This review (2023) explores the potential mechanisms behind the efficacy of MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD). The article examines recent preclinical and clinical evidence, focusing on MDMA's mnemonic (memory) effects, its impact on fear extinction and reconsolidation, and its relevance for PTSD treatment.
The application of MDMA in conjunction with psychotherapy has in recent years seen a resurgence of clinical, scientific, and public interest in the treatment of posttraumatic stress disorder (PTSD). Clinical trials have shown promising safety and efficacy, but the mechanisms underlying this treatment form remain largely unestablished. This article explores recent preclinical and clinical evidence suggesting that the treatment’s efficacy may be influenced by the mnemonic effects of MDMA. We review data on the effects of MDMA on fear extinction and fear reconsolidation and the utility of these processes for PTSD treatment. We corroborate our findings by incorporating research from cognitive psychology and psychopharmacology and offer recommendations for future research.
Sarmanlu and colleagues situate their review within a renewed clinical and scientific interest in administering MDMA alongside psychotherapy for posttraumatic stress disorder (PTSD). They frame PTSD as a disorder in which the memory of traumatic events—particularly their accessibility, vividness, emotional intensity and centrality to identity—plays a central mediating role in symptoms such as intrusions, avoidance and hyperarousal. The paper contrasts a "Basic Mechanisms View" (traumatic memories governed by general memory mechanisms) with a "Special Mechanisms View" (trauma-specific memory disruption) and argues that accumulated evidence supports the primacy of basic autobiographical memory processes in PTSD pathology. The review sets out to examine whether mnemonic effects of MDMA—specifically influences on fear extinction and fear reconsolidation—could plausibly mediate the clinical benefits observed in MDMA-assisted psychotherapy for PTSD. To do so, the authors synthesise data from preclinical and clinical studies of MDMA's effects on learning, consolidation, extinction and reconsolidation of fear- and autobiographical-type memories, and integrate findings from cognitive psychology and psychopharmacology to recommend directions for future research. The extracted text does not specify a formal search strategy, inclusion criteria, or whether this is a systematic review or a narrative synthesis.
Papers cited by this study that are also in Blossom
Baggot, M. J., Kirkpatrick, M. G., Bedi, G. et al. · Journal of Psychopharmacology (2015)
Bahji, A., Forsyth, A., Groll, D. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2020)
Barone, W., Beck, J., Mitsunaga-Whitten, M. et al. · Journal of Psychoactive Drugs (2019)
Bedi, G., Cecchi, G. A., Slezak, D. F. et al. · Neuropsychopharmacology (2014)
This paper is a narrative review that integrates findings from animal and human studies, neuropharmacology, cognitive psychology and epigenetics to assess whether MDMA's mnemonic effects could underlie its therapeutic action in PTSD. The authors state they identified four preclinical studies and two clinical studies that directly examined MDMA's effects on fear extinction and/or reconsolidation; additional relevant preclinical behavioural, neurochemical and epigenetic studies are discussed to elucidate potential mechanisms. The extraction does not report a detailed literature-search methodology, dates searched, databases, or formal inclusion/exclusion criteria. In the sections summarised, the review describes experimental paradigms used in the cited studies (for example, rodent auditory or contextual fear conditioning measuring freezing or fear‑potentiated startle (FPS); human conditioning paradigms using skin conductance response (SCR) or FPS), dosing regimens (reported doses range widely across species, e.g. 1–10 mg/kg intraperitoneal/subcutaneous in rodents and single oral doses of 100–125 mg in humans), timing of drug administration relative to conditioning/extinction/reactivation (pre- or post-reactivation, or pre-extinction), and molecular or anatomical assays reported (e.g. BDNF mRNA/protein assays, dendritic arborisation measures, DNA methylation of HPA-axis genes). The review also summarises pharmacological pre‑treatment or antagonist experiments used in the primary studies (e.g. selective serotonin reuptake blockade, 5-HT2A antagonists, glucocorticoid receptor antagonists) that inferred contributions of serotonergic, noradrenergic, dopaminergic and HPA-axis systems. Where studies included human participants, the authors describe procedural details provided by those studies: healthy volunteers underwent fear conditioning followed by administration of MDMA or placebo and subsequent extinction and recall testing; separate clinical MDMA‑assisted psychotherapy trials provided epigenetic and qualitative data in patients with PTSD. The extracted text does not present pooled quantitative synthesis methods, risk-of-bias assessment procedures, or statistical meta-analytic models, so it appears to be a qualitative integration rather than a formal meta-analysis.
The review collates heterogeneous findings from four preclinical and two clinical studies focused on fear extinction and reconsolidation, plus ancillary studies addressing BDNF, HPA-axis markers and episodic/autobiographical memory. Preclinical findings in mice: One set of mouse experiments administered intraperitoneal MDMA at 3.0, 5.6 and 7.8 mg/kg 30 minutes before extinction training. The highest dose (7.8 mg/kg) significantly reduced conditioned freezing within-session and at 24 hours and showed persistence at a 10‑day follow-up; extinction generalised across contexts. MDMA increased BDNF mRNA expression in the basolateral amygdala (BLA) one hour post-extinction when extinction enhancement occurred, and direct infusions of MDMA into infralimbic medial prefrontal cortex or BLA enhanced extinction. Blockade of BDNF in the BLA (anti-BDNF antibody) prevented MDMA's extinction effects. A separate mouse study using multiple pharmacological pre‑treatments found that chronic citalopram (a selective serotonin reuptake inhibitor) blocked MDMA-induced reductions in conditioned freezing, and a 5-HT2A antagonist (M100) attenuated MDMA's effects; fenfluramine, noradrenergic and dopaminergic pre-treatments did not reliably block the effect. These results point to SERT and 5-HT2A involvement in MDMA-induced extinction enhancements in mice. Preclinical findings in rats: Rat experiments produced partly contrasting results. In one study, 3 and 10 mg/kg MDMA administered before auditory extinction increased freezing at the 24‑hour test (i.e. interfered with extinction), whereas MDMA given immediately after memory reactivation reduced freezing at 7 days, consistent with reconsolidation disruption. Contextual extinction effects were not observed in that protocol. Another rat programme using a predator‑scent stress model investigated four experiments: MDMA given paired with a trauma cue reduced long-term behavioural stress measures (anxiolytic effect) but only when administered in conjunction with trauma reactivation; unpaired MDMA lacked long-term benefits. The anxiolytic effects were attenuated by pre-treatment with the glucocorticoid receptor antagonist RU486, the 5-HT2A antagonist ketanserin, and the partial 5-HT1A agonist pindolol, implicating glucocorticoid and serotonergic receptors. These rat studies also reported associated neuroanatomical changes such as increased dendritic arborisation in dentate gyrus granule neurons and decreased pyramidal neurons in the BLA following MDMA paired with trauma cue. Human experimental findings: Two laboratory conditioning studies in healthy volunteers reported mixed results. One study administering 125 mg oral MDMA found enhanced extinction recall measured by SCR but no effect on FPS; there was no association between oxytocin levels and extinction recall. Another study reported no significant effect of MDMA on FPS but a greater prevalence of "extinction retainers" in the MDMA group, suggesting inter‑individual variability. Differences in paradigms (timing of conditioning and recall, strength of unconditioned stimuli) and outcome measures (SCR vs FPS) were discussed as potential causes of discrepant human findings. Memory and emotional processing in humans: Separate human studies showed that MDMA (1 mg/kg or 100 mg oral) attenuated encoding and recollection of salient emotional details while reducing negative affect during recall of worst autobiographical memories and increasing positive affect/vividness for favourite memories. Clinical qualitative data from MDMA‑assisted psychotherapy reported patients experienced greater safety and reduced avoidance when accessing traumatic memories; these reports did not indicate global amnesia for traumatic events but rather altered emotional responses. BDNF and neuroplasticity: Rodent studies measuring BDNF reported heterogenous results depending on species, dose, timing and brain region. Several rat studies observed increased BDNF expression in cortical regions (prefrontal/frontal cortex, striatum) after MDMA, while hippocampal subfields (CA1, CA3, dentate gyrus) sometimes showed decreased BDNF. In mice, an increase in BLA BDNF was reported only when MDMA was combined with extinction training. A human study measuring plasma BDNF after MDMA found no significant effect, though the authors note plasma may be a less reliable matrix than serum. Epigenetic findings: In a clinical MDMA‑assisted psychotherapy sample (MDMA n = 16, placebo n = 7), changes in DNA methylation across three HPA‑axis genes (NR3C1, FKBP5, CRHR1) were examined. Two CpG sites survived multiple-comparison correction as predictors of treatment response, and one NR3C1 site (cg01391283) showed a significantly greater methylation change in the MDMA group compared with placebo. Synthesis of the empirical pattern: Across species and paradigms, evidence points to both potential enhancement of extinction (particularly when MDMA is paired with extinction training) and to reconsolidation interference (particularly when MDMA is administered within the reconsolidation window after memory reactivation). The direction of effects depends on species, dose, timing relative to reactivation/extinction, brain region, and outcome metric. Overall, human evidence is limited and mixed, rodent data are heterogeneous and sometimes contradictory, and mechanistic studies implicate serotonergic receptors, the HPA axis and BDNF dynamics.
