assess whether MDMA could be safe for clinical usage. Early studies from the 1980s noted that MDMA was an entactogen, engendering feelings of love and warmth. However, negative experiences can also occur with MDMA since it is not selective in the thoughts or emotions it releases. This unpredictability in the psychological material released is similar to another serotonergic drug, LSD. Acute MDMA has powerful neurohormonal effects, increasing cortisol, oxytocin, testosterone, and other hormone levels. The release of oxytocin may facilitate psychotherapy, whereas cortisol may increase stress and be counterproductive. MDMA administration is followed by a period of neurochemical recovery, when low serotonin levels are often accompanied by lethargy and depression. Regular usage can also lead to serotonergic neurotoxicity, memory problems, and other psychobiological problems.
Discussion
Proponents of MDMA-assisted therapy state that it should only be used for reactive disorders (such as PTSD) since it can exacerbate distress in those with a prior psychiatric history. Overall, many issues need to be considered when debating the relative benefits and dangers of using MDMA for psychotherapy.
Papers cited by this study that are also in Blossom
Greer, G. R. · Journal of Psychoactive Drugs (1986)
Liechti, M. E., Gamma, A., Vollenweider, F. X. · Psychopharmacology (2001)
Papers in Blossom that reference this study
Morgan, L. · Annals of General Psychiatry (2020)
Schmid, Y., Gasser, P., Oehen, P. et al. · Journal of Psychopharmacology (2020)
The paper opens with a historical overview of MDMA's emergence as an agent considered for psychotherapy. Parrott recounts Alexander Shulgin's early reports that MDMA produced ‘‘entactogenic’’ effects—feelings of warmth, love and increased emotional openness—and how informal therapeutic uses in the 1970s–1980s prompted interest in MDMA as a drug adjunct. At the same time, recreational use expanded and, after legal prohibition in 1986, a growing empirical literature documented both positive subjective effects and a range of adverse outcomes associated with repeated use. Against this background, the paper sets out to critically review contrasting lines of evidence on MDMA’s acute psychological and neurohormonal effects, the post-use recovery period, and longer-term psychobiological consequences. Parrott aims to assess whether MDMA could plausibly be safe for clinical use in psychotherapy, emphasising questions about unpredictability of emergent material, neurochemical after-effects, possible neurotoxicity and psychiatric vulnerability in recipients.
This article is a narrative, critical review of the MDMA literature rather than a systematic review or a new empirical study. The extracted text does not provide a formal methods section, a search strategy, inclusion/exclusion criteria, or a PRISMA-style flow of sources. Instead, Parrott draws on a mix of historical case reports, early therapeutic case series, recreational-user surveys, controlled laboratory studies, neuroimaging investigations, and small clinical trials to build an argument. Sources discussed include Shulgin’s early informal therapeutic reports, controlled lab assessments of mood and neurohormonal responses, neuroimaging studies reporting serotonergic markers, prospective observational studies of recreational users, and small clinical trials of MDMA-assisted psychotherapy (for example work by Greer & Tolbert and by Mithoefer and colleagues). Where available, the review incorporates quantitative findings cited in the text, but the extraction does not present a structured appraisal of study quality or a formal meta-analytic synthesis.
