MDMA: a compound with unique properties, potential therapeutic use, and illegal status in the US (segment 01)
MDMA: A potent compound with stimulant effects, affecting dopamine and serotonin, commonly used recreationally (Segment 03)
MDMA's distinctive effects on dopamine and serotonin promote trust, and empathy, and enhance therapy for PTSD (Segment 05)
MDMA-assisted therapy for PTSD reduces connectivity between the amygdala and insula, improving symptoms (Segment 07)
MDMA enhances social connection and reward processing, while SSRIs impede MDMA's empathogenic effects (Segment 09)
MDMA's neurotoxicity and safety concerns necessitate further research and caution in recreational use (Segment 11)
Elevated prolactin levels may influence the post-MDMA crash, warranting further research and potential interventions (Segment 13)
MDMA with therapy may be a safe and effective treatment for severe post-traumatic stress disorder. Investigate further (Segment 15)

Summary

The present episode features Dr. Andrew Huberman's discussion on methylenedioxymethamphetamine (MDMA), a psychoactive drug that is colloquially referred to as "ecstasy" or "molly". Dr. Huberman delves into the mechanisms of action of MDMA in the brain, elucidating its effects on emotional processing and the resultant short- and long-term alterations. Additionally, he sheds light on the clinical applications of MDMA in the treatment of post-traumatic stress disorder (PTSD), alcohol addiction, and other substance-use disorders. The speaker will expound upon the neuronal mechanisms underlying the mood-enhancing, empathy-boosting, motivation-increasing, socially-engaging, and threat-detection-reducing effects of MDMA, and how these effects can potentially complement talk therapy. The present discourse elucidates the ongoing controversy surrounding the plausible neurotoxic effects of MDMA, dispels prevalent misconceptions regarding the etiology and remedies for post-MDMA "crash," examines the dynamic legal milieu pertaining to the therapeutic application of MDMA, and advises against the perilous adulterants (e.g., fentanyl) that are frequently present in illicitly obtained MDMA. This topic may pique the interest of individuals with a curiosity in MDMA, neuropharmacology, the inception of emotional processing in the brain, empathy, PTSD, neuroplasticity, mental health, and psychiatry.

(01): 00:00:00 MDMA “Ecstasy”

MDMA, also known as "ecstasy," is a compound with the chemical formula methylenedioxymethamphetamine. While it shares some similarities with methamphetamine, it also possesses unique properties that set it apart from the latter. Methamphetamine is a frequently abused substance that is classified as an illicit drug. It is known to elicit rapid and substantial elevations in the neuromodulatory neurotransmitter dopamine. Methamphetamine is utilized as a prescription medication in a restricted capacity within clinical settings. MDMA and methamphetamine share a common property in that they are both capable of significantly enhancing the release of dopamine. MDMA is classified as a distinct compound from classic psychedelics such as psilocybin or LSD due to its stimulant properties and potent control over the release of serotonin. MDMA is known to primarily affect the serotonin system, leading to mystical experiences. It is important to note that MDMA differs from pure stimulants, like methamphetamine, as it acts as an empathogen by significantly increasing both dopamine and serotonin levels. MDMA has been found to potentially enhance social connectedness and empathy, not only toward others but also towards oneself. While it is commonly used as a recreational drug, recent clinical trials have shown promising results in its use as an empathogen for treating PTSD in therapeutic settings. As of 2023, the possession and sale of MDMA remains illegal in the United States [1].

Figure 01. MDMA structure [2].

References

1. MDMA (Ecstasy/Molly) DrugFacts. Available from: https://nida.nih.gov/publications/drugfacts/mdma-ecstasymolly.

2. What is MDMA? Structure. Available from: https://nida.nih.gov/publications/research-reports/mdma-ecstasy-abuse/what-mdma

(02): 00:08:18 MDMA History & Synthesis; Legality

MDMA, scientifically known as 3,4-methylenedioxymethamphetamine, is a commonly used recreational substance, especially within the demographic of young adults who engage in social gatherings. Commonly referred to as "Molly" or "Ecstasy." MDA, which is also known as 3,4-methylenedioxyamphetamine, has various aliases such as "Sally," "Sassafras," and "Sass." MDA is a psychoactive substance that possesses hallucinogenic properties, capable of inducing psychedelic effects. The chemical compound known as MDMA has garnered significant attention from researchers and scholars alike, owing to its distinctive molecular composition and notable impact on the subjective experiences of individuals. Furthermore, its fascinating past enhances its appeal. The initial synthesis of MDMA was conducted by Merck during the early 1900s. Nevertheless, this methodology has not been executed in any particular clinical context and has garnered restricted consideration in laboratory environments. The compound was subsequently rediscovered by Alexander Shulgin, a chemist who specialized in psychoactive substances and was known for his non-conformist approach. During the 1960s, Shulgin was involved in the synthesis of various compounds that exhibited a close association with MDMA, including MDA, MMDA, and MDE. Nevertheless, it is significant to mention that these pursuits did not yield any influence on his later rediscovery of MDMA. During the mid-1970s, Shulgin became aware of a unique effect produced by MDMA. Subsequently, the individual reconstructed the aforementioned material and proceeded to carry out personal experimentation on it in September 1976, as substantiated by the laboratory documentation. In the year 1977, an individual administered MDMA to Leo Zeff, who then incorporated it as an additional modality in psychotherapy and disseminated its usage to other professionals in the field. Shulgin and his research team conducted self-experimentation with MDMA to investigate its potential health benefits, as the substance was not yet classified as illegal in the United States at the time [3]

MDMA is a synthetic compound that is not naturally occurring, in contrast to Mescaline. The chemical and subjective properties of MDMA and Mescaline differ significantly. Mescaline is derived from the plant kingdom, while LSD is derived from ergot and psilocybin can be found in magic mushrooms. Within the scientific community, there exists a competitive dynamic between the two factions. One faction endeavors to substantiate the harmful effects of MDMA, thereby impeding its potential legalization. Conversely, the other faction strives to demonstrate the therapeutic benefits and minimal toxicity of MDMA, with the aim of facilitating its legalization for the treatment of PTSD [4].

Figure 02: Alexander Shulgin conducted an experiment involving MDMA [5].

References

3. Benzenhöfer, U. and T. Passie, Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin. Addiction, 2010. 105(8): p. 1355-61.

