The Neurological Mechanisms of MDMA-Assisted Psychotherapy
By Yana Lazarova-Weng
In 2017, MDMA-assisted psychotherapy for the treatment of Post-Traumatic Stress Disorder (PTSD) was given breakthrough therapy designation by the Food and Drug Administration. This status is meant to expedite the process of drug development and review for drugs intended to treat serious or life-threatening conditions. While clinical trials have repeatedly shown that MDMA-assisted psychotherapy leads to a significant reduction in symptomatology and/or remission in patients with PTSD, not many studies have explored the neural mechanisms underlying the process of this therapy (MAPS, 2019). This article will present recent evidence for an MDMA-induced alteration of the memory reconsolidation process as a potential neural mechanism of MDMA-assisted psychotherapy.
MDMA is an empathogen - a specific class of psychoactive drugs that when ingested, produce feelings of empathy, sympathy, connection, and social acceptance (Meyer, 2013). These subjective effects can be attributed to MDMA-driven alterations to the brain’s neurochemistry, specifically, an increase in serotonin (5-HT) and dopamine (DA) levels (Meyer, 2013). The main function of 5-HT in MDMA-assisted psychotherapy is mood regulation, and the main function of DA is the generation of prediction errors (Feduccia and Mithoefer, 2018). In combination, these neurotransmitters play a role in a special form of brain plasticity called memory reconsolidation.
Memory reconsolidation allows memories to be updated with and retain new information (Squire, 2015). In order for a memory to form, it must be transferred from the short-term memory (STM) to the long-term memory (LTM) in a process called memory consolidation (Squire, 2015). Whenever a memory is recalled, it must move from the LTM back to the STM in a process called memory recollection (Squire, 2015). When a memory is recollected, it becomes destabilized for a short period of time, meaning that the memory is vulnerable to modification (Lee et al., 2017). This is critical for learning, as it allows new information to be assessed and incorporated into the original memory (Lee et al., 2017). After recollection, the updated memory is re-transferred from the STM to the LTM in a process called memory reconsolidation, essentially “solidifying” any changes that occurred to the memory during the period of recollection (Squire, 2015).
MDMA-assisted psychotherapy provides a way to take advantage of the labile nature of recollected memories in a way that decreases the intensity of the negative emotions associated with the trauma memory. This process is primarily influenced by the MDMA-induced increase in DA and 5-HT and involves the generation of a prediction error (Feduccia and Mithoefer, 2018). Prediction errors, which are driven by DA, are generated when there is a difference between what is expected and what occurs (Schultz, 2016). These signals are responsible for making memories malleable during recollection (Schultz, 2016). In MDMA-assisted psychotherapy, the increase in 5-HT promotes feelings of empathy, openness, and connection which allows the patient to feel that they are in a safe and therapeutic setting (Feduccia and Mithoefer, 2018). In contrast, previous negative experiences from encountering trauma-related cues condition the patient to anticipate negative emotions, like fear and anxiety, to arise during psychotherapy (Feduccia and Mithoefer, 2018). This mismatch between expecting negative emotions and experiencing positive emotions generates a prediction error, which is important because the Emotional Processing Theory explains that fear reduction is achieved when the patient incorporates information that is incompatible with their original fear structure (Feduccia and Mithoefer, 2018). In this case, the positive effect patients experience while on MDMA is incompatible with what they expect to feel when the trauma memory arises (Rauch and Foa, 2006). Hence the MDMA-induced increase in 5-HT and DA promotes the generation of strong prediction errors, rendering the trauma memory extremely labile. This enables the brain to incorporate this new positive experience into the original trauma memory, which may reduce the intensity of negative emotions associated with the trauma memory (Feduccia and Mithoefer, 2018).
In summary, many studies have indicated that MDMA is neurologically compatible with psychotherapy for PTSD and that many patients experience a reduction of symptomatology and/or remission after only 2-3 sessions. However, there is a lack of research on the neural mechanisms underlying MDMA-assisted psychotherapy. This article proposes recent evidence for an MDMA-driven alteration of the memory reconsolidation process, which may explain the significant reduction of PTSD symptomatology observed after MDMA-assisted psychotherapy. Due to our limited understanding of this drug, it is very likely that there are numerous more mechanisms involved in this process. More research must be conducted in order to understand the mechanisms of MDMA-assisted psychotherapy. This will allow us to better understand the neurological correlates of MDMA and PTSD, which is essential for refining current therapies and developing new ones.