Parrott synthesises evidence on several domains: immediate effects, post-use recovery, longer-term consequences, and clinical-trial observations. Immediate effects: MDMA produces broad monoaminergic activation (serotonin, dopamine, noradrenaline) and acute increases in neurohormones such as cortisol, oxytocin and testosterone. Subjectively, users commonly report positive mood states—euphoria, warmth, sociability and emotional openness—but the drug also elevates anxiety, apprehensiveness and fear-related states in some individuals. Parrott cites early therapeutic reports in which, of 29 volunteers, 18 reported positive moods while 16 reported negative moods during sessions. Acute negative reactions can include overheating, tremor, feelings of loss of control and scepticism about the authenticity of drug-induced feelings. Post-MDMA recovery: The acute MDMA experience typically lasts about 5–6 hours, after which many users enter a period of neurochemical depletion characterised by anhedonia, lethargy, irritability, insomnia and depressed mood—the so-called ‘‘midweek blues.’' Controlled laboratory and observational studies report symptoms such as reduced energy, brooding, bad dreams and, in some data, a greater burden of adverse moods among women. Appetite reductions, altered pain thresholds and increased aggression have also been observed during recovery periods. Longer-term and neurobiological findings: Several neuroimaging studies in abstinent recreational MDMA users report reductions in serotonin transporter (SERT) markers and other signs consistent with serotonergic dysfunction. Parrott summarises reviews that conclude MDMA can produce persistent serotonergic neurotoxicity in humans; he also links long-term MDMA exposure to memory deficits, impaired higher cognition, disrupted sleep, reduced immunocompetence and occupational or psychosocial difficulties. The author notes ongoing debate about confounding factors but reports that some large studies claim effects remain after controlling for many potential confounds. Clinical and vulnerability-related observations: Small therapeutic series and pilot trials have shown both potential benefits and harms. Greer & Tolbert reported clinical ‘‘abreactions’’ in 2 of 9 clients who had prior psychiatric episodes, suggesting risk of recurrence. Mithoefer and colleagues’ controlled work with PTSD embedded MDMA sessions within longer drug-free therapy; clinicians rated greater PTSD improvement for the MDMA group, but blinding was poor (19 of 20 clients correctly guessed their condition; therapists were correct in all cases). Self-report psychiatric scales (SCL-90R) showed reductions in depression over time in both MDMA and placebo groups, with somewhat larger decreases in the MDMA-treated group (examples provided: depression scores falling from 52.4 to 38.5 in the MDMA group versus 49.5 to 42.1 in placebo), while anxiety reductions were non-significant. Parrott highlights cases where MDMA-stimulated emergent material produced prolonged distress, eating/appetite problems, or required extended non-drug therapy after sessions. Risk of misuse and legal/ethical scenarios: The review raises the possibility that clinical exposure to MDMA could encourage illicit self-medication in some clients, with decreasing efficacy and increasing adverse midweek effects leading to worsening psychiatric outcomes. Parrott illustrates potential medicolegal scenarios where MDMA-assisted therapy might be implicated in subsequent aggression or harm, and he cites empirical work linking MDMA with aggressive or psychotic presentations in some users.
Parrott interprets the assembled evidence as showing that MDMA has distinctive acute effects that could conceivably facilitate psychotherapy—for example, via enhanced emotional openness and oxytocin release—but that these potential benefits are counterbalanced by a range of risks. He emphasises unpredictability: MDMA is not selective about which memories or emotions it releases, so sessions can elicit deeply distressing material and occasion clinical ‘‘abreactions’’ that may persist beyond the acute session. The author also highlights neurohormonal and physiological sequelae, and a post-use recovery period during which negative mood states predominate. Against proponents who see MDMA as a targeted tool for reactive disorders such as PTSD, Parrott stresses psychiatric vulnerability as a central concern. He reports evidence that individuals with prior psychiatric histories may be at elevated risk of harm and that recreational and repeated use is associated with cognitive deficits and markers of serotonergic dysfunction. Limited clinical-trial data are described as preliminary and confounded by unblinding and small samples; while therapist ratings in some trials show improvement, self-report outcomes and longer-term durability of gains are less clear. The author acknowledges the importance of the psychotherapeutic context, noting that most investigators embed MDMA sessions within extended drug-free therapy and that enduring change is likely to depend on psychotherapeutic processes rather than the drug alone. Parrott also identifies broader concerns: the possibility of drug-dependent learning, legal and ethical liabilities for therapists, and public misunderstanding that legal clinical use implies recreational safety. He concludes that, given the current evidence, widespread clinical adoption is inadvisable and that psychotherapy without co-drugs is generally the safer route; MDMA might provide an initial boost in selected cases, but risks and uncertainties remain substantial.