4. US could soon approve MDMA therapy — opening an era of psychedelic medicine. Available from: https://www.nature.com/articles/d41586-023-01296-3.

5. Alexander Shulgin: Chemist whose discovery of an easy way of making Ecstasy led to the rave culture of the 80s and 90s. Available from: https://www.independent.co.uk/news/obituaries/alexander-shulgin-chemist-whose-discovery-of-an-easy-way-of-making-ecstasy-led-to-the-rave-culture-of-the-80s-and-90s-9488294.html.

(03): 00:14:45 MDMA, Methamphetamine (Meth), Dopamine & Serotonin

MDMA, also known as 3,4-Methylenedioxymethamphetamine, is a potent empathogen-entactogen with stimulant effects that is commonly used for recreational purposes. The substance commonly referred to as ecstasy is obtainable in tablet formulation, while its crystal variant is recognized by the names molly or mandy [6]. The substance in question exhibits noteworthy characteristics, such as its ability to impede the reuptake of dopamine from neurons subsequent to its release, as well as its capacity to generate a net elevation in dopamine levels. This is due to the presence of the methamphetamine component. Neurons, which are specialized cells of the nervous system, release neurotransmitters at their synaptic junctions to facilitate communication between adjacent cells. Synapses refer to the small gaps that exist between neurons. Neurons release small vesicles known as synaptic vesicles. The aforementioned vesicles are known to contain either neurotransmitters or neuromodulators. Dopamine serves as a neuromodulatory agent, capable of modulating the activity of adjacent neurons through the facilitation or inhibition of their activity. The axonal bouton is located at the termination of the neuron. The axon is a crucial component of the neuron responsible for transmitting signals to other neurons. Upon reaching the axonal bouton, neurotransmitters are released via vesicular fusion at the neuron's edge, diffusing into the synapse. The neuromodulator dopamine, for instance, binds to receptors on the post-synaptic side, thereby modulating the neural activity of the receiving neuron. Depending on the degree of binding, the neuron may either increase its activity and release neurotransmitters or suppress its activity, thereby halting communication between neurons. Contrary to popular belief, MDMA does not inhibit the release of dopamine at the synapse; rather, it has been shown to have the opposite effect. The substance in question effectively impedes the reuptake of dopamine that has been released and remains unbound to its corresponding receptor. Essentially, its mechanism of action involves the inhibition of dopamine transporter. The process of dopamine reuptake inhibition results in an increased concentration of dopamine in the synaptic cleft, allowing for a greater opportunity for dopamine to bind to available receptors [7].

The second constituent of MDMA, methamphetamine, penetrates the presynaptic neuron responsible for dopamine release and disrupts the process of dopamine repackaging into vesicles. Subsequently, a surplus of dopamine accumulates within the presynaptic neuron. Upon the arrival of an electrical impulse in a neuron, a substantial quantity of dopamine is discharged, which is a characteristic feature of methamphetamine. The primary mechanism by which MDMA and methamphetamine elevate dopamine levels is through their respective pharmacological actions. It is important to note that MDMA is not a mere derivative of methamphetamine, but rather a distinct compound known as methylenedioxymethamphetamine. Additionally, MDMA possesses a unique attribute in that it not only induces significant dopamine release but also elicits a marked increase in serotonin levels. This is due to the presence of additional serotonin-releasing neurons that possess serotonin transporters, commonly referred to as "serts". These transporters function similarly to dopamine transporters. The mechanism involves the regulation of the reuptake of serotonin that has been released into the synapse and has not yet bound to the serotonin receptor on the adjacent neuron. This process facilitates the prolonged presence of serotonin in the synapse, thereby increasing the likelihood of its binding to available receptors and exerting its effects. MDMA has an additional effect on the presynaptic neuron by modulating the packaging of serotonin into the vesicle monoamine transporter for serotonin. This results in a significant accumulation of serotonin in the presynaptic terminals, leading to a substantial surge in serotonin release [8].

The neurochemical impact of MDMA is characterized by a notable elevation in serotonin levels, which has been reported to be three to eight times higher than the corresponding increase in dopamine levels. MDMA is a psychoactive substance that induces a significant surge in dopamine and serotonin levels, resulting in a range of positive effects such as mood elevation and heightened stimulation, akin to those produced by methamphetamine. Individuals who consume MDMA experience heightened excitement and positive motivation, which are attributed to the drug's release of dopamine. Similar effects are observed with other drugs such as amphetamines and cocaine. However, following the initial high, users often experience a crash characterized by feelings of depression and lethargy [9].

Figure 03: MDMA's effects on the brain [10].

References

6. MDMA. Available from: https://en.wikipedia.org/wiki/MDMA#:~:text=3%2C4%2DMethyl%E2%80%8Benedioxy,primarily%20used%20for%20recreational%20purposes.

7. Mustafa, N.S., et al., MDMA and the Brain: A Short Review on the Role of Neurotransmitters in Neurotoxicity. Basic Clin Neurosci, 2020. 11(4): p. 381-388.

8. Schenk, S. and Q. Highgate, Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse. 2021. 157(5): p. 1714-1724.

9. Wardle, M.C. and H. de Wit, MDMA alters emotional processing and facilitates positive social interaction. Psychopharmacology (Berl), 2014. 231(21): p. 4219-29.

10. What are MDMA’s effects on the brain? ; Available from: https://nida.nih.gov/publications/research-reports/mdma-ecstasy-abuse/what-are-mdmas-effects-on-brain.

(04): 00:23:30 MDMA vs Psychedelics vs Ketamine

Psilocybin and LSD are known as classic psychedelics that primarily enhance serotonin activation in the brain. These substances bear a striking resemblance to serotonin and stimulate the serotonin 5T 2A receptor, leading to profound mystical experiences. Their therapeutic potential for depression treatment has been extensively investigated.

Ketamine is an alternative compound utilized in the management of depression. Ketamine is a receptor blocker of the N-methyl-D-aspartate (NMDA) receptor. The substance in question is a dissociative anesthetic that bears resemblance to PCP (phenyl cyclohexyl piperidine), which was formerly known as "angel dust" in colloquial contexts. Ketamine is utilized in the therapeutic management of depression and is currently authorized, in contrast to psilocybin and LSD, which have been granted breakthrough status for depression research but remain illegal, similar to MDMA. Ketamine has been found to alleviate depression by inducing a state of emotional dissociation.