Sarmanlu and colleagues interpret the heterogeneous literature as supporting two plausible, not mutually exclusive, mechanisms by which MDMA‑assisted psychotherapy could reduce PTSD symptoms: enhancement of fear extinction when MDMA is combined with extinction-oriented psychotherapy, and interference with reconsolidation when MDMA is administered around memory reactivation. They underscore that extinction produces new inhibitory learning rather than erasing the original memory trace, leaving a risk of relapse, whereas reconsolidation disruption targets the original trace and might yield more durable reductions in fear expression. The authors position their synthesis within existing preclinical and clinical work: mouse studies showing BLA BDNF increases and extinction enhancement are contrasted with rat studies showing reconsolidation disruption and dependence on glucocorticoid and serotonergic receptors. Human experimental studies yield mixed outcomes depending on physiological measure (SCR versus FPS), timing of conditioning and recall, and the strength of aversive stimuli. The review highlights species differences in MDMA pharmacokinetics and stereoselective protein binding as potential explanations for divergent animal findings and cautions about direct translational inference from mice to humans. Key limitations acknowledged in the text include substantial methodological heterogeneity across studies (species, doses, timing, single versus repeated dosing, outcome measures), the small number of clinical studies directly testing extinction or reconsolidation hypotheses, and incomplete characterisation of MDMA's pharmacology in humans. The authors also note that the reconsolidation literature more broadly is in an early stage and that the specific conditions required to induce reconsolidation disruption and the precise memory components targeted remain incompletely understood. They point out that PTSD involves multi‑level biological and psychosocial changes beyond autobiographical memory and that their focus on mnemonic mechanisms does not exclude other contributors to treatment response. For future research, the authors recommend: experimental designs that explicitly test timing and dose relationships between MDMA administration and memory reactivation/extinction training; use of robust fear metrics such as FPS alongside SCR and behavioural measures; assessment of autobiographical memory characteristics pre‑ and post‑treatment using tools like the Centrality of Event Scale (CES), the Autobiographical Memory Questionnaire (AMQ) and the Memory of Experiences Questionnaire (MEQ); investigation of BDNF dynamics, HPA‑axis function and epigenetic markers (e.g. NR3C1 methylation) as potential mediators; and careful control for MDMA's broader cognitive effects (attention, working memory) which could confound mnemonic measures. The authors emphasise that clarifying whether MDMA primarily facilitates extinction, disrupts reconsolidation, or does both will require coordinated preclinical and clinical studies with harmonised protocols.
The authors conclude that accumulating evidence implicates traumatic memory accessibility and centrality in PTSD, and that MDMA‑assisted psychotherapy may exert therapeutic effects through mnemonic pathways. Current data are insufficient to favour extinction enhancement versus reconsolidation interference decisively, although several preclinical findings tilt toward reconsolidation disruption as a promising mechanism. They call for further research to elucidate MDMA's pharmacology and neurohormonal mediators (notably serotonergic signalling, BDNF and HPA‑axis function), to define the conditions under which reconsolidation can be disrupted, and to employ detailed autobiographical memory and epigenetic measures in clinical studies to link memory change to symptom outcomes.
In recent years, there has been a revitalization of scientific, clinical, and public interest in the employment of psychedelic substances adjunctive with psychotherapeutic interventions for the treatment of mental disorders. Although not conventionally regarded as a traditional psychedelic substance, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has re-emerged as a promising treatment modality for posttraumatic stress disorder (PTSD). PTSD is a trauma-and J o u r n a l P r e -p r o o f mechanisms rather than basic mechanisms that affect all types of memories. Contrary to the assumption of disrupted traumatic memory, studies support that, in most cases, traumatic memories are particularly well-remembered with pronounced vividness, emotional intensity, and sensory reliving. Traumatic experiences are distinctive, rare, emotionally intense, frequently rehearsed, and involve the release of stress hormones. These are among the mechanisms posited to contribute to enhanced encoding and consolidation of a traumatic experience into memory, which subsequently results in potentiated accessibility of the traumatic memory for both voluntary and involuntary recall. These factors contribute to the traumatic experience being perceived as a turning point in the victim's life story by profoundly changing their life course and a reference point for generating expectations for future events and interpretations of other experiences. In most cases, the traumatic experience becomes a core, emblematic component of the trauma victim's identity. Basic factors such as personality traits, gender, educational level, socioeconomic status, and more, in addition to the aforementioned mechanisms, interact in influencing the memory of a traumatic event. Traumatic memories are influenced by an interplay of factors pertaining to the traumatic event and the individual experiencing the event. These factors influence the memory of any type of experience, not just traumatic experiences. They are not inherently pathological or trauma-exclusive mechanisms that selectively impact traumatic memories, for which there is limited evidence to support. This view that memory of a traumatic experience is influenced by basic rather than trauma-special mechanisms is often denoted as the "Basic Mechanisms View" of traumatic memories. PTSD is distinct from most disorders in the DSM-5 (American Psychiatric Association, 2013) and thegiven that its aetiology is specified. Clinicians and researchers can causally presume that one or multiple traumatic experiences preceded the development of PTSD (traumatic experience → PTSD). In "The Mnemonic Model" of PTSD,introduce an extra component in this conceptualization of PTSD, which is the memory of the event and reactions to it, which change with time and situation (traumatic experience → traumatic memory → PTSD). The model presupposes that basic rather than special mechanisms account for the memory of a traumatic event. Indeed, memory mediates several key symptoms of PTSD. Arousal and distress from reminders, intrusive recollections, avoidance, and flashbacks of the traumatic event are all predicated on some form of memory representation of the traumatic experience. Some researchers have even characterized PTSD as a memory-related disorderJ o u r n a l P r e -p r o o f. The human memory is a complex system and is often conceptualized in many different and often dichotomous and independent subsystems, e.g. implicit versus explicit memory. However, it is important to stress that memory is holistic and integrative with complex and reverberating interconnections between various regions of the brain. Traumatic representations can be registered, encoded, and subsequently expressed through multiple channels, e.g. affectively, behaviourally, verbally, and symbolically. Implicit memory of the traumatic event has been documented to mediate PTSD symptoms as exemplified by findings from paediatric PTSD, i.e. in infants and toddlers without matured cognitive abilities, including the capability for explicit traumatic memory storage and recollection. Nonetheless, findings from cognitive psychology suggest that explicit memory, particularly the autobiographical memory system, exerts a significant role in PTSD. Autobiographical memories are memories of personally significant experiences from one's past. They are the foundation of one's identity, personality, self, and schemas. The autobiographical memory system is posited to begin emerging from the pre-school years (i.e. three-to-five years of age) onwards. PTSD has been proposed to reflect a disorganization of autobiographical memory and identity induced by the traumatic event. The autobiographical memory system permits the expression of personal experiences in the form of verbal recall and ensures the formation of retrievable and coherent autobiographical narratives of traumatic events. This view that PTSD reflects a disorganization of the autobiographical memory system is in accordance with multiple findings within cognitive psychology. PTSD has been associated with overgeneral retrieval of autobiographical memories, and overgeneral autobiographical memory following traumatic exposure is also predictive of subsequent PTSD development. This view is also in accordance with research into the centrality of a traumatic experience for one's identity and life story. The Centrality of Event Scale (CES) byis a tool to measure the degree to which a traumatic or stressful event is central to one's identity, a turning point in one's life story, and a reference point in one's autobiographical memory for the organization and interpretation of other memories and expectations for the future. These are common characteristics of highly accessible memories, particularly traumatic memories, and the CES is therefore a measure of the general accessibility of a traumatic memory. The CES should therefore correlate with the ease with which a traumatic memory is involuntarily recalled and voluntarily accessed. The CES and its individual components (i.e. centrality, reference point, self-definition) have been positively correlated with PTSD symptoms (e.g. intrusions, avoidance, hyperarousal) and with enhanced recollection of the J o u r n a l P r e -p r o o f traumatic event (e.g. sensorial vividness, emotional intensity, visceral reactions), even when controlling for potentially confounding variables such as comorbid disorders. These findings contradict the assumption commonly emanating from the "Special Mechanisms View" of impoverished integration of traumatic experiences into memory and differential subsequent accessibility for recall. There is an inadequate and unpersuasive empirical basis for this assumption of a relationship between impaired traumatic memory and PTSD. Indeed, the inability to recall important aspects of a traumatic experience correlates poorly with other PTSD symptoms. There is a positive correlation between the level of PTSD symptoms and the degree to which a traumatic memory is perceived as central to the trauma victim's life story and identity and serves as a cognitive reference point for other experiences. PTSD symptoms decrease when traumatic memory accessibility decreases and increase when accessibility increases. In short, PTSD symptoms correlate positively with the traumatic incident being highly accessible for recollection; central to one's identity, self, and life story; and a reference point in one's autobiographical memory. Based on these findings that the accessibility and centrality of a memory contribute to PTSD symptom severity, it is a corollary that an intervention that successfully diminishes the accessibility of the traumatic memory also targets PTSD symptomatology. Accordingly,found support for this in their review of several studies of brain injury-induced amnesia, childhood amnesia, and pharmacologically induced amnesia of the traumatic memory. These studies support that inducing amnesia, insofar as it targets traumatic memory, can abate PTSD symptom severity. These reviewed autobiographical memory alterations (i.e. overgeneralization, enhanced centrality, enhanced accessibility) all significantly relate to PTSD development and maintenance. In contrast, these alterations are less pronounced in traumatized individuals without PTSD. Collectively, these findings support the involvement of the autobiographical memory system in mediating PTSD development and maintenance. However, by emphasizing the importance of the autobiographical memory system, we do not disregard the involvement of other memory systems or non-mnemonic mechanisms in mediating PTSD symptoms. For example, incidents of PTSD in infants and toddlers without matured cognitive abilities negate that PTSD development is fully predicated upon the autobiographical memory system. These results suggest that the autobiographical memory system is influential to, but not the sole determiner of, PTSD development and maintenance. It is important to acknowledge that the biological and psychological mechanisms of memory, including learning, consolidation, and storage of information, still remain largely empirically unfolded. PTSD J o u r n a l P r e -p r o o f has been associated with alterations in multiple biological, social, psychological, and behavioural domains, including epigenetic, genetic, molecular, cellular, and brain changes. Understanding PTSD development, maintenance, and treatment, including the relationship between trauma memory and PTSD, necessitates an integrative, cross-disciplinary approach that combines knowledge from various scientific fields beyond what an exclusive focus on the autobiographical memory system can offer. To recapitulate, clinical theories of PTSD often posit that special trauma-specific mechanisms result in inadequate integration of traumatic experiences into memory and impaired voluntary recall of the event, but studies cumulatively do not support this assumption. On the contrary, traumatic memories often exhibit pronounced accessibility for both voluntary and involuntary recollection. The memory of a traumatic experience is more parsimoniously claimed to be governed by basic mechanisms that affect the memory of any other type of experience, including non-traumatic experiences. The autobiographical memory system exerts a significant influence in mediating PTSD development and maintenance following traumatic exposure. The perception of a traumatic event as central to one's identity, self, and life story; the use of the traumatic event as a reference point in one's autobiographical memory; and enhanced recollection of the traumatic memory all correlate positively with PTSD symptoms. It therefore follows that targeting the centrality and accessibility of the traumatic memory could theoretically benefit PTSD treatment.