Alexander Shulgin was a crucial figure in early MDMA research. He described its subjective effects as positive and life-affirming, and suggested to therapist colleagues that it might be useful as a drugadjunct for psychotherapy. This led to informal studies into this novel "entactogenic" drug, which helped the individual get in touch with their true feelings. These therapeutic experiences were described by, and this report remains a key paper in this field. Crucially, they described both the a Professor of Psychology, Department of Psychology, Swansea University, Swansea, Wales, UK; Adjunct Professor of Psychopharmacology, Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia. Please address correspondence to Andrew C. Parrott, Department of Psychology, Swansea University, Swansea, SA2 8PP, Wales, UK; email: a.c.parrott@swansea.ac.uk positive and negative experiences of their 29 clients, who were mainly colleagues, personal friends, or informal referrals from other psychotherapists. For each session, the informed volunteer was administered an oral dose of 75-150 mg MDMA, followed by a smaller successive dose to prolong the experiential session. Some of the findings from these and subsequent therapeutic studies are noted below. In 1986, MDMA was categorized as an illegal drug, and therapeutic trials were stopped for a period of time. Around this time, MDMA was being increasingly used as a recreational drug.described the experiences of American MDMA users, who could be seen going around their college campus in joyful groups, holding hands and smiling (note: this was the "pre-rave" period). In their interviews with these early MDMA users, they reported that whereas many first-year students liked the drug, second-and third-year students tended not to, since with repeated use the beneficial effects lessened and the adverse effects increased. Solowij et al.
(1992) described a similar investigation of 100 Australian MDMA users from this early period. In the U.K., we used standardized mood assessment measures to empirically compare the subjective effects of MDMA with other recreational drugs. We found: "Polydrug users report that its mood effects to be generally intermediate between those of amphetamine and LSD, although certain of its mood consequences are more unique". Hence, in, we stated that 100% of a small sample of recreational users reported feeling happy and exhilarated, warm and friendly. The predominant impression was of a very positive drug profile although, even in those early studies, some negative consequences were apparent. Hence, five of the 20 participants inreported having had an unpleasant drug reaction, with some of these adverse reactions being quite pronounced. Subsequent research has found that MDMA is associated with various deficits in memory and higher cognition. Other drugrelated problems have included changes in sleep), reduced immunocompetence, altered pain thresholds (O'Regan & Clow 2004), depression and other forms of psychiatric distress), occupational problems, neurohormonal changes, reduced happiness and greater everyday stress. In a recent review of this literature, I debated the relationship between these functional deficits and the structural changes to the serotonergic neurotransmitter system found with MDMA. Several neuroimaging studies have found evidence for "serotonin neurotoxicity" in abstinent MDMA users, with a reduction in SERT markers for this important modulatory neurotransmitter. For many years, there has been an active debate around the meaning of these changes. In one recent review,concluded that MDMA was a persistent serotonergic neurotoxin for humans. In another review, Biezonki and Meyer (2011) similarly concluded: "Given the plethora of evidence showing the 5-HT and SERT-depleting effects of MDMA, this substance can certainly be considered 'neurotoxic' in terms of causing serotonergic dysfunction." In summary, in the past 30 years there has been a gradual accumulation of scientific evidence, showing that recreational ecstasy/MDMA can be damaging for humans. Furthermore the deficits are not an artifact of other co-factors. In a comprehensive review), I examined many potential co-factors, including the use of cannabis and other recreational drugs, and concluded that the deficits mainly reflected cumulative ecstasy/MDMA use, with other psychoactive drugs contributing to the adverse profiles. In the most comprehensive of the neuroimaging studies,similarly concluded that serotonergic deficits of recreational MDMA users remained present, after controlling for "every potential confound we could address." It is, however, important to note that the psychobiological effects of MDMA are often modulated by the environmental conditions. This may be especially pertinent here, since the key paper on MDMA and psychotherapy similarly noted that the main factor for successful therapy was a supportive environment). In the next section, I will review the immediate effects of MDMA on mood states. This will be followed by a section outlining the post-MDMA recovery period; then a discussion about the types of clinical disorder which might be suitable for drug-assisted psychotherapy; and finally, a general overview.