On the other hand, MDMA is classified as an empathogen or entactogen, which promotes feelings of affiliation and social bonding. These two compounds exhibit distinct properties from one another. MDMA is primarily classified as an empathogen with stimulant properties, and its empathogenic effects are attributed to its serotonergic component. It is not typically considered a potent psychedelic substance. MDMA exhibits notable distinctions from other substances classified as psychedelics, prompting some scholars to suggest that it may be more accurately categorized under a distinct classification. In contrast to classic psychedelics, MDMA typically does not induce visual or auditory hallucinations. Its effects are primarily mood-altering rather than mystical in nature [11].

Figure 04: MDMA vs Psychedelics Vs Ketamine

References

11. Varker, T., et al., Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin. J Psychoactive Drugs, 2021. 53(1): p. 85-95.

(05): 00:26:54 MDMA & Serotonin 1B Receptor, Subjective Feelings, Trauma

We currently possess a comprehensive understanding of the mechanisms underlying the distinctive and remarkable effects of MDMA, which are distinct from those of other psychoactive substances such as psilocybin, LSD, ketamine, and methamphetamine. The confluence of a substantial surge in dopamine and an even more pronounced surge in serotonin is responsible for inducing a state of heightened energy and pleasure in individuals, without any accompanying feelings of irritability. It appears that they aspire to attain a state of high energy. Due to a significant surge in serotonin levels, the substance elicits a sensation of emotional affection towards oneself and others, which is commonly referred to as the empathogenic aspect. Additionally, it enhances trust. The primary impact of MDMA in the context of post-traumatic stress disorder (PTSD) treatment is not curative in nature but rather serves to enhance the efficacy of psychotherapeutic interventions for PTSD. MDMA has been shown to demonstrate the potential to augment the outcomes of talk therapy in individuals diagnosed with post-traumatic stress disorder. This is achieved by activating particular neural pathways. The impact of MDMA-induced serotonin elevation appears to engage distinct receptors compared to the substantial surge in serotonin levels observed with LSD and psilocybin. Psilocybin and LSD exhibit molecular similarity to serotonin and exhibit preferential activation of the serotonin 2A receptor, resulting in enhanced interconnectivity among distinct brain regions. This leads to heightened contemplation of novel possibilities pertaining to past, present, and future events, as well as the induction of neuroplasticity, which involves the rewiring of neural connections that endure beyond the cessation of psilocybin or LSD effects [12].

MDMA has been observed to stimulate the serotonin 2A receptor, however, it appears to predominantly stimulate the serotonin 1B receptor. The activation of the serotonin 1B receptor appears to be responsible for the potent impact of MDMA on the neural pathways associated with trust and social engagement. This effect is not limited to an increased willingness to engage socially and confide in a therapist or another individual but also encompasses a profound desire to do so. Elevated levels of dopamine in the brain have been shown to enhance mood, as well as augment one's drive and inclination towards goal-directed behavior. The augmentation of serotonin activity on the serotonin 1B receptor appears to foster the development of interpersonal connections, engender trust, and facilitate meaningful discourse encompassing both positive and challenging topics [13].

Trauma is an experience that fundamentally alters the functioning of the brain in a negative manner. It is important to note that not all negative experiences from our past qualify as trauma. Rather, it is those experiences that result in maladaptive changes to our thinking patterns, emotional states, or behaviors going forward that are considered traumatic. The aforementioned factors do not effectively cater to our needs as they tend to cause significant distractions, induce anxiety, disrupt sleep patterns, and result in other maladaptive consequences that are characteristic of traumatic experiences. Under the influence of MDMA, individuals exhibit a heightened willingness to trust both their therapist and their own cognitive abilities to delve into challenging topics related to their traumatic experiences. This is likely due to the concurrent increase in dopamine and serotonin levels, which facilitate a more open and exploratory mindset. Given that trauma can often consist of multiple events and complex thought patterns, this increased trust and openness may enable individuals to reframe their relationship to the trauma and explore new possibilities for rewiring their cognitive and emotional responses [14].

Figure 05. Trauma causes changes in the brain [15].

References

12. Mitchell, J.M., et al., MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 2021. 27(6): p. 1025-1033.

13. Orejarena, M.J., et al., Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behavior. Int J Neuropsychopharmacol, 2011. 14(7): p. 927-40.

14. Oehen, P. and P. Gasser, Using an MDMA- and LSD-Group Therapy Model in Clinical Practice in Switzerland and Highlighting the Treatment of Trauma-Related Disorders. 2022. 13.

15. TAU achieves breakthrough in the treatment of post-traumatic stress disorder. Available from: https://www.aftau.org/news_item/tau-achieves-breakthrough-in-treatment-of-post-traumatic-stress-disorder/.

(06): 00:34:51 Amygdala & Threat Detection, Pro-Social Behavior, MDMA Dosages

It is possible to subject an individual who has not previously consumed MDMA to an FMRI scanner and instruct them to shut their eyes. Resting functional connectivity, also known as resting state functional connectivity, pertains to the examination of the interconnectivity of various brain regions, as well as the identification of active and inactive brain regions during periods of rest. The establishment of a baseline comprehension of MDMA's effects is crucial, as it pertains not only to the default mode network's activation in the brain during periods of inattention to external stimuli or lack of focus on specific cognitive tasks but also to its potential impact on said network. There exists a correlation between daydreaming and imagination. The phenomenon under consideration is closely linked to self-referential cognition and self-conceptualization. Specifically, when an individual is inattentive while situated in a communal setting, such as on a bus or at a dinner table, their brain enters a default mode network characterized by introspective thought. By utilizing functional magnetic resonance imaging (fMRI), it is possible to discern the degree of activation within the default mode network and identify the specific regions of the brain that exhibit heightened or diminished activity. Subsequently, administering MDMA to an individual within the (fMRI) apparatus would enable the investigation of the fluctuations in activation across distinct neural networks. One could conduct an evaluation of the alterations in the default mode network and other brain networks during the days, weeks, and years following the cessation of drug use. Neuroplasticity induces permanent alterations [16].