In order to examine the effects of MDMA on traumatic memory, we first commence with an examination of the pharmacological properties of the substance. Synthesizing the empirical literature pertaining to the pharmacological properties of MDMA will augment understanding the mechanisms involved in mediating its effects on memory. In humans, studies have namely employed a pre-treatment paradigm, e.g. using serotonin transporter (SERT) or noradrenaline transporter (NET) inhibitors, to elucidate the pharmacological properties of MDMA and their associations with the psychological and physiological effects of the substance. While research has often implicated various neurochemicals and neuromodulatory systems in mediating the effects of MDMA, including cortisol and oxytocin, the effects of MDMA on serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) processes have been the principal targets of the pharmacological studies. The pharmacological properties of MDMA pertaining to the 5-HT, NE, and DA systems and their relationships with the effects of MDMA in humans will be the main focus of the following section. Generally, binding at the NET and SERT appear to account for most of the psychological and physiological effects of MDMAJ o u r n a l P r e -p r o o f. Stimulation of the α 2 -receptors and ventricular release of NE appear inconsequential to the effects of MDMA. β and α 1 receptors have been found to contribute to the cardiostimulant and thermogenic effects of MDMA. One study found a minor influence of postsynaptic 5-HT 1A receptors on the subjective effects of MDMAwhile other studies found noneusing Pindolol as pre-treatment. However, since Pindolol does not fully bind at either pre-or postsynaptic 5-HT 1A receptors, it may not have effectively blocked them. Some subjective and to a lesser extent physiological effects have been attributed to 5-HT 2A receptors. Findings suggest that SERT-mediated 5-HT release is more involved in the mood-related and subjective effects (e.g.and NET-mediated NE release is more involved in the stimulant-like and cardiovascular effects (e.g.of MDMA. Two studies reported the involvement of D 2 receptors in some subjective and mood effects using Haloperidol (i.e. a D 2 receptor antagonist) as pre-treatment. However, Haloperidol administration alone increased self-rated state anxiety and decreased scores of well-being in one of these two studies, which limits the validity of their conclusion. In one study using clinically healthy human participants, intravenous injection of 1.4 mg of Haloperidol 10 minutes before oral administration of 1.5 mg/kg MDMA failed to significantly impact the effects of MDMA on pre-pulse inhibition and startle habituation, but it did significantly reduce scores of self-reported positive mood and mania-like experience. In another study, oral administration of 60 mg immediate-release Methylphenidate, which elevates DA and NE levels by inhibition of their corresponding transporters, an hour before 125 mg MDMA administration produced the same subjective effects as MDMA alone, including self-reported measures of mood rating. It did, however, increase cardiovascular and adverse effects. These results suggest that binding at the dopamine transporter (DAT) and DA release exert a limited influence on the effects of MDMA. However, it is important to emphasize that other indirect processes may affect dopaminergic mechanisms upon administration of MDMA. For example, NE and 5-HT release through NET-and SERT-binding, respectively, and 5-HT 2 receptor activation have also been associated with MDMA-induced increased DA release in rats, independent of DAT-binding. Numerous animal studies, especially in rodents, have also explored the pharmacological properties of MDMA. While non-human translational models unarguably offer rich avenues for neurobiological research, it is also important to emphasize the notorious difficulties of inter-special translational research in MDMA (see de la Torre. For example, studies have associated MDMA with impaired pre-pulse inhibition in rodents J o u r n a l P r e -p r o o f, but with enhanced pre-pulse inhibition in humans. Therefore, translational behavioural models should be used with caution as the validity of generalizing preclinical results to humans in vivo may be limited. The pharmacological profile of MDMA in vivo and in vitro in animals and in vitro in human cells show similar trends as those outlined previously. MDMA promotes the release of the three monoamines more potently than it inhibits their reuptake. There is a clear trend towards greater release and inhibition of reuptake of 5-HT and NE than DA through binding and inverting at their corresponding transporters. In terms of receptors, studies report higher affinity for 5-HT 2B , 5-HT 1A , 5-HT 2A , and ɑ 2 receptors compared with other receptor subtypes, but binding at SERT and NET appear to account for most of the effects of MDMA. To recapitulate, findings from human studies suggest that binding at SERT and NET account for most of the effects of MDMA. Serotonergic and noradrenergic mechanisms appear more involved than dopaminergic mechanisms in mediating the effects of MDMA. Preclinical findings show similar patterns. The pharmacological profile of MDMA is still notoriously enigmatic with limited and tentative extant evidence from both human participants and non-human subjects for any definite conclusion pertaining to its pharmacological profile.
In the previous section, we discussed some of the findings pertaining to the pharmacological profile of MDMA. In the following, we expound upon empirical literature on the processes of fear extinction and fear reconsolidation before examining recent preclinical and clinical findings of the effects of MDMA on these processes. Common proposals of the underlying cognitive mechanisms of MDMA-assisted psychotherapy are effects on fear extinction and reconsolidation. During a traumatic event, inherently aversive, trauma-related stimuli may emerge concurrent with inherently nonaversive, neutral stimuli and elicit fear responses. In Pavlovian fear conditioning literature, these neutral stimuli (conditioned stimuli, CS) may subsequently inherit the ability of the trauma-related stimuli (unconditioned stimuli, US) to elicit fear responses (conditional response, CR). Learning this association is known as fear acquisition, but the subsequent storage of this association in long-term memory is called fear consolidation. Fear extinction involves exposing a conditioned subject to the fear responses-eliciting, but inherently non-aversive, conditioned stimuli in the absence of the inherently aversive, unconditioned stimuli to diminish the ability of the conditioned stimuli to elicit fear responsesJ o u r n a l P r e -p r o o f Journal Pre-proof. The result is not an alteration in the original association between the conditioned stimuli and fear responses (i.e. unlearning), but the formation of a new association (i.e. new learning) between the conditioned stimuli and the absence of fear responses. This new association takes precedence over the original association upon subsequent exposure to the conditioned stimuli. Following the consolidation of a memory, activation of the memory trace is posited to instigate a trinary sequence of processes: retrieval, labilization to maintenance or modification, and restabilization (i.e. reconsolidation) of the memory into a more solidified state. This sequence is known as reconsolidation of memory. It has been proposed that memory can be altered by modifying it during the labile state or by obstructing its reconsolidation following activation. Thus, reconsolidation and extinction differ mechanistically as extinction involves the formation of a new inhibitory memory while reconsolidation involves alterations of the original memory. Patients with PTSD often display extinction impairments. There is theoretical and clinical support that enhancing fear extinction, e.g. by prolonged exposure (PE) therapy, is beneficial for PTSD treatment. However, extinction does not affect the original fear contingencies. Relapse can therefore be common as the original fear contingencies can resurface, unlike reconsolidation interference which targets and modifies the original memory trace itself. Indeed, in some studies, pharmacologically induced post-retrieval amnesia of fear memories appear to produce more long-lasting reductions in fear memory expression than extinction. Thus, reconsolidation disruption may be more effective in some instances than enhancement of extinction. The conditions necessary for disrupting the reconsolidation of memories and the specific aspects of the memory that are targeted by reconsolidation disruption remain elusive. Extinction and reconsolidation appear contingent upon an extensive array of common and differential biological, psychological, and contextual processes(see. Fear extinction and reconsolidation both require re-exposure to stimuli triggering the recall of the fear memory. Both processes also necessitate a mismatch between the original memory and the novel experience (i.e. a violation of expectations), which is known as a prediction error. Extinction and reconsolidation are putatively mutually distinct and exclusive processes, but others have proposed that there is some interaction between the two processes.