MDMA administration induces neurotransmitter activation across the main neural pathways, including serotonin, dopamine, noradrenaline, and others. This general neurochemical activation means that MDMA can induce a wide range of mood changes. In a medical setting,found significant mood increases in every positive mood state being assessed, including emotional excitation and sensitivity. However, negative moods were also boosted by MDMA, including apprehensiveness anxiety, and fear-of-loss of thought control. This mixture of positive and negative mood changes also occurs with recreational ecstasy/MDMA users. Again, positive moods typically predominate, as in: "I felt very much in love with everyone around"; "Imagine the best feeling you have ever had and times it by ten." . . . "Nerve endings are alive and just tingling all over the body"). However, the acute ecstasy/MDMA experience can sometimes be negative: "Out of control. Too much energy"; "Feel very hot or very cold" . . . "twitching or shaking of the leg". Some recreational users also feel skeptical about their drug-induced experiences: "Is the feeling of happiness real or is it just from a pill". This mixture of positive and negative mood changes is also evident in the psychotherapeutic situation.reported that in their overall group of 29 volunteers, 18 reported positive mood such as euphoria, while 16 reported less-desirable negative moods such as anxiety. Many psychotherapists have suggested that one of the key effects of MDMA is to stimulate the emergence Parrott MDMA and Psychotherapy of deep-seated thoughts and feelings which are normally troubling for the individual. Their emergence is stimulated by MDMA, and this negative material can then be resolved via the professional guidance of the psychotherapist). Thus, MDMA may help the client to get in touch with previously painful emotions or memories, and so facilitate their re-evaluation. However, if this is the main mode of operation for MDMAassisted psychotherapy, then it does have potential dangers. The emergent material may be distressing and difficult to cope with. If the therapists are inexperienced, the dangers of a drug-induced abreaction are obvious. Even with experienced psychotherapists, they may still occur.described two such cases. One of their participants experienced the re-emergence of previously distressing and disabling anxiety, which had first developed some years earlier. During their MDMA session, this material re-emerged, and they started feeling being overwhelmed by unwanted emotions. Furthermore, this anxiety continued for a period afterwards. Indeed, they needed an extended period of (non-drug) therapy afterwards to resolve the emergent problems. Another client developed some problems around appetite and eating following their MDMA-assisted therapy. Appetite problems and food cravings have also been noted in recreational ecstasy/MDMA users; note: serotonin is involved in appetite control and feeding behavior).
The period of mood activation induced by acute MDMA is comparatively brief, typically around 5-6 hours. Afterwards, there is a period of neurochemical depletion, when feelings of anhedonia, lethargy, anger, and depression can develop). These adverse recovery phenomena have also been noted in controlled laboratory studies.found some reports of feelings such as lack of energy, irritability, brooding, and bad dreams. They also noted a gender effect, with more adverse moods reported by women than men. In the psychotherapeutic situation,similarly noted that "All subjects reported some undesirable experiences during or after their sessions." The short-term recovery phenomena included depression, anxiety, insomnia, and appetite reductions. Recreational ecstasy/MDMA users often refer to this period as the "midweek blues," with the levels of depression even reaching clinical levels in a minority of users. Other adverse recovery effects following MDMA can include disrupted sleep, increased aggression, greater susceptibility to pain (O'Regan & Clow 2004), reduced appetite and food intake. Hence, there are numerous aspects of psychobiological well-being which would need to be monitored if MDMA were used in the therapeutic situation. Hopefully, these problems would not be too great in the therapeutic situation, since the dosage levels would be lower.