An alternative approach to investigating the neurological impact of MDMA involves soliciting participation from individuals in the general populace who have ingested the substance. These individuals would be invited to undergo brain imaging procedures in a laboratory setting, with the resulting data being compared to that of individuals who have never consumed MDMA. By conducting such a comparative analysis, it may be possible to glean insights into the effects of MDMA on the brain. Research indicates that MDMA is currently undergoing human trials to assess its impact on brain activity in response to stimuli such as images depicting positive or negative emotions, as well as those that evoke memories of past traumatic experiences. Additionally, research has demonstrated that the administration of MDMA to mice and octopuses elicits specific physiological responses. A study published in a reputable academic journal has shown that the administration of MDMA to octopuses results in an increased preference for social interaction with other octopuses. The study further identified the presence of a serotonin transporter in octopuses, which exhibited a significant degree of homology with the corresponding receptor in humans. All of these studies have demonstrated that MDMA therapy results in increased activation of serotonin release [17].

A recent study has identified three significant alterations in brain activation resulting from the use of MDMA. The findings suggest that the administration of MDMA may have the potential to enhance sociability in individuals by reducing their reactions to threatening stimuli and increasing their responses to positive social cues. The present study provides initial insights into the neurobiological underpinnings of the subjective effects of MDMA with respect to sociability. The study revealed that individuals under the influence of MDMA exhibit a decreased response to threatening faces, as opposed to threatening stimuli, which can be attributed to a reduction in amygdala activity. The amygdala, a component of the brain, is implicated in the detection of potential threats and is occasionally referred to as the "fear center" of the brain. The amygdala, also known as the amygdaloid complex, is implicated in a multitude of functions beyond the processing of fear. The administered dosages of MDMA in both the present study and the clinical investigation of PTSD vary between 0.75mg/kg and 1.5mg/kg of body weight. The consideration of MDMA dosages is a crucial aspect when examining the toxicity of MDMA [18].

Figure 06. Amygdala & Threat Detection [19].

References

16. Müller, F., et al., MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens. Neuropsychopharmacology, 2021. 46(3): p. 545-553.

17. Edsinger, E. and G. Dölen, A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus. Current Biology, 2018. 28(19): p. 3136-3142.e4.

18. Bedi, G., et al., Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology, 2009. 207(1): p. 73-83.

19. Alexandra Kredlow, M., et al., Prefrontal cortex, amygdala, and threat processing: implications for PTSD. Neuropsychopharmacology, 2022. 47(1): p. 247-259.

(07): 00:45:48 Interoception, MDMA & Post-Traumatic Stress Disorder (PTSD)

A prominent characteristic of post-traumatic stress disorder (PTSD) appears to be an elevated level of connectivity between the amygdala and the insula, a region of the brain. The insula is a cerebral region that holds significant importance in the realm of interoception. Interoception refers to the perception of both pure sensations and emotional states, as well as feelings of well-being and lack thereof, pertaining to bodily experiences ranging from the skin inward. While interoception is a constant process, it is possible to enhance its degree of interception. By directing your attention towards the points of contact between your body and the surface it is in contact with, such as the chair's backrest against the back of your legs, or the soles of your shoes or sandals against the floor, you can effectively induce a state of relaxation. This can be achieved by simply closing your eyes and focusing on these contact points. The nervous system is consistently detecting the contact points, however, typically they do not fall under conscious awareness unless one directs their interceptive capacity toward them. Interoception refers to the process of directing one's attention towards the internal sensations of the body, as the information conveyed through the skin and other sensory organs is not typically readily accessible without such deliberate attention. Interception refers to the perception of internal bodily sensations, such as the feeling of fullness in the gut, or emotional states like happiness, sadness, or fatigue. In contrast, exteroception pertains to the capacity and inclination to attend to stimuli outside of one's body, such as visual or auditory cues. The phenomenon under consideration pertains to the observation of various occurrences such as avian movement and other comparable incidents. Additionally, individuals are constantly engaged in a state of equilibrium, wherein the interplay between interoception and exteroception is characterized by a push-pull dynamic. The insula is a crucial brain region for interoception, as it contains a comprehensive map of the entire body surface, including internal organs. When subjected to FMRI or electrode recordings, stimulation of neurons in one end of the insula elicits sensations in the stomach, indicating a systematic mapping of interoception within the insula. The amygdala and insula exhibit direct connections, and despite being commonly regarded as a fear center or threat detection center, the amygdala is actually part of a larger network that receives input from the hippocampus, a brain region involved in memory storage [20].

Numerous studies have revealed that individuals with post-traumatic stress disorder exhibit a heightened or intensified association between the amygdala and insula, in comparison to those without the disorder. The present observations suggest an increased activation of the insula, a brain region responsible for interoception, in response to threat detection signals in individuals with PTSD. This may account for the common experience of bodily sensations, such as discomfort or pain, associated with traumatic memories in this population. The administration of MDMA in conjunction with PTSD therapy, both prior to, during, and subsequent to the drug intake, has been found to result in a reduction of connectivity between the amygdala and insula in individuals. This reduction is directly proportional to the amelioration of PTSD symptoms, which is a noteworthy observation. This is particularly significant as it is not merely the activation or deactivation of a brain network that is being observed [21].

Figure 07. FMRI image of PSTD [22].

References

20. Latimer, D., et al., MDMA to Treat PTSD in Adults. Psychopharmacol Bull, 2021. 51(3): p. 125-149.

21. Smith, K.W., et al., MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta-Analysis. J Clin Pharmacol, 2022. 62(4): p. 463-471.

22. Shin, L.M., et al., An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biological Psychiatry, 2001. 50(12): p. 932-942.

(08): 00:52:36 Long-Term Effects, Threat Detection & PTSD

Psilocybin and LSD, which are considered classic psychedelics, have been found to induce increased lateral connectivity between distinct regions of the brain, specifically the neocortex. These changes are believed to be long-lasting and may contribute to the alleviation of major depression symptoms, as well as the enhancement of creativity and other observed effects associated with psilocybin treatment. In contrast, MDMA does not appear to induce enduring enhancements in the lateral connectivity among those identical brain networks, likely due to its influence on distinct serotonin receptors. However, it appears to alter the functional connectivity at rest in limbic structures such as the amygdala and other related structures that are linked to the detection of threats. The present investigation aimed to assess the effects of acute MDMA administration on the intrinsic brain activity of healthy individuals. To achieve this objective, arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) resting state functional connectivity (rsFC) were utilized. The findings of the investigation indicate that the ingestion of MDMA was associated with an elevation in the worldwide (ASL) signal, a decrease in the BOLD signal in the left hippocampus, and a surge in (rsFC) between the left hippocampus and the right amygdala. The results of this study indicate that MDMA possesses the capacity to elicit a range of cerebral functional alterations, such as heightened global cerebral blood flow, reduced hippocampal activity, and augmented amygdala-hippocampal connectivity. Furthermore, individuals tend to experience reduced feelings of threat, increased prosocial behavior, and heightened empathy towards both themselves and others. Additionally, post-session, participants exhibit a diminished threat response to memories compared to their pre-session state, and these neurobiological changes appear to be widespread. This study mentioned above may have substantial implications for understanding the mechanisms underlying the acute effects of MDMA on behavior, cognition, and mood [23].