Several studies have been conducted to examine the mnemonic effects of MDMA. Out of these studies, we identified four preclinical studiesand two clinical studiesthat examined the effects of MDMA on fear extinction and/or fear reconsolidation. In the following, we expound upon these studies before discussing their benefits for PTSD treatment within the context of MDMA-assisted psychotherapy. In, the researchers employed a translational behavioural model using mice subjects to examine the effects of MDMA on fear memory and the pharmacological mechanisms underlying these memory effects. For fear conditioning, mice were exposed to one or multiple pairings of a single tone as the conditioned stimulus (CS) and a foot shock as the aversive, unconditioned stimulus (US). Upon exposure to the conditioned stimulus (i.e. tone), fear responses were measured in the percentage of time spent freezing (i.e. the presence or absence of nonrespiratory movements) relative to the time spent in the experimental apparatuses. Mice were exposed to fear conditioning on day 1, extinction training on day 3, and extinction testing on day 4 (and day 10 for assessment of long-term effects).injected 0, 3.0, 5.6, and 7.8 mg/kg MDMA intraperitoneally into the mice 30 minutes before extinction training.found that 7.8 mg/kg significantly reduced conditioned freezing during extinction training. Mice in both the 5.6 and 7.8 mg/kg groups exhibited significantly reduced freezing at extinction testing 24 hours after extinction training. The extinction enhancements observed 24 hours after extinction training in the 7.8 mg/kg group were persistent at 10 days follow-up. The extinction effects of 7.8 mg/kg MDMA were observed when extinction testing was carried out in the same context as extinction training as well as when it was carried out in a different, novel context, reflecting generalization of extinction. 7.8 mg/kg MDMA administered immediately following extinction training did not affect freezing the following day.also examined whether the observed effects were due to interference with reconsolidation. 7.8 mg/kg MDMA administered 30 minutes before re-exposure to a single conditioned stimulus significantly reduced freezing, but the effects did not persist 24 hours later at extinction testing, indicating no effects on reconsolidation. In mice that exhibited enhanced fear extinction following MDMA in combination with extinction training, brain-derived neurotropic factor (BDNF) mRNA expression was increased in the basolateral amygdala but not in the medial prefrontal cortex one-hour post-extinction. BDNF expression was not increased in animals that did not exhibit enhanced extinction. Infusing 7.8 mg/kg MDMA directly into the infralimbic subregion of the medial prefrontal cortex or basolateral amygdala (i.e. subregions required for extinction learning) in combination with extinction training increased extinction when tested 24 hours later.J o u r n a l P r e -p r o o f found that disrupting BDNF signalling in the basolateral amygdala by injecting 0.2 µg BDNFneutralizing antibody prevented the effects of MDMA on extinction. Accordingly, studies have also shown that BDNF in the basolateral amygdala aids in the consolidation of extinction memory. MDMA administration only increased BDNF expression in the basolateral amygdala when MDMA was combined with extinction training, which could explain the inefficacy of postextinction training administration of MDMA on extinction. In conclusion,found that MDMA combined with extinction training enhanced the extinction of conditioned fear responses mediated by BDNF expression in the basolateral amygdala.hypothesized that MDMA's ability to rapidly increase NE and 5-HT levels and binding at 5-HT 2A receptors could mediate its effects on BDNF and thereby fear extinction. These pharmacodynamic hypotheses were investigated by. They examined the effects of 3.0, 5.6, and 7.8 mg/kg MDMA on fear extinction using auditory fear conditioning to measure effects on freezing behaviour as well as fear-potentiated startle (FPS). Conditioned freezing is a more stereotypic fear behaviour in rodents while FPS is a highly conserved fear behaviour across species, including in humans. For the extinction of conditioned freezing,employed a similar procedure to. Mice were exposed to cued fear conditioning on day 1, extinction training on day 3, and extinction testing on day 4. Mice were exposed to multiple tones (CS) followed by foot shocks (US) for fear conditioning. Saline or MDMA was administered 30 minutes before extinction training in these experiments. For the experiments with FPS, mice were placed in startle chambers on days 1-3 for acclimation and exposed to multiple white noise startle stimuli. On day 4, mice were given an acclimation period in the chamber followed by multiple startle stimuli and then multiple trials of an auditory tone (CS) followed by the startle stimuli. On day 5, mice underwent fear conditioning in the form of multiple CS+US pairings. FPS was assessed on day 6 by exposing mice to interspersed startle stimuli alone and CS plus startle tone pairings. On day 7, the effects of MDMA on within-session extinction of FPS were assessed by administering vehicle or MDMA 20 minutes before placing mice in the startle chamber. Extinction testing was conducted on day 8. In multiple experiments,administered selective pharmacological inhibitors of NET (Reboxetine: 0, 1, 5, and 10 mg/kg), DAT (RTI-336: 0, 3, 5, and 10 mg/kg), SERT (Citalopram: 0, 5, 10, and 20 mg/kg), or a control drug vehicle 30 minutes prior to MDMA treatment. 0, 3, 5.6, and Within-session extinction training was conducted on day 26 in which mice were treated with MDMA, and between-extinction (retention) testing occurred on day 27. 7.8 mg/kg MDMA significantly reduced freezing during extinction training and testing. Only acute pre-treatment with 10 mg/kg Citalopram significantly interfered with MDMA-induced reductions of conditioned freezing at extinction testing. Chronic injections of 10 mg/kg Citalopram blocked MDMA's reductions in freezing during training and testing but did not significantly affect conditioned freezing when administered alone without MDMA. Citalopram administered 24 hours before extinction training did not influence the effects of MDMA on freezing at extinction testing. Fenfluramine dose-dependently increased freezing at extinction training, but these effects did not persist the following day upon re-exposure to the conditioned stimuli. Mice treated with injections of 1 mg/kg of the 5-HT 2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) 48 hours prior to the last chronic dose of Citalopram exhibited significantly less DOI-induced head-twitch behaviour. This behaviour is argued to be dependent on 5-HT 2A receptors.therefore administered the selective 5-HT 2A receptor antagonist M100 30 minutes prior to MDMA treatment to evaluate the influence of 5-HT 2A receptors in MDMA-induced extinction effects. M100 inhibited the effects of MDMA at extinction training and significantly reduced the effects of MDMA on conditioned freezing 24 hours later. All three doses of MDMA administered before extinction training significantly reduced FPS at extinction training, but only 7.8 mg/kg MDMA resulted in significantly less FPS the subsequent day at extinction testing. The reductions of FPS by MDMA were obstructed by chronic Citalopram treatment. Acute treatment with Fenfluramine did not influence the effects of MDMA on fear extinction, suggesting a role outside potent 5-HT release. NET and DAT are also unlikely to be involved as Reboxetine and RTI-336 administered in combination with MDMA failed to interact with MDMA-induced enhanced fear extinction. However, it cannot be dismissed that other noradrenergic or dopaminergic mechanisms are involved in the observed effects of MDMA besides direct binding at NET and DAT.) conducted a study using rat subjects to examine the effects of MDMA on fear extinction and reconsolidation, which would evaluate the results of. Rats
Journal Pre-proof were exposed to either auditory or contextual fear conditioning followed by fear extinction training 24 hours later. Rats received either Saline, or 1, 3, 5, or 10 mg/kg MDMA 30 minutes before auditory fear extinction training and either Saline, or 3 or 5 mg/kg MDMA 30 minutes before contextual fear extinction training. Auditory or contextual fear extinction memory tests were employed 24 hours later, but an auditory fear extinction memory test was also conducted 7 days later. To examine the effects of these doses of MDMA on reconsolidation, cued fear memories were reactivated in the absence of fear extinction by either a single auditory conditioned stimulus or by reexposure to the conditioned context for three minutes immediately after reactivation or 6 hours later. Saline or MDMA was administered after either type of re-exposure. Fear memory tests were identical to the fear extinction memory tests and occurred 24 hours and 7 days after extinction training. Rats were exposed to 10 seconds of an auditory stimulus (CS) followed by a foot shock (US) and then 1-minute inter-trial-intervals for a total of 4 or 5 blocks of trials in the auditory fear experiments. In the contextual conditioning paradigm, rats were exposed to either 5 (in the contextual fear extinction experiment) or 3 (in the contextual fear reconsolidation experiment) foot shocks (US). Freezing in the contextual fear experiments was measured in minutes. In, 3 and 10 mg/kg MDMA administered during auditory fear extinction training interfered with the retrieval of fear extinction memory at testing 24 hours later by increasing freezing. 5 mg/kg MDMA almost reached similar significance. These increases in freezing ceased at extinction testing 7 days later. No effects were observed for contextual fear extinction. No effects on reconsolidation were observed 24 hours later, but 7 days later, 3 and 5 mg/kg MDMA administered immediately after reactivation yielded less freezing than the Saline group during the third trial block of the auditory fear memory test. For contextual reconsolidation, 5 mg/kg MDMA administered immediately after reactivation disrupted reconsolidation 24 hours later at the fifth and final 2-minute block. Rats that received 5 mg/kg immediately after reactivation froze less than the 3 mg/kg group during the first and third 4-minute block and less than all other groups at the second 4minute block 7 days later. Administration of MDMA 6 hours after reactivation yielded no significant differences compared to the Saline group, which suggests that MDMA affects fear responses through reconsolidation processes when administered during the reconsolidation window. 