About the Author
Yana Lazarova-Weng is a sophomore at Harvard College concentrating in Neuroscience.
References
Aa, Feduccia, and Mithoefer Mc. “MDMA-Assisted Psychotherapy for PTSD: Are Memory Reconsolidation and Fear Extinction Underlying Mechanisms?” Progress in Neuro-Psychopharmacology & Biological Psychiatry, 8 June 2018, pubmed.ncbi.nlm.nih.gov/29524515/.
Lee, Jonathan L. C., et al. “An Update on Memory Reconsolidation Updating.” Trends in Cognitive Sciences, vol. 21, no. 7, 1 July 2017, pp. 531–545, www.cell.com/trends/cognitive-sciences/fulltext/S1364-6613(17)30078-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1364661317300785%3Fshowall%3Dtrue, 10.1016/j.tics.2017.04.006. Accessed 12 Dec. 2020.
“MDMA-Assisted Psychotherapy - MAPS.” MAPS, 2019, maps.org/research/mdma.
Meyer, Jerry. “3,4-Methylenedioxymethamphetamine (MDMA): Current Perspectives.” Substance Abuse and Rehabilitation, Nov. 2013, p. 83, www.ncbi.nlm.nih.gov/pmc/articles/PMC3931692/, 10.2147/sar.s37258.
Rauch, Sheila, and Edna Foa. “Emotional Processing Theory (EPT) and Exposure Therapy for PTSD.” Journal of Contemporary Psychotherapy, vol. 36, no. 2, June 2006, pp. 61–65, link.springer.com/article/10.1007%2Fs10879-006-9008-y, 10.1007/s10879-006-9008-y.
Schultz, Wolfram. “Dopamine Reward Prediction Error Coding.” Dialogues in Clinical Neuroscience, vol. 18, no. 1, 2016, pp. 23–32, www.ncbi.nlm.nih.gov/pmc/articles/PMC4826767/.
Squire, Larry R., et al. “Memory Consolidation.” Cold Spring Harbor Perspectives in Biology, vol. 7, no. 8, Aug. 2015, p. a021766, 10.1101/cshperspect.a021766.
Young, Matthew B., et al. “Inhibition of Serotonin Transporters Disrupts the Enhancement of Fear Memory Extinction by 3,4-Methylenedioxymethamphetamine (MDMA).” Психофармакология и биологическая нарко / Psychopharmacology and Biological Narcology, vol. 234, no. 19, 1 Oct. 2017, pp. 2883–2895, open.library.emory.edu/publications/emory:tdq5h/.
MDMA is an empathogen - a specific class of psychoactive drugs that when ingested, produce feelings of empathy, sympathy, connection, and social acceptance (Meyer, 2013). These subjective effects can be attributed to MDMA-driven alterations to the brain’s neurochemistry, specifically, an increase in serotonin (5-HT) and dopamine (DA) levels (Meyer, 2013). The main function of 5-HT in MDMA-assisted psychotherapy is mood regulation, and the main function of DA is the generation of prediction errors (Feduccia and Mithoefer, 2018). In combination, these neurotransmitters play a role in a special form of brain plasticity called memory reconsolidation.
Memory reconsolidation allows memories to be updated with and retain new information (Squire, 2015). In order for a memory to form, it must be transferred from the short-term memory (STM) to the long-term memory (LTM) in a process called memory consolidation (Squire, 2015). Whenever a memory is recalled, it must move from the LTM back to the STM in a process called memory recollection (Squire, 2015). When a memory is recollected, it becomes destabilized for a short period of time, meaning that the memory is vulnerable to modification (Lee et al., 2017). This is critical for learning, as it allows new information to be assessed and incorporated into the original memory (Lee et al., 2017). After recollection, the updated memory is re-transferred from the STM to the LTM in a process called memory reconsolidation, essentially “solidifying” any changes that occurred to the memory during the period of recollection (Squire, 2015).