Figure 08. Threat Detection & PTSD [24].

References

23. Carhart-Harris, R.L., et al., The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level– Dependent Resting State Functional Connectivity. Biological Psychiatry, 2015. 78(8): p. 554-562.

24. van Rooij, S.J.H., et al., Defining focal brain stimulation targets for PTSD using neuroimaging. 2021. 38(7): p. 768-785.

(09): 00:56:14 MDMA, Social Connection & Empathy; Meth, SSRIs

The present investigation employed fMRI to examine the neural underpinnings of the prosocial and rewarding outcomes of MDMA in a sample of healthy participants. The findings indicate that the administration of MDMA was correlated with heightened activity in two brain regions, namely the nucleus accumbens (NAc) and the ventral tegmental area (VTA). These regions are respectively responsible for processing rewards and releasing dopamine, a neurotransmitter that is linked to motivation and reward. MDMA augmented the connectivity between the (NAc) and the amygdala, a cerebral area that plays a role in the processing of emotions. The results of this study indicate that MDMA has the potential to enhance prosocial and rewarding behaviors through its impact on brain regions that are responsible for regulating emotions and processing rewards. Further research is warranted to examine the enduring impact of MDMA on these cerebral areas and to ascertain the viability of MDMA as a therapeutic intervention for conditions characterized by social impairments and anomalies in reward processing. Furthermore, the investigation revealed that the administration of MDMA was linked to a reduction in hippocampal activity, a cerebral area that plays a crucial role in memory and cognitive processes. The present discovery implies that MDMA could potentially elicit detrimental impacts on cognitive abilities. It is noteworthy that the investigation was carried out on individuals who were in good health, and it is plausible that the impact of MDMA on cognitive function may vary among individuals with psychiatric conditions. In general, the outcomes of this research offer novel perspectives on the neural processes that underlie the prosocial and rewarding impacts of MDMA. These discoveries could potentially have ramifications for the advancement of novel therapies aimed at addressing conditions characterized by impairments in social interaction and malfunctioning reward systems [25].

Selective serotonin reuptake inhibitors (SSRIs) constitute a distinct class of drugs that have been shown to significantly elevate serotonin levels. Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, Prozac, and citalopram, function by inhibiting the reuptake of serotonin, resulting in elevated levels of serotonin. However, these medications are incapable of producing effects that are comparable to those of MDMA. Research has demonstrated that the administration of selective SSRIs prior to the ingestion of MDMA can impede the pro-social and empathogenic outcomes of the latter substance, as evidenced by both human and animal studies. The administration of MDMA results in an elevation of dopamine levels in specific regions of the brain, including the nucleus accumbens. This area is a component of the mesolimbic reward pathway, which is responsible for the establishment of a positive reinforcement mechanism for the ongoing experience. The conceptualization of MDMA and its impact on the brain can be understood as an empathogen that reinforces empathy and social connection. The drug's influence on neural networks is intense and powerful, resulting in their strengthening and sustained activity even after the drug's effects have dissipated [26].

Figure 09. fMRI of MDMA-treated patients [27].

References

25. Heifets, B.D., et al., Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. 2019. 11(522): p. eaaw6435.

26. Liechti, M.E., et al., Acute Psychological Effects of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) are Attenuated by the Serotonin Uptake Inhibitor Citalopram. Neuropsychopharmacology, 2000. 22(5): p. 513-521.

27. Bauernfeind, A.L., et al., Human Ecstasy Use is Associated with Increased Cortical Excitability: An fMRI Study. Neuropsychopharmacology, 2011. 36(6): p. 1127-1141.

(10): 01:07:22 Oxytocin & MDMA

The phenomenon of MDMA's impact on neurotransmitters has been studied in both animal and human literature. It has been observed that MDMA not only enhances the release of dopamine and serotonin but also significantly elevates the levels of oxytocin release. Oxytocin functions as a neuromodulator by modulating the activity of various circuits and hormones, thereby exhibiting neurohormonal properties. Hormonal effects are known to exert a widespread influence on various sites throughout the brain and body, rather than being confined to local action. The activation of neurons is linked to neural networks that facilitate pair bonding. This bonding can occur between parents and their offspring, including both biological and non-biological caretakers. Additionally, it can also occur between friends and romantic partners. It is believed that this phenomenon is also implicated in the painful process of bond dissolution that occurs when individuals are no longer present as caregivers or partners, whether due to separation, death, or departure. Empirical evidence suggests that humans exhibit a robust oxytocin response towards their canine companions, while dogs display significant oxytocin release patterns towards their respective owners. Oxytocin is purportedly implicated in the establishment and dissolution of social connections among individuals and other organisms [28].