3 mg/kg MDMA did not differ at any point from Saline. Thus, the effects of MDMA on reconsolidation were more pronounced 7 days than 24 hours after reactivation. In sum, MDMA interfered with fear extinction and disrupted fear reconsolidation in certain conditions, both findings in contrast with those of.conducted four experiments to examine the bio-behavioural foundations of MDMA in a translational behavioural model of PTSD using rat subjects. In the first experiment, rats were exposed to predator scent stress (PSS) or sham-PSS. Seven days later (i.e. on day 7), 5 mg/kg J o u r n a l P r e -p r o o f MDMA or Saline was administered 30 minutes prior to exposure to a trauma cue. Seven days after this (i.e. on day 14), behaviour was assessed in the elevated plus maze and acoustic startle response tests. Based on the rats' stress responses in these tests, rats were grouped into one out of three behavioural response groups, i.e. extreme, partial, and minimal behavioural responders. On day 15, rats were exposed to situational reminders, and freezing behaviour was assessed. One day later (i.e. on day 16), rats were sacrificed for morphological staining of their brains to measure the neurochemical and neuroanatomical effects of MDMA. In the second experiment,sought to investigate the effects of MDMA on reconsolidation processes. Rats were exposed to PSS, and seven days later (i.e. on day 7), MDMA or Saline was administered with or without a trauma cue. Another two groups of rats were exposed to PSS, and MDMA or Saline was then administered six days later (i.e. on day 6), a day before exposure to the situational reminder on day 7, which would evaluate the effects of MDMA on fear responses when MDMA treatment was unpaired from the traumatic reminder. Similar behavioural assessments were conducted as in experiment 1.found that MDMA paired with a trauma cue produced beneficial effects on measures of behavioural stress and decreased the severity of behavioural stress responses. These effects on stress responses are dependent on MDMA being administered in conjunction with trauma reactivation. Thus, this provides preliminary support for the anxiolytic effects of MDMA being mediated by effects on reconsolidation processes. In the third experiment,used Lewis rats who are characterized by hypoactive and hyporeactive HPA responses and exhibit greater susceptibility to experimentally induced PTSDphenotype. The pathophysiology of Lewis rats, particularly the HPA axis response to stressors, is therefore proposed to provide an efficient and practical model of the human PTSD phenotype for experimental procedures. MDMA treatment had no long-term behavioural effects, suggesting a role of glucocorticoids in mediating the beneficial effects of MDMA on stress-related behaviour. In the fourth experiment,found that the anxiolytic effects of MDMA were reduced by pre-treatment with 7.5 mg of the glucocorticoid receptor antagonist RU486, 5 mg/kg of the 5-HT 2A receptor antagonist Ketanserin, and 0.3 mg/kg of the partial 5-HT 1A receptor agonist Pindolol, but not by 3 mg/kg of the 5-HT 2C receptor antagonist SB242084. These results support the involvement of glucocorticoid, 5-HT 2A , and 5-HT 1A , but not 5-HT 2C , receptors in the anxiolytic effects of MDMA.hypothesized that the observed effects may be due to effects on reconsolidation and not extinction due to the duration of memory reactivation, age of trauma memory, and time span between reactivation and behavioural testing. The beneficial effects of MDMA paired with a trauma cue accompanied prominent increases in the dendritic arborization of granular neurons in the dentate gyrus and a decrease in pyramidal neurons in the basolateral amygdala. The absence of glucocorticoid receptor reactivity, either due to genetics using Lewis rats or due to pharmacological J o u r n a l P r e -p r o o f blockade using RU486, inhibited the anxiolytic effects of MDMA.therefore speculate that the HPA axis mediated the anxiolytic effects of MDMA. Similarly, 5-HT 1A and 5-HT 2A receptors also appeared to mediate these anxiolytic effects. Activation of these receptors can increase corticosterone concentrations, further suggesting a potential role of the HPA axis in these anxiolytic effects. According to, glucocorticoid receptor antagonists and agonists have both been shown to impair reactivated memories.therefore speculate that there may exist an inverted U-shaped dose-response relationship between corticosterone and memory processes for memory impairment, and that the increased levels of corticosterone induced by MDMA mediate its disruptive effects on memory reconsolidation. One explanation could be that this relationship is due to the enhanced inhibition of the negative cortisol feedback loop in PTSD patients which can result in increased responsiveness of the glucocorticoid receptors. Further supporting the potential involvement of the HPA axis in mediating the clinical effects of MDMA, a recent study) investigated epigenetic changes in HPA genes in response to MDMA-assisted psychotherapy for PTSD. Epigenetic alterations have been proposed to underlie neuroendocrine abnormalities in PTSD and have been proposed as risk factors for developing PTSD following trauma exposure. According to, findings from multiple studies suggest that certain epigenetic alterations on HPA axis genes may be markers or potential predictors of the treatment responses in PTSD.measured changes in DNA methylation of three HPA axis genes (i.e. NR3C1, FKBP5, and CRHR1) before and after MDMA-assisted psychotherapy in patients with PTSD. Changes in DNA methylation of these three genes have been associated with treatment responses in PTSD.found that DNA methylation changes in 37 sites of these three genes predicted treatment responses, but only one site in the NR3C1 gene (i.e. cg01391283) and one site in the CRHR1 gene (i.e. cg08276280) predicted treatment responses following false discovery rate correction. Of these two sites, only NR3C1 cg01391283 showed a significantly greater change in DNA methylation in the MDMA group (n = 16) compared with the placebo group (n = 7). The NR3C1 gene encodes for glucocorticoid receptors that are part of the HPA axis and thereby influence the regulation of stress responses. In sum,propose that MDMA-assisted psychotherapy may allow for a state of epigenetic malleability with the potential of modifying epigenetics (in this case, DNA methylation of HPA axis genes) underlying PTSD symptom reduction. Evaluating the results ofand, MDMA-assisted psychotherapy may cause epigenetic alterations underlying glucocorticoid receptor functioning. This might increase the dendritic arborization of granular neurons in the dentate gyrus and decrease pyramidal neurons in the basolateral amygdala, which affect the reconsolidation of memories. These changes in the dentate gyrus and basolateral amygdala were associated with the beneficial effects of MDMA treatment J o u r n a l P r e -p r o o f Journal Pre-proof paired with a trauma cue in. As such, an underlying mechanism of MDMAassisted psychotherapy may be its interference with the reconsolidation of traumatic memories which is mediated by epigenetic and functional alterations of the HPA axis, more specifically of glucocorticoid functioning.) did not find any effect of MDMA on fear extinction enhancement in humans, in contrast with the preclinical findings of. The prevalence of extinction retainers was significantly greater in the MDMA group than in the placebo group, suggestive of intra-individual differences between study participants mediating extinction retention.also examined the effects of 125 mg of orally administered MDMA on fear extinction in healthy human participants. Participants either received MDMA or a placebo (Mannitol) and underwent fear conditioning using skin conductance response (SCR) or FPS paradigms with aversive, auditory stimuli and an air puff to the throat, respectively. First, participants would undergo fear conditioning using either paradigm. In the following hour, participants would receive either MDMA or a placebo. Two hours following MDMA or placebo administration, the participants would undergo corresponding extinction training. Extinction testing was conducted 24 hours after the instruction and acquisition sessions (i.e. 19-20 hours after extinction training). Oxytocin release has been shown to enhance fear extinction in humans, andtherefore examined whether changes in oxytocin levels contributed to the effects of MDMA on extinction. MDMA significantly increased extinction recall measured using SCR, and the acute effects of MDMA were associated with increased extinction recall in this paradigm. No association was observed between oxytocin levels and extinction recall. No effects were observed in the FPS paradigm, in accordance with the findings of.
Journal Pre-proof Using a similar cut-off method asto identify extinction retainers versus non-retainers yielded no significant difference in the prevalence in either group.speculate that this difference could be due to them using a stronger and longer aversive, unconditioned stimulus compared with Maples-Keller et al. () and/or because of the timing of the fear acquisition and recall phases. In Maples-Keller et al. (), the fear acquisition was conducted 24 hours before and recall training 48 hours after extinction learning. In, the fear acquisition was conducted 2 hours before and recall training 24 hours after extinction learning. According to, SCR is a measure of the electrical conductance of the skin and changes as a result of emotional arousal, but it is less specific for measuring emotional valence. Additionally, PTSD symptoms are more strongly associated with deficits in extinction using FPS than SCR.also noted that the absence of effects using FPS could be due to a ceiling effect given the relatively high extinction recall rate in the placebo group and that increased sympathomimetic activation could result in increased sweating, which could interfere with accurate SCR measurements during extinction training. Furthermore, due to the proximity of the fear) also speculated that MDMA may have interfered with the consolidation of the fear acquisition due to MDMA being administered shortly after the fear conditioning. In sum, the results ofshow that MDMA enhanced fear extinction retention as measured by SCR, but not FPS.administered MDMA 30 minutes prior to re-exposure to a single conditioned stimulus, which significantly reduced freezing, but these effects did not persist 24 hours later at extinction training, which they interpreted as no effects on reconsolidation.propose that the timing of the experiment bymay not have allowed them to adequately capture the effects of MDMA on reconsolidation. In, the effects on reconsolidation were observed when MDMA was administered after memory reactivation, and although some significant effects were observed at the contextual fear memory tests 24 hours later, these effects were even more pronounced seven days later, and only seven days later were significant effects observed at the auditory fear memory tests. Similarly, the effects of MDMA on fear behaviour in Arluk et al.) also propose that inter-species differences between mice and rats could account for the discrepant responses to MDMA observed between their study and those of. Based on a review by,write that the J o u r n a l P r e -p r o o f serotonergic system appears more sensitive to MDMA in rats, and the dopaminergic system appears more sensitive to MDMA in mice. Thus, serotonergic mechanisms could explain the memorydisruptive effects observed in. Considering the limited evidence of dopaminergic mechanisms mediating the effects of MDMA in humans and the reviewed evidence suggesting a more serotonergic-and noradrenergic-dominated neuropharmacological profile in humans, one may speculate that the results with rat subjects are more generalizable to humans than those with mouse subjects. Wanexamined the stereoselective protein binding of MDMA enantiomers in human plasma, rat serum, and mouse serum. Protein bindings were similar between human plasma and rat serum, but lower in mouse serum. Stereoselectivity in protein binding was found only in mouse serum with S-MDMA being bound to a higher extent than R-MDMA (Wan. MDMA enantiomers have been shown to display different pharmacodynamics due to differences in binding affinities to receptor sites. S-MDMA has been shown to induce greater release of dopamine and serotonin, produce more stimulant-like effects, and a higher rate of elimination whereas R-MDMA is associated more with hallucinogenic properties (Wan. As such, differences in stereoselectivity and the MDMA enantiomers administered can limit the translational value of inter-species studies of MDMA, especially when translating findings from mice to humans. Earlier, it was already demonstrated that mice metabolize MDMA differently from rats. Differences in pharmacodynamic and pharmacokinetic responses to MDMA could therefore account for the differential effects on memory observed between studies of mice versus rats and humans.also write that "5-HT signaling through the 5-HT2-family receptors can decrease BDNF" in rats, and that "the increase in BDNF produced by MDMA in mice is dependent on DA".hypothesized that the discrepant findings between their study and those ofcould also be due to serotonergic mechanisms decreasing BDNF in rats, which impaired fear extinction in, and dopaminergic mechanisms increasing BDNF in mice, which enhanced fear extinction in.