MDMA-assisted psychotherapy provides a way to take advantage of the labile nature of recollected memories in a way that decreases the intensity of the negative emotions associated with the trauma memory. This process is primarily influenced by the MDMA-induced increase in DA and 5-HT and involves the generation of a prediction error (Feduccia and Mithoefer, 2018). Prediction errors, which are driven by DA, are generated when there is a difference between what is expected and what occurs (Schultz, 2016). These signals are responsible for making memories malleable during recollection (Schultz, 2016). In MDMA-assisted psychotherapy, the increase in 5-HT promotes feelings of empathy, openness, and connection which allows the patient to feel that they are in a safe and therapeutic setting (Feduccia and Mithoefer, 2018). In contrast, previous negative experiences from encountering trauma-related cues condition the patient to anticipate negative emotions, like fear and anxiety, to arise during psychotherapy (Feduccia and Mithoefer, 2018). This mismatch between expecting negative emotions and experiencing positive emotions generates a prediction error, which is important because the Emotional Processing Theory explains that fear reduction is achieved when the patient incorporates information that is incompatible with their original fear structure (Feduccia and Mithoefer, 2018). In this case, the positive effect patients experience while on MDMA is incompatible with what they expect to feel when the trauma memory arises (Rauch and Foa, 2006). Hence the MDMA-induced increase in 5-HT and DA promotes the generation of strong prediction errors, rendering the trauma memory extremely labile. This enables the brain to incorporate this new positive experience into the original trauma memory, which may reduce the intensity of negative emotions associated with the trauma memory (Feduccia and Mithoefer, 2018).
In summary, many studies have indicated that MDMA is neurologically compatible with psychotherapy for PTSD and that many patients experience a reduction of symptomatology and/or remission after only 2-3 sessions. However, there is a lack of research on the neural mechanisms underlying MDMA-assisted psychotherapy. This article proposes recent evidence for an MDMA-driven alteration of the memory reconsolidation process, which may explain the significant reduction of PTSD symptomatology observed after MDMA-assisted psychotherapy. Due to our limited understanding of this drug, it is very likely that there are numerous more mechanisms involved in this process. More research must be conducted in order to understand the mechanisms of MDMA-assisted psychotherapy. This will allow us to better understand the neurological correlates of MDMA and PTSD, which is essential for refining current therapies and developing new ones.
About the Author
Yana Lazarova-Weng is a sophomore at Harvard College concentrating in Neuroscience.
References
Aa, Feduccia, and Mithoefer Mc. “MDMA-Assisted Psychotherapy for PTSD: Are Memory Reconsolidation and Fear Extinction Underlying Mechanisms?” Progress in Neuro-Psychopharmacology & Biological Psychiatry, 8 June 2018, pubmed.ncbi.nlm.nih.gov/29524515/.
Lee, Jonathan L. C., et al. “An Update on Memory Reconsolidation Updating.” Trends in Cognitive Sciences, vol. 21, no. 7, 1 July 2017, pp. 531–545, www.cell.com/trends/cognitive-sciences/fulltext/S1364-6613(17)30078-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1364661317300785%3Fshowall%3Dtrue, 10.1016/j.tics.2017.04.006. Accessed 12 Dec. 2020.
“MDMA-Assisted Psychotherapy - MAPS.” MAPS, 2019, maps.org/research/mdma.
Meyer, Jerry. “3,4-Methylenedioxymethamphetamine (MDMA): Current Perspectives.” Substance Abuse and Rehabilitation, Nov. 2013, p. 83, www.ncbi.nlm.nih.gov/pmc/articles/PMC3931692/, 10.2147/sar.s37258.
Rauch, Sheila, and Edna Foa. “Emotional Processing Theory (EPT) and Exposure Therapy for PTSD.” Journal of Contemporary Psychotherapy, vol. 36, no. 2, June 2006, pp. 61–65, link.springer.com/article/10.1007%2Fs10879-006-9008-y, 10.1007/s10879-006-9008-y.
Schultz, Wolfram. “Dopamine Reward Prediction Error Coding.” Dialogues in Clinical Neuroscience, vol. 18, no. 1, 2016, pp. 23–32, www.ncbi.nlm.nih.gov/pmc/articles/PMC4826767/.
Squire, Larry R., et al. “Memory Consolidation.” Cold Spring Harbor Perspectives in Biology, vol. 7, no. 8, Aug. 2015, p. a021766, 10.1101/cshperspect.a021766.
Young, Matthew B., et al. “Inhibition of Serotonin Transporters Disrupts the Enhancement of Fear Memory Extinction by 3,4-Methylenedioxymethamphetamine (MDMA).” Психофармакология и биологическая нарко / Psychopharmacology and Biological Narcology, vol. 234, no. 19, 1 Oct. 2017, pp. 2883–2895, open.library.emory.edu/publications/emory:tdq5h/.