The present research endeavors to examine the impact of MDMA and intranasal oxytocin on plasma oxytocin levels and their plausible effect on pro-social conduct. The research comprised a cohort of fourteen individuals who had a history of MDMA use and were in good health. The study was conducted over four sessions and was double-blind in design. The study administered MDMA orally at two distinct dosages (0.75 and 1.5 mg/kg), intranasal oxytocin at two varying dosages (20 IU and 40 IU), and a placebo to the participants. The investigators evaluated the levels of oxytocin in the plasma, cardiovascular reactions, and subjective experiences both pre- and post-administration of the drug. The findings of the study revealed that the administration of MDMA, particularly at the higher dosage of 1.5 mg/kg, resulted in a significant elevation of plasma oxytocin levels, with a mean peak of 83.7 pg/ml observed at around 90-120 minutes. In contrast, the administration of placebo only led to a mean peak of 18.6 pg/ml. By comparison, the administration of intranasal oxytocin at a dosage of 40 IU resulted in a significant elevation of plasma oxytocin levels to 48.0 pg/ml within a time frame of 30-60 minutes. The research study additionally discovered that the administration of MDMA exhibited a dose-dependent escalation in heart rate, blood pressure, sensations of euphoria, and sociability. Nonetheless, the administration of intranasal oxytocin did not result in any discernible cardiovascular or subjective effects. The study revealed that there was no significant correlation between plasma oxytocin levels and the subjective as well as cardiovascular responses to MDMA. However, it is important to note that the sample size for this analysis was relatively limited. The results indicate that the altruistic impacts of MDMA may not be exclusively facilitated by the discharge of oxytocin. Subsequent research endeavors that explore the impact of oxytocin antagonists on reactions to MDMA may offer additional comprehension regarding the mechanisms underlying MDMA's prosocial outcomes. The present investigation shows that the impact of acute doses of MDMA and intranasal oxytocin on plasma oxytocin concentrations in humans is distinguishable. Although the administration of MDMA leads to an increase in plasma oxytocin levels and the induction of pro-social subjective experiences, the sole administration of intranasal oxytocin does not result in comparable effects. These studies enhance our comprehension of the neurobiological processes that underlie the pro-social impacts of MDMA and offer significant perspectives for subsequent investigations in this domain [29].

Figure 10. Impact of MDMA and intranasal oxytocin [30].

References

28. Kirkpatrick, M.G., et al., Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing. Neuropsychopharmacology, 2014. 39(7): p. 1654-1663.

29. Kirkpatrick, M.G., et al., Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans. Psychoneuroendocrinology, 2014. 46: p. 23-31.

30. Quintana, D.S., et al., Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research. Molecular Psychiatry, 2021. 26(1): p. 80-91.

(11): 01:16:10 Safety & Neurotoxicity; Recreational Use, Caffeine & Fentanyl

Currently, most recreational drugs, with the exception of MDMA, are frequently tainted with fentanyl. Although fentanyl has legitimate medical applications, it is an extremely lethal substance. According to recent estimates, a significant proportion of drugs sold on the gray market, ranging from 60% to 80%, are suspected to be repackaged or reformulated with fentanyl. This has resulted in numerous fatalities associated with fentanyl use, affecting both children and adults. The procurement of MDMA is of utmost significance and the associated safety concerns cannot be disregarded. The potential neurotoxicity of MDMA has been investigated in laboratory and clinical settings through the use of pure MDMA. The neurotoxicity of methamphetamine and MDMA can be attributed to their significant elevation of dopamine levels in the case of methamphetamine and dopamine and serotonin levels in the case of MDMA. A significant surge in dopamine and serotonin levels, with a particular emphasis on the former, has been observed to stimulate the electrical activity of adjacent neurons. It is important to note that these neurotransmitters function as neuromodulators, regulating the activity of neighboring neurons. Specifically, dopamine has been found to upregulate the activity of adjacent neurons. While dopamine is not inherently neurotoxic, excessive release of dopamine can lead to neurotoxicity. It is widely recognized that even a singular administration of methamphetamine can result in neurotoxicity not only for dopamine neurons but also for other types of neurons such as serotonergic neurons. It is widely understood that the consumption of methamphetamine leads to varying degrees of degeneration in the brain, which is contingent upon factors such as frequency of use, potency of the drug, and potential co-administration with other substances [31].

It has been reported that the co-administration of caffeine and amphetamine may augment the neurotoxicity of amphetamine, including methamphetamine. Similarly, animal studies suggest that the concurrent use of caffeine and MDMA within a short timeframe may increase the toxicity of MDMA. Limited research has been conducted on the human toxicity of MDMA; however, studies have been conducted on animal models. Several animal studies have demonstrated that the administration of MDMA at a dosage of 0.75mg/kg of body weight can lead to a reduction in serotonergic tone, but not serotonin neurons, in the brains of laboratory mice and rats. The mechanism of action of MDMA involves the facilitation or promotion of significant dopamine and serotonin releases. It is unsurprising that if animals administered with MDMA are sacrificed later that day and their brains are subjected to protein staining related to serotonin synthesis or release. It is unsurprising that a decrease in such proteins would occur given the substantial release and subsequent depletion of dopamine and serotonin. However, it is important to note that the depletion of neuromodulators in the short term should not be conflated with their depletion in the long term, nor should it be equated with the loss of neurons responsible for the release of dopamine and serotonin [32].

Empirical evidence indicates that the recurrent dispensation of MDMA in the aforementioned dosages can result in a reduction of the aggregate quantity of serotonin or other proteins involved in the serotonin synthesis pathway, as well as dopamine or proteins implicated in the dopamine synthesis pathway, within distinct regions of the brain that are associated with reinforcement, mood, motivation, and related functions. According to a study, the neurotoxicity of MDMA may not be as significant as previously believed, contrary to findings from rodent studies. This has resulted in a protracted history of debate and exchange between various laboratories and regulatory agencies, who are striving to maintain the legality of MDMA. Additionally, members of the therapy community are enthusiastic about the possibility of MDMA being authorized for the treatment of PTSD. According to a study, nonhuman primates who were subjected to a regimen of multiple sequential doses of MDMA, modeled after the one used by humans, exhibited severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. The findings of the research indicate that the commonly held perspective, which posits MDMA as a neurotoxin that selectively targets serotonin, requires reevaluation. The study's findings on neurotoxicity have significant implications for comprehending the mechanisms of MDMA and indicate that individuals who engage in recreational MDMA use may be exposing themselves to the possibility of developing neuropsychiatric disorders associated with a deficiency in brain dopamine and/or serotonin, without their knowledge. It is noteworthy that the previous research has been retracted as a result of subsequent findings that challenged its conclusions [33].

Figure 11. MDMA induced Neurotoxicity [34].

References

31. Costa, G. and K. Gołembiowska, Neurotoxicity of MDMA: Main effects and mechanisms. Experimental Neurology, 2022. 347: p. 113894.

32. Contribution of Caffeine to the Psychostimulant, Neuroinflammatory, and Neurotoxic Effects of Amphetamine-Related Drugs. 2013. 3(2): p. 79-84.

33. Ricaurte, G.A., et al., RETRACTED: Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy"). 2002. 297(5590): p. 2260-2263.

34. Mercer, L.D., et al., MDMA-induced neurotoxicity of serotonin neurons involves autophagy and rilmenidine is protective against its pathobiology. Neurochemistry International, 2017. 105: p. 80-90.