BDNF has been implicated in several learning and memory processes, including fear consolidation, extinction, and reconsolidation. One studyexamined the effects of MDMA on BDNF plasma concentrations in humans but did not find significant effects. However, it has been suggested that the use of serum or whole blood to determine BDNF levels is more reliable and accurate than plasma.may therefore not have achieved valid measures of BDNF levels.
Journal Pre-proof Four studiesinvestigated the effects of MDMA on BDNF in rats, but with vastly different methodologies and regions of interest, i.e. chronic versus acute administration, timing, and the brain regions and subregions investigated. None of these studies examined BDNF levels in the basolateral amygdala, whichfound to be involved in mediating fear extinction in their experiment.injected rats with four doses of 10 mg/kg MDMA subcutaneously at 2-hour intervals between each dose and examined their brains 1, 7, and 24 hours after the last of the four doses.found a time-dependent increase in BDNF levels in several brain regions, including the prefrontal cortex, frontal cortex, striatum, and more. In terms of hippocampal subfields,found elevated BDNF levels in the CA1 region only 24 hours after administration and decreased levels in the CA3 region and dentate gyrus only 1-and 7-hours postadministration. Soleimani Asl et al. () injected rats intraperitoneally with either single doses of 10 mg/kg MDMA or 1 ml Saline in the acute group. In the chronic group, rats received 10 mg/kg MDMA or 1 ml Saline for two consecutive days per week for two months. Rats were killed 24 hours later in the acute group and one week later in the chronic group after which their hippocampi were removed for analyses. Soleimanifound that rats administered acute MDMA treatment showed a more prominent reduction of hippocampal BDNF than those who received chronic treatment.investigated the effects of intraperitoneal injection of 10 mg/kg MDMA on BDNF expression in the hippocampus and frontal cortex of rats. They found that BDNF expression in the frontal cortex was significantly increased 24 hours post-injection and further increased 48 hours post-injection, but expression returned to control levels after seven days. BDNF expression was significantly decreased in the CA1, CA3, and dentate gyrus of the hippocampus 48 hours post-injection and further decreased 7 days post-injection.reported increased BDNF levels in the frontal cortex, striatum, hippocampus, and brainstem of rats after chronic treatment with 20 mg/kg subcutaneous injections of MDMA twice daily for 10 days. Neurochemistry tests of brain samples were conducted the day after the last dose. The findings of these studies are diverging, but there is a trend towards increased BDNF expression in most of the examined brain regions, including the prefrontal cortex, frontal cortex, parietal cortex, entorhinal cortex, and striatum, and decreased expression in the CA1, CA3, and/or dentate gyrus of the hippocampus following MDMA administration. In, MDMA administration only increased BDNF expression in the basolateral amygdala of mice when combined with extinction training. In,,, administration of MDMA in rats produced induction of BDNF levels in most brain regions. These increases were observed in the absence of any training paradigm. Methodological heterogeneity between studies could therefore
Journal Pre-proof influence the effects of MDMA on BDNF and thereby potentially account for differences related to the mnemonic effects of MDMA.claimed that serotonin signalling through 5-HT 2 receptors can decrease BDNF in rats based on two studies. However,reported increased BDNF expression in rats in most of the brain regions examined except in the dentate gyrus after intraperitoneal injection of 8 mg/kg DOI (i.e. a selective 5-HT 2A/2C agonist).found that blockade of 5-HT 2A receptors using 1 mg/kg MDL-100,907 (i.e. a selective 5-HT 2A receptor antagonist) inhibited stress-induced downregulation of BDNF expression in the dentate gyrus and CA3 subfields of the hippocampus in rats. Preclinical studies of 5-HT-releasing agents injected into rats show decrements in BDNF expression being restricted to some hippocampal subfields with either no effect on or increases in BDNF expression in other brain regions. Preclinical studies using 5-HT 2A agonists such as lysergic acid diethylamide (LSD) and ayahuasca report similar findings of induction of BDNF expression in various brain regions (see. Importantly, findings from studies examining the effects of 5-HT 2A receptor activation on BDNF expression are not unequivocal. One in vitro study found that the more selective 5-HT 2A agonists LSD, DOI, and DMT did not increase the expression of BDNF transcript, and while they doubled BDNF protein levels, this increase was not statistically significant. Another study found increased hippocampal BDNF expression following 5 µg/1 µL intracerebroventricular injection of the 5-HT 2A agonist TCB-2 in rats treated with streptozotocin-induced memory deficits with suppressed BDNF expression.found increased BDNF protein levels and mRNA expression in several brain regions, including the hippocampal CA1 and CA3 subfields, in rats following 3 mg/kg intraperitoneal injection of DOI (i.e. a 5-HT 2A receptor agonist). They also found decreased levels and expression following 5 mg/kg intraperitoneal injection of Ketanserin (i.e. a 5-HT 2A receptor antagonist). As such, whilefound DOI to upregulate BDNF expression in cortical regions and downregulate expression in the hippocampus,found DOI to increase BDNF expression in all the examined brain regions.speculate these differences can be due to methodological differences related to the used stress paradigms, the brain regions examined, and/or the technique to determine BDNF levels and expression. In sum, the available data is equivocal but suggests that agonistic activation of 5-HT 2A receptors and 5-HT-releasing agents increase cortical BDNF expression and either have no effect on or decreases hippocampal BDNF expression.postulate that 5-HT signalling through the 5-HT 2 -family receptors can decrease BDNF based on the results of, but neithernor other studies using 5-HT 2A agonists or 5-HT-releasing agents support their claim. Rather, these J o u r n a l P r e -p r o o f studies exhibit a trend in the opposite direction (i.e. increased BDNF expression in most regions except for the hippocampus). Interestingly,, whose findings pertaining to fear extinctionsought to evaluate, wrote that MDMA binds directly to 5-HT 2A receptors that have been observed to increase BDNF signalling, based on the results of. As such, the hypothesis oflikely stems from a misinterpretation ofand contradicts findings from most studies in that field.also claim that the increase in BDNF produced by MDMA in mice is dependent on DA, based on the results of.reported increased BDNF expression in multiple brain regions, albeit not in the hippocampus, following subcutaneous injection of 10 mg/kg MDMA. However, they only examined the influence of dopaminergic mechanisms on BDNF expression in the nucleus accumbens. Using subcutaneous injections of 0.1 mg/kg of the D 1 antagonist SCH23390 and 2 mg/kg of the D 2 antagonist Raclopride as pre-treatments,found that D 1 and D 2 receptors mediate MDMA-induced decrements in BDNF expression in the nucleus accumbens of mice. Thus,only found that DA is involved in BDNF expression in a single brain region in mice, which contrasts with the wider claim of. In sum, the differential effects of MDMA on BDNF expression do not provide a compelling explanation for the diverging results of studies with mice versus rats. The impetus remains to connect the reviewed preclinical data on BDNF expression with the results of studies examining the effects of MDMA on memory in humans. The collated studies of the effects of MDMA on BDNF expression in rats show some mixed results, but they point towards decreased hippocampal and increased cortical BDNF expression following administration of various doses of MDMA ranging from a single 10 mg/kg injection to multiple 10-20 mg/kg injections for several days or weeks. Findings from studies of 5-HT 2A receptor agonists and 5-HT-releasing agents show similarly mixed results, but also point towards decreased hippocampal and increased cortical BDNF expression. It can be hypothesized that the effects of MDMA on BDNF are mediated by serotonergic mechanisms, but more research is needed for more definitive conclusions pertaining to the effects of MDMA on BDNF, and how these effects may relate to memory functioning in humans. The only obvious difference between the effects of MDMA on BDNF expression in mice and rats from the reviewed studies is the trend towards decreased hippocampal BDNF expression in rats and the absence of changes in hippocampal BDNF expression in mice reported by. One study found that intrahippocampal infusion of a function-blocking anti-BDNF antibody following extinction learning impaired reconsolidation. This could lend credence to a hypothesis of MDMA-induced decrements of BDNF in some hippocampal subfields resulting in impaired reconsolidation in rats. This hypothesis, however, rests upon a precipice of assumptions derived from inconsistent results from heterogeneous studies. The extant evidence J o u r n a l P r e -p r o o f currently does not allow for more than conjectures about changes in BDNF expression mediating the memory effects of MDMA. Overall, the methodological heterogeneity of studies examining the effects of MDMA on fear extinction and reconsolidation cumbers more definitive conclusions appertaining to the mnemonic effects of MDMA. Some have proposed that MDMA may act on both fear extinction and reconsolidation (e.g., but as the two processes are said to be mutually exclusive, the impetus remains to elucidate exactly how each would manifest in conjunction with each other. More definite conclusions pertaining to the involvement of fear extinction versus reconsolidation, and the mechanisms they are predicated upon, in MDMAassisted psychotherapy for the treatment of PTSD currently do not allow for more than conjectures with the available evidence. More research is needed to uncover the effects of MDMA on memory and the mechanisms mediating these effects.