Greer and Tolbert (1986) warned against using MDMA with psychiatrically vulnerable individuals. They found clinical abreactions to MDMA in two of their nine clients with prior psychiatric episodes, and noted that: "There is an indication that MDMA may predispose people to a recurrence of previous psychological disabilities." This important limitation to the potential utility of MDMA has also been noted by one of the main proponents for MDMA-assisted psychotherapy, Rick Doblin. He has written: "MDMA assisted psychotherapy should initially be explored not in patients whose psychiatric symptoms originated with biological imbalances with possible genetic components. . . but rather in patients who need some assistance in process difficult emotions that have a deep seated component of fear and/or anxiety. Two of the main categories of patient who fit this description are people suffering from Post Traumatic Stress Disorder (PTSD), and people facing terminal illness". This important limitation to the utility of MDMA needs to be more widely acknowledged. Many of the popular articles about MDMA-assisted therapy, on television or in the press, fail to acknowledge these potential dangers. Many readers of these articles may believe that if a drug is made legally available by the government for psychotherapy, then it must be safe for personal or recreational use. This is not so, as discussed above. They may also see themselves as "self-medicating" their personal problems, in ways that many tobacco or cannabis users state that they are "self-medicating" their everyday problems. Unfortunately, this belief is also mistaken. Although many of these drugs do provide temporary relief, in the longer term, their repeated use tends to increase rather than reduce everyday stress. Hence, taking up tobacco smoking leads to more daily stress, while quitting smoking leads to reduced daily stress. In a similar way, regular ecstasy/MDMA users report more psychiatric symptoms, while quitting-ecstasy/MDMA leads to improved psychiatric functioning in the majority of recreational users.found that teenage schoolchildren who started using MDMA reported
significantly more depression one year later. In another prospective study,found that quitting ecstasy/MDMA led to significantly reduced feelings of depression 15 months later. The psychobiological reasons underlying why stimulant drug use can increase everyday distress and heighten psychiatric problems are covered more fully elsewhere. It may also be noted that these drug-induced problems can be most pronounced in those with prior psychiatric susceptibilities; see also.
There are other issues which need to be examined and debated.suggested that one session with MDMA would be sufficient to engender enduring gains. This seems very optimistic. My own belief is that any drug-related gains may last for a few weeks or months, but any enduring changes can only occur through the psychotherapeutic element. In this respect,noted that while the drug was seen as an aid for therapy, they explicitly suggested that the therapeutic element was the core element. Furthermore, any therapeutic gains will typically take a number of sessions over an extended time frame. Mithoefer et al. () empirically investigated the effects of MDMA-assisted psychotherapy, but crucially they embedded the MDMA-assisted sessions, into a longer series of drug-free sessions; hence, the majority of sessions experienced by their PTSD clients were drug-free. This is probably important, since the effects of any single session are likely to be comparatively transitory.noted that 19 of the 20 clients correctly guessed their drug condition, while the therapists were correct in all cases. The clinicians assessed each client using the post-traumatic stress disorder scale, and these therapist ratings indicted significantly better gains after MDMA than placebo. Each client also completed the Symptom Check List (SCL-90R) for psychiatric symptoms, although these findings were not described in the journal report. However, they have been provided by Rick. The ANOVA showed that there were no significant changes over time with the anxiety subscale, although both groups showed non-significant trends for reduced anxiety (the MDMA group reduced from 51.0 at baseline to 39.7 at 2 months; the placebo group reduced from 51.4 at baseline to 45.1 at 2 months). With the depression scale, there was a significant ANOVA time effect, while the ANOVA group effect was not significant. Hence, self-rated depression reduced over time in both groups, with these gains being slightly stronger in the MDMA-treated group (the MDMA group reduced from 52.4 to 38.5; the placebo group reduced from 49.5 to 42.1). Although these preliminary findings are useful, we await the full publication of the SCL-90R findings. There are other issues which need to be mentioned, although they have been debated more fully in two earlier articles. For instance, one key question is the neurochemical model thought to underlie therapeutic improvement. Another is the need for a more detailed description of the type of