(12): 01:26:36 Is MDMA Neurotoxic?; Poly-Pharmacology, Body Temperature

The study carried out by Halpern et al. sought to examine the cognitive consequences of long-term use of ecstasy among individuals with restricted exposure to other substances. The aim of the research was to mitigate the influence of extraneous factors that could potentially result in an inflated estimation of neurocognitive harm caused by ecstasy. The methodology of the study involved a comparative analysis between individuals who partake in unauthorized ecstasy consumption and those who abstain from it. The study excluded subjects who had significant exposure to other illicit substances or alcohol over the course of their lives. The research required that all subjects have affiliation with the 'rave' subculture, and stringent screening protocols were employed to prevent any undisclosed drug consumption, including the use of breath, urine, and hair samples. The research performed a comparative examination of the cohorts while regulating for various factors such as age, gender, race/ethnicity, family-of-origin factors, history of conduct disorder during childhood, and attention deficit hyperactivity disorder. The study comprised a battery of 15 neuropsychological tests that assessed a range of cognitive functions. The findings suggest a paucity of substantial evidence concerning the reduction in cognitive functioning among ecstasy users, except for a decline in strategic self-regulation. The observed decline in the phenomenon under consideration could potentially be ascribed to an increase in impulsive tendencies. However, it is plausible to attribute this observation to a pre-existing characteristic of individuals who partake in ecstasy consumption, rather than a persistent neurotoxic effect of the substance. The current investigation endeavored to alleviate limitations observed in previous studies and produced unfavorable outcomes concerning significant cognitive effects among individuals who have used ecstasy for an extended period with restricted exposure to other substances. The aforementioned deduction was arrived at subsequent to a comprehensive examination of the gathered data. The findings of the current study differ from several previous inquiries, including the authors' own prior research, emphasizing the importance of exercising caution when interpreting cognitive function analyses of individuals who consume illegal ecstasy [35].

The retraction of a primate study was conducted subsequent to the examination of data obtained from mice, rats, and humans. The investigator initially ascribed the occurrence of neurodegeneration in animals to the administration of MDMA. Subsequently, the primates were administered with methamphetamine. The present study examined the veracity of individuals who consume MDMA at moderate and heavy levels in the absence of other stimulant substances. The study also encompassed an analysis of clinical trials administering one, two, or three doses of MDMA to individuals with no prior exposure to the substance. According to these studies, the controlled clinical administration of pure MDMA without the concomitant use of other neurotoxic medications is deemed safe. The potential hazards associated with MDMA may have been overstated in popular media. The administration of high doses of MDMA or the concomitant use of MDMA with other neurotoxic substances may result in neurotoxicity. The consumption of MDMA may lead to neurotoxicity in users, which can be attributed to environmental factors. The term "settings" refers to various external conditions that have the potential to significantly elevate an individual's blood pressure or body temperature. All studies conducted on mice, non-human primates, and humans have consistently demonstrated that MDMA induces an elevation in blood pressure and heart rate. MDMA is classified as a psychostimulant due to its ability to activate the sympathetic nervous system, which governs the fight-or-flight response. Elevated levels of activity have the potential to stimulate heightened levels of verbal communication and bodily movement. The consumption of MDMA and cocaine has been found to elicit physiological responses such as an increase in blood pressure, heart rate, and body temperature. Inadequate hydration and electrolyte intake may lead to neurotoxicity induced by temperature. The notion is substantiated by the presence of serotonin and dopamine in the medial preoptic region of the hypothalamus, which is responsible for temperature regulation. Elevated bodily temperature has the potential to negatively impact the well-being of neurons. The brain has the ability to maintain its integrity and function even in the face of reductions in body temperature. Nevertheless, a rise in body temperature of three to four degrees has the potential to cause neuronal death. The neurotoxic effects of MDMA are contingent upon the environmental and behavioral factors of the user. All chemicals that are ingested simultaneously hold equal significance. The degree of neurotoxicity associated with MDMA exhibits variability. The chemical compound commonly known as MDMA is typically identified as methamphetamine in its pure form. The substance exhibits toxic properties [36].

Figure 12. Examining the effects of prolonged exposure to MDMA on the brain [10].

References

35. Halpern, J.H., et al., Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs. 2011. 106(4): p. 777-786.

36. Kalant, H., The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. Cmaj, 2001. 165(7): p. 917-28.

(13): 01:37:07 Post-MDMA “Crash”, Prolactin & P 5 P

The post-MDMA crash is a frequently observed occurrence that shares similarities with the crash experienced after consuming various types of stimulants, such as caffeine and amphetamines. This crash is characterized by a decrease in mood, an increase in lethargy, and a lack of motivation. There exists a common misconception among individuals that the cause of the crash following MDMA ingestion is attributable to the depletion of serotonin, and dopamine, or the death of serotonergic neurons. However, it is improbable that such factors would be responsible for the immediate onset of the crash within 24 to 48 hours post-ingestion. Certain individuals consume tyrosine, an amino acid precursor of dopamine, in an attempt to elevate dopamine levels during a period commonly referred to as a crash. There is a lack of empirical support for the potential benefits of any of these aforementioned entities. There could be certain factors that could have an adverse impact. The concurrent consumption of L-tryptophan and L-tyrosine may lead to a reduction in serotonin and dopamine levels. MDMA has the potential to induce an elevation not only in dopamine, serotonin, or oxytocin levels but also in prolactin levels following a surge in dopamine. Prolactin is a hormone that plays a role in milk ejection during lactation in females, as well as in the refractory period following sexual arousal and the processes of erection and ejaculation in males. It is implicated in various physiological and neurological processes, such as the accumulation of adipose tissue and the manifestation of symptoms like fatigue and reduced activity levels. Dopamine plays a crucial role in regulating prolactin levels, which is why drugs that elevate dopamine levels are utilized to reduce prolactin secretion, albeit temporarily. For instance, cabergoline is a wise choice of medication that enhances dopamine levels and is employed to inhibit prolactin production. The ingestion of MDMA has been found to significantly elevate prolactin levels, and there is a growing recognition that the surge in prolactin during and after MDMA consumption may contribute to certain aspects of the "crash" phenomenon, such as feelings of fatigue, reduced motivation, and depressed mood. Consequently, individuals have initiated an investigation into the utilization of substances such as p5p, a derivative of vitamin B6 that is recognized for its ability to inhibit prolactin, in an attempt to mitigate the effects of a crash [37].

Figure 13. Structure of Prolactin hormone [38].

References

37. Murnane, K.S., et al., The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine ("ecstasy"): a concurrent microdialysis and plasma analysis study. Horm Behav, 2012. 61(2): p. 181-90.

38. Robles, J.P., et al., Vasoinhibin comprises a three-helix bundle, and its antiangiogenic domain is located within the first 79 residues. Scientific Reports, 2018. 8.

(14): 01:43:07 PTSD & Trauma; Talk Therapy, SSRIs

Post-traumatic stress disorder (PTSD) is a condition that arises from exposure to a traumatic event. Trauma, whether physical or emotional, can have a detrimental impact on brain function, leading to long-term consequences. PTSD is commonly defined as a psychological condition resulting from exposure to a traumatic event, such as a car accident or sexual assault, which causes emotional distress. The aforementioned instances pertain to firsthand encounters that result in psychological trauma and subsequently, PTSD. Third-person events may involve individuals who witness traumatic occurrences that can have both immediate and long-term effects on their well-being. PTSD can arise from exposure to multiple traumatic events, and the management of trauma has demonstrated some level of efficacy through high-quality psychotherapeutic interventions. The term "quality talk therapy" refers to a therapeutic approach in which the therapist and patient, who may also be referred to as a client, establish a positive rapport. This rapport fosters a sense of support and safety, which enables the patient to explore their trauma and gain insight into how it is influencing their adaptive and maladaptive behaviors and emotional states. In addition to the crucial elements of rapport and support, effective talk therapy for trauma entails a third component: insight. This refers to the ability of the individual to comprehend the reasons behind their emotional state and to connect it to a broader context, which can lead to a certain degree of relief. However, this aspect of therapy can be somewhat abstract, and it is worth noting that while talk therapy can be efficacious in treating PTSD, approximately half of those who undergo this form of therapy do not experience lasting relief from their symptoms. Furthermore, only a small percentage of individuals achieve complete remission of their PTSD, with many experiencing only slight or transient improvements. Apart from psychotherapy, pharmacotherapy is also utilized for treating PTSD, primarily through the administration of selective serotonin reuptake inhibitors (SSRIs) [39].

SSRIs have demonstrated efficacy in the management of PTSD. Research has shown that a significant proportion of individuals, ranging from 40 to 60 percent, who received selective serotonin reuptake inhibitors (SSRIs) for PTSD experience a reduction in symptoms. However, it is important to note that SSRIs are also associated with adverse effects such as decreased libido, appetite suppression, or increased appetite. Consequently, there is a need to investigate the optimal dosage of SSRIs that can provide symptom relief for PTSD while minimizing adverse effects. The integration of talk therapy and pharmacotherapy has been utilized in the treatment of PTSD by some individuals, resulting in improved outcomes. However, it should be noted that not all individuals have experienced a significant improvement or relief from symptoms with this combined therapeutic approach. PTSD is characterized by a range of symptoms, including distractibility, cognitive impairment, sleep disturbances, suicidal ideation, anxiety, and an increased susceptibility to substance abuse. The prevalence of alcohol and opioid use disorder is higher among this patient population. Individuals with PTSD experience various degrees of suffering. At present, a prevalence rate of 8% has been reported for individuals experiencing PTSD in the United States. Approximately 65% of individuals diagnosed with PTSD exhibit comorbidities with other mental health conditions, with addiction being a prominent example [40].

Figure 14. Patients suffering from PTSD [41].

References

39. Asnis, G.M., et al., SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations. Drugs, 2004. 64(4): p. 383-404.

40. Cuijpers, P., et al., Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis. World Psychiatry, 2014. 13(1): p. 56-67.

41. Post-traumatic stress disorder: When fear strikes the heart. Available from: https://www.health.harvard.edu/heart-health/post-traumatic-stress-disorder-when-fear-strikes-the-heart.

(15): 01:54:09 PTSD Treatment: Talk Therapy + MDMA

A clinical investigation was conducted to evaluate the efficacy and safety of administering MDMA in combination with therapy for the treatment of severe PTSD. The study findings have been reported. The aim of the inquiry was to evaluate the feasibility of employing MDMA-assisted psychotherapy as a treatment option for individuals who have been diagnosed with severe PTSD, including those who have comorbidities such as dissociation, depression, alcohol and substance use disorders, and childhood trauma. The research involved a cohort of 90 individuals who were randomly assigned to receive either manualized therapy with MDMA or a placebo, along with preparatory and integrative therapy sessions. The primary endpoint of the study was assessed by means of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), whereas the secondary endpoint was gauged using the Sheehan Disability Scale (SDS). The study's results indicate that the administration of MDMA led to a significant reduction in CAPS-5 scores compared to the placebo, suggesting a substantial improvement in PTSD symptoms. Additionally, it was noted that the administration of MDMA resulted in a decrease in the overall SDS score, suggesting an improvement in functional impairment. The study's results suggest that the implementation of MDMA-assisted therapy is a notably efficacious therapeutic modality for individuals afflicted with severe post-traumatic stress disorder. Furthermore, the research indicates that the therapy is deemed safe and well-tolerated, even in instances where comorbidities are present. The findings suggest that the application of MDMA-assisted therapy shows promise as an innovative approach for treating severe PTSD and warrants further clinical evaluation [12].

Figure 15. Mental health patient with MDMA-assisted talk therapy.

References

12. Mitchell, J.M., et al., MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 2021. 27(6): p. 1025-1033.

(16): 02:02:46 MDMA & Addiction; Dissociative PTSD & Empathy

Several research studies have suggested that the utilization of MDMA-assisted psychotherapy can effectively treat alcohol addiction. The development of alcohol use disorder and other addictive disorders can frequently be attributed to disruptions in neural circuitry that bear resemblance to those observed in PTSD, albeit arising from distinct brain wiring mechanisms. The co-occurrence of addiction and PTSD is a commonly observed phenomenon. The treatment of PTSD may not necessarily result in the complete resolution of Alcohol Use Disorder (AUD) or other co-occurring disorders. Empirical studies examining the efficacy of utilizing MDMA in conjunction with talk therapy for the treatment of dissociative post-traumatic stress disorder have indicated that this particular manifestation of the