To recapitulate,showed that MDMA in combination with extinction training can enhance the extinction of conditioned fear in mice. The extinction enhancements persisted over multiple days and generalized to a novel context, and these enhancements were hypothesized to be mediated by MDMA affecting serotonergic mechanisms that increase BDNF in the basolateral amygdala.found that MDMA interfered with fear extinction in rats. Bothandfound that MDMA reduced fear responses when administered in conjunction with fear memory reactivation, suggesting interference with fear memory reconsolidation as the mediating mechanism. This disruption of reconsolidation is hypothesized to be due to MDMA decreasing BDNF via serotonergic mechanisms according toor by the influence of MDMA on serotonergic mechanisms and the HPA axis according to.found no significant effect of MDMA on fear extinction measured using FPS in healthy humans, although more participants in the MDMA group exhibited retained fear extinction than in the placebo group.found that MDMA enhanced fear extinction in healthy humans, but only when measured using SCR, not FPS. As previously mentioned, PTSD symptoms are more strongly associated with deficits in extinction using FPS than SCR, and while conditioned freezing is more stereotypic fear behaviour in rodents, FPS is a highly conserved fear behaviour across species, including in humans. Studies using FPS may therefore provide a more reliable measure of fear behaviour than studies using conditioned freezing and SCR. Bothandinvolved healthy human participants. As mentioned earlier, PTSD is associated with changes in various biological, psychological, social, and behavioural domains, including epigenetic, genetic, cellular, molecular, and brain changes. Fear conditioning in healthy humans may therefore not approximate the same J o u r n a l P r e -p r o o f perturbations as those observed in patients with PTSD. It cannot be ruled out that the mnemonic effects of MDMA may differ between participants with PTSD and those without due to the perturbations associated with PTSD. In contrast, rodent models can circumvent the limitations of using human participants. Rodent models of PTSD have been shown to induce core neurobiological phenotypes of PTSD. However, caution is encouraged when generalizing preclinical findings to humans as inter-species differences can yield differential results. This has, as we previously mentioned, been demonstrated before when comparing the effects of MDMA on rodents versus humans (e.g. on pre-pulse inhibition). In the preclinical studies, the timing, sequence, dosage, and frequency of MDMA administration relative to extinction training and/or fear memory reactivation were varied. In the clinical studies, only a single dose was used. The use of single doses contrasts with the clinical trials of MDMA-assisted psychotherapy in which one-to-three full doses or split doses are administered. The preclinical studies may therefore better model the dosing paradigm utilized in clinical trials of MDMA-assisted psychotherapy. Findings from two clinicaland two preclinicalstudies point towards MDMA being able to enhance fear extinction. The results ofsuggest that this effect on fear extinction may only work in combination with extinction training. MDMA administration alone may therefore not be sufficient for enhancing extinction in patients with PTSD. Instead, it may be necessary to combine it with psychotherapy to activate the fear associations and to provide corrective, adaptive information to associate conditioned stimuli with. Enhancement of extinction would unarguably be beneficial for PTSD treatment, particularly given the extinction deficits often observed in patients with PTSD. MDMA-assisted psychotherapy could therefore ameliorate extinction deficiencies in participants with PTSD. This effect could provide corrective, adaptive information for the development of novel contingencies that take precedence over the former maladaptive contingencies pertinent to the traumatic event. The results offurther suggest that these effects can persist over multiple days and generalize to other stimuli related to the conditioned stimuli, which would argue against the extinction enhancements being confined to the therapeutic sessions. Nonetheless, while extinction-based approaches undoubtedly offer rich avenues for treatment of PTSD, the obvious limitation remains of the original fear contingencies resurfacing, and the patient thereby relapsing. Extinction does not modify the original contingencies, hence the risk of impermanence of extinction. Reconsolidation, in contrast, does, and interference with the reconsolidation process presents an alternative that compensates for this limitation of extinction. We previously expounded upon the diverging findings betweenandand. Multiple possible explanations were provided for these J o u r n a l P r e -p r o o f Journal Pre-proof discrepancies.may not have allowed adequate time for detecting effects on reconsolidation. The extinction enhancements incould be due to neurobiological differences between mice and rats, including differential effects of MDMA on dopaminergic and serotonergic mechanisms and different pharmacodynamic and pharmacokinetic responses between rats and mice. Humans and rats did not display stereoselectivity in protein binding, in contrast with mice, and serotonergic and noradrenergic mechanisms appear to account for most of the effects of MDMA in humans with limited evidence of the involvement of dopaminergic mechanisms. As such, while these differences do not provide definitive conclusions regarding the involvement of fear extinction and fear reconsolidation as mediating mechanisms of MDMA-assisted psychotherapy, the results of studies using rats as subjectsmay offer more valid translational value to interpretation of effects in humans with PTSD. It is therefore possible that an underlying mechanism of MDMA-assisted psychotherapy is the ability of MDMA to interfere with the reconsolidation of traumatic memories to reduce their pathological impact on the patient. Indeed, the idea that MDMA attenuates or modifies memories of traumatic experiences is in accordance with other preclinical and clinical studies reporting impairments in learning and memory following MDMA administration. For example, multiple preclinical studies have associated various dosages of acute intraperitoneal or subcutaneous MDMA administration with deficits in spatial learning and memory, reinforcement-based learning, episodic memory performance, reference memory, and working memory. In clinical studies, findings also show transient impairments in verbal, spatial, and working memory following oral administration of 75 mg, 75 mg plus a subsequent 50 mg, and 100 mg Of the studies that focused on the effects of MDMA on emotional or fear memories, but not in the context of fear extinction or reconsolidation,examined the effects of MDMA on learning and memory in mice. Mice were assigned to groups based on the amount of MDMA they received, ranging from 0 to 10 mg/kg intraperitoneally. MDMA or Saline was given 30 minutes before a 10-minute training session in which a single auditory stimulus was paired with a foot shock, and training was followed by a post-shock test for measuring effects on short-term memory. Seven days after training, mice were returned to the training context for assessment of their contextual memory. One day after context testing, mice were placed in an alternative context for tone testing. Fear responses were measured in time spent freezing. Mice administered 10 mg/kg MDMA exhibited reduced freezing at training, reflective of short-term memory impairment.found that this impairment was not confounded by the effects of MDMA on J o u r n a l P r e -p r o o f either nociception or locomotor activity. Mice administered 3 and 10 mg/kg MDMA also exhibited reduced freezing at context and tone testing.exposed human participants to emotional images to examine the effects of 1 mg/kg MDMA on learning and memory. They found that MDMA attenuated the encoding and recollection of salient details of emotional memories, but not the overall ability to recollect the occurrence of these emotional events.examined the effects of 100 mg orally administered MDMA on the recollection of favourite and worst autobiographical memories in healthy human participants. MDMA significantly attenuated negative affect during the recollection of the participants' worst autobiographical memories. From the qualitative reports of some participants, this effect made it easier for the participants to approach their traumatic experiences and reinterpret them. Favourite memories were also experienced as more vivid, emotionally intense, and positive following MDMA administration. These findings suggest that MDMA may carry the potential to inhibit recall of certain aspects of a memory and/or modify the emotional valence of the memory trace itself. If indeed MDMA affects the reconsolidation of traumatic memories, the nature of these effects remains unestablished. Some clinical and preclinical studies of pharmacological reconsolidation disruption show patterns of alterations in the emotional characteristics of traumatic memories and fear memories, i.e. diminished negative emotional valence and reduced fear responses (see. Some studies on reconsolidation disruption have also found declarative memory of fear experiences to be intact. As such, extant findings do not support that reconsolidation disruption can affect the memory of a traumatic memory as a whole. Similarly, the available evidence also does not indicate that MDMA induces a general amnestic effect on the traumatic memory, i.e. by making all aspects of the memory more difficult to recall.found that MDMA inhibited the encoding and recall of emotional aspects of emotional memories, but MDMA did not affect memory for the occurrence of the emotional event. Carhart-Harris et al. () found that MDMA altered the recall of emotional aspects of memories. These effects, according to, are consistent with increased serotonergic functioning and with MDMA inducing a positivity bias. Accordingly, multiple studies have found that MDMA causes an affective bias as manifested in increased recognition of positive information (e.g. happy countenances) and/or decreased recognition of negative information (e.g. angry or fearful countenances) (e.g.. MDMA has also been found to increase comfort when reporting emotional autobiographical memoriesand to facilitate more direct and open communication between individuals in an emotional relationship. Additionally, MDMA has also been found to promote positive changes in mood, emotional states, attitudes, goals, and beliefs.examined the qualitative J o u r n a l P r e -p r o o f effects of MDMA-assisted psychotherapy on patients with PTSD. Some participants reported experiencing greater resilience and safety when accessing their traumatic experiences, whereas they were previously too overwhelmed and exerted avoidant behaviours. It does not appear from these findings that MDMA affected participants' ability to recall their traumatic experiences, but rather their thoughts and emotions pertaining to these experiences. In sum, findings do not support that MDMA induces a general amnestic effect. Instead, two hypotheses remain more probable. First, it can be hypothesized that MDMA via reconsolidation processes may promote a window of malleability in which adaptive information can be incorporated into the patient's traumatic memory. Although the science behind and findings related to reconsolidation updating are still tentative and at times diverging, some reconsolidation studies have shown that fear memories can be updated with corrective, adaptive information during the reconsolidation window.found that MDMA affected the experienced emotions of recalled autobiographical memories. The positivity bias might contribute to the experience of more positive emotional valence and/or decreased negative emotional valence upon MDMA consumption. In the context of PTSD, a positivity bias is useful given that a core symptom of PTSD is the experience of persistent negative emotional states and persistent inability to experience positive emotions (American Psychiatric Association, 2013). In the context of MDMA-assisted psychotherapy, it can therefore be hypothesized that MDMA allows for updating the memory of the traumatic experience during the reconsolidation process. There is limited evidence to suggest that reconsolidation updating affects declarative aspects of negative memories or that MDMA affects declarative aspects of patients' traumatic memories. As such, we hypothesize that MDMA may promote a transient window in which corrective, emotional information can be incorporated into the original traumatic memory trace. MDMA could promote the development of more positive emotions, goals, and attitudes in patients with PTSD given its serotonin-induced subjective effects, which could affect the reconstruction of emotional aspects of their traumatic experience more adaptively. Indeed, autobiographical memories are constructive, and memory recall is influenced by the current attitudes, goals, and concerns of the individual. One mechanism through which MDMA may modify the emotional characteristics of memories through reconsolidation is by targeting fear contingencies. A positivity bias could manifest in diminished negative emotional valence (e.g. fear and anxiety) and/or increased positive emotional valence (e.g. safety, empathy, perceived self-resilience). Recalling a traumatic memory without being overwhelmed by fear and anxiety responses could provide a sufficient mismatch between expected and actual expectations (i.e. a prediction error). Somehave proposed prediction error to be a necessary (but not sufficient) condition for successful reconsolidation interference. Thus, MDMA may affect the emotional characteristics of traumatic J o u r n a l P r e -p r o o f memories by modifying the fear contingencies associated with the traumatic memories to incorporate more adaptive information. This would be in accordance with studies of reconsolidation disruption that have found decreased expression of fear responses to conditioned stimuli, reflective of decreased negative emotional valence attributed to the conditioned (and related) stimuli. Another hypothesis is that MDMA interferes with the reconsolidation of traumatic memory by temporarily or permanently impairing memory of emotionally salient aspects of the traumatic experience. As such, instead of updating the memory with corrective information, MDMA may diminish the ability to recall emotional of the traumatic event, i. The emotional information that could be targeted also remains to be uncovered. Obstructing recall of emotional information is also in accordance with studies of pharmacological reconsolidation disruption in which recollection of emotional aspects of memories is impaired. The result would be a decrease in fear responses upon subsequent exposure to trauma-related stimuli and/or recall of the traumatic memory. In addition to the emotional positivity bias, MDMA has also been found to increase prosocial attitudes, speech, and behaviours, including mutual trust with the therapist, cooperation, openness, closeness to others, emotional empathy, and direct and open communication (e.g.. Patients have also reported reduced fear responses and greater experience of safety when engaging with their traumatic experience and less avoidant behaviours during their sessions with MDMA. Given that PTSD is characterized by interpersonal difficulties, hypervigilance, hyperarousal, and avoidant behaviours (American Psychiatric Association, 2013), these aforementioned effects could bolster the patient's ability to engage with their traumatic experience without being emotionally overwhelmed and without applying avoidant coping mechanisms. These effects would unarguably be conducive to efforts of fear extinction and/or reconsolidation interference by bolstering the patient's ability to engage with their traumatic experience.
Taken together, studies have reported that MDMA enhances fear extinction and/or disrupts fear reconsolidation. Hypotheses about the processes that mediate the effects of MDMA on either of these two mechanisms are currently limited or conjectural. Whether one or both of these processes are involved in mediating the efficacy of MDMA-assisted psychotherapy for the treatment of PTSD remains undetermined. MDMA may allow for enhanced extinction of fear conditioning pertaining to the traumatic event. It could also be hypothesized that MDMA may allow for a state in which a participant's traumatic memory can be modified with more adaptive information or that MDMA may diminish recollection of emotional aspects of a traumatic memory. Emotional aspects of traumatic memories are often remembered more frequently and are the most easily recalled, contribute to the severity of PTSD symptoms, and contribute to the consolidation and accessibility of traumatic memories. These effects could potentiate the centrality and importance of the traumatic memory for the trauma victim. Extinguishing fear contingencies, adaptive modification of emotional aspects of the traumatic memory, and/or obstructing recall of emotional aspects of the traumatic memory could diminish the centrality of the traumatic event for the patient's identity, self, and life story and diminish the accessibility of aspects of the traumatic memory for recollection. These effects would all be viabilities for PTSD treatment.
An accumulating number of studies within cognitive psychology have substantiated the important role of the traumatic memory in mediating PTSD development and maintenance. In particular, enhanced traumatic memory accessibility for recall and centrality to identity and life story correlate positively with PTSD symptomatology. Recent years have seen a resurgence of the clinical augmentation of MDMA to psychotherapeutic interventions for PTSD. The clinical efficacy of this treatment method has been underpinned in multiple trials, but the mechanisms mediating its efficacy remain largely unknown. Some hypothesized mechanisms include MDMA enhancing fear extinction and/or interfering with the reconsolidation of traumatic memories. We explored these hypotheses in this article. It could be hypothesized that MDMA in conjunction with psychotherapy enhance the extinction of conditioned fear. Another hypothesis is that MDMA in conjunction with psychotherapy interfere with the reconsolidation of traumatic memory. This would allow for adaptive modification and/or diminished recollection of emotional aspects of the traumatic memory. Overall, the extant evidence does not allow fully discrediting one of these two proposed mechanisms over the other, but some preclinical findings favour interference with reconsolidation as a mediating mechanism. Future research is needed to uncover the effects of MDMA on memory, and how these effects could mediate the treatment efficacy of MDMA-assisted psychotherapy. Further, the biological underpinnings and the pharmacological profile of MDMA mediating these potential mnemonic effects J o u r n a l P r e -p r o o f Journal Pre-proof remain to be elucidated. Some have proposed several mechanisms that could mediate the influence of MDMA on memory, including the 5-HT system, BDNF, and the HPA axis, but the involvement of these mechanisms needs to be fully evaluated. The pharmacological profile of MDMA is still largely enigmatic with only tentative evidence, and more research is encouraged to uncover its pharmacology and the biological and psychological processes that MDMA instigates. Furthermore, research on the reconsolidation of memories is still in its incipiency. The conditions necessary to induce reconsolidation disruption, and the aspects of a memory that are targeted by such disruption, are still not fully understood nor elucidated. PTSD has been associated with an extensive array of changes, including epigenetic, genetic, cellular, molecular, and brain changes, that have not been fully accounted for in this article. Instead, this article focuses primarily on the cognitive (i.e. autobiographical memory-related) aspects of PTSD. Accordingly, this article primarily examined the neurohormonal and monoamine effects of MDMA in relation to its mnemonic effects. It cannot be ruled out that other processes such as molecular or neuroanatomical changes can also be implicated in its mnemonic effects. We also do not exclude the possibility that the treatment efficacy of MDMA-assisted psychotherapy is mediated by other mechanisms that are not related to the mnemonic effects of MDMA or that other memory systems, besides the autobiographical memory system, could be implicated. If one mechanism of action behind MDMA-assisted psychotherapy is disrupted reconsolidation of traumatic memories, future research is needed to explicate the influence of this effect on traumatic memories. The CES can be used to correlate changes in PTSD symptomatology to changes in the perceived centrality of the traumatic event in the patient's life story and identity. Autobiographical memory measures could be used to assess pre-and post-treatment changes in the patient's traumatic memories. One such measure is the Autobiographical Memory Questionnaire (AMQ), which measures various components of autobiographical memories, including emotional, narrative, and sensory qualities, availability for recall, and specificity. Another measure is the Memory of Experiences Questionnaire (MEQ), which measures ten phenomenological properties of autobiographical memories, including vividness, accessibility, emotional intensity, and sensory details. These tests could aid in understanding how MDMA-assisted psychotherapy affects core components of the patient's traumatic memories. It can also be necessary to measure pre-and post-treatment changes in non-traumatic, autobiographical memories to assess how MDMA affects memory functioning in general. MDMA has also been associated with impairments in various forms of attention (de laand verbal, spatial, and working memory(see, for a review of preclinical findings of the J o u r n a l P r e -p r o o f cognitive effects of MDMA). Prospective autobiographical memory research on MDMA-assisted psychotherapy should involve controlling the potentially confounding impact of these deficits.
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