interactive therapy needed to embed any drug-induced experiences into enduring neurocognitive cognitive models. For instance, it is unclear how a transitory acute-MDMA experience (lasting only a few hours) can produce any long-lasting changes in internal cognitions and beliefs. Again, the interpersonal therapy aspect is crucial for any long lasting gains, rather than a transitory drug effect. Another safety issue is the effects of MDMA on the HPA axis, and the many somatic changes it causes. There is also the issue of drug-dependent learning, where information learned during a particular drug state is best recalled under that same drug state. There may also be potential legal issues if a powerful and unpredictable CNS stimulant such as MDMA were to be used for medical purposes. Two hypothetical scenarios were outlined in. The first was: A Special Air Forces soldier is discharged from the army with Post-Traumatic Stress Disorder. His therapist attempts MDMA-assisted therapy, but the drug stimulates the remergence of unpleasant war experiences. It induces feelings of aggression, which the soldier manages to control while still in the clinic. However, later that evening he violently attacks a stranger in the street. Following his arrest, the lawyer argues that this aggressive act had been triggered by the MDMA-assisted therapy session. For some empirical descriptions of aggression induced by MDMA, see the ecstasy/MDMA review article entitled "Hug Drug or Thug Drug" by. Other similar articles are listed in, including a psychiatric study by, who reported: "Psychosis with a high level of aggressiveness and violence constitutes an important 'side-effect' that surely runs counter to the expected entactogenic actions of ecstasy." The second hypothetical case from Parrott (2013b) is based around a female rape victim; this scenario is also based around the empirical evidence: After the first MDMA-assisted therapy session, the client feels much better, but the gains do not endure over time. Following a second MDMA-assisted therapy session some time later, again there is a brief period of symptomatic relief. A third session is requested, but the therapist explains that this cannot be clinically recommended, since the gains were not enduring. The client now seeks out their own illicit supplies of ecstasy/MDMA. The only time she feels good is on MDMA, and she becomes a habitual user. However, with reducing efficacy and increasing mid-week blues, her chronic anxiety,
MDMA and Psychotherapy depression, and low self-esteem steadily worsen. She is hospitalized after an unsuccessful suicide attempt. The family discovers her diary, which is given to the lawyer. In both cases the therapist is sued, along with the pharmaceutical company which provided the MDMA; see also Parrott in press). When this paper was being reviewed, one of the external reviewers made an interesting comment. The reviewer was a drug abuse counselor in San Francisco, and the following comment is included with permission: "I have seen patients with previously diagnosed depression become worse after an MDMA 'session' for another reason-it worked TOO well, acutely, made them feel great or at least 'normal,' and then the crash make them feel all the worse than before. Could it be posited that this is a risk for both exacerbated depression and drug abuse-'I want more of that.'"
MDMA is a unique type of drug with positive acute effects which led Alexander Shulgin to suggest that it might be useful for psychotherapy). However, several issues need to be addressed before MDMA can be accepted as a safe co-drug for therapy. First, acute MDMA can stimulate the release of difficult feelings and memories, which may be distressing. Second, the emergent material can be susceptible to environmental influences and this also makes the MDMA-induced experiences difficult to control. Hence, there may be clinical reactions to this powerful and unpredictable drug. There is also the issue of neurochemical recovery afterwards, when negative moods tend to predominate. This period of negative cognitions may be counter-productive, especially in psychiatrically vulnerable clients, for instance those with predispositions to anxiety, depression, or psychosis. For example, it could increase the likelihood of suicide in those individuals with strong post-recovery feelings of depression. This is linked to the particular inadvisability of psychiatrically vulnerable individuals taking stimulant or psychedelic drugs. Finally, the main advocates for MDMA-assisted therapy are psychotherapists, who suggest that the most important aspect is always the psychotherapy element, and that MDMA may simply facilitate this process. My own position is that it will always be far safer to undertake psychotherapy without using co-drugs. In selected cases MDMA might provide an initial boost, but it also has far too many potentially damaging effects for safe general usage. For enduring gains, cognitive restructuring via highquality psychotherapy should always be the main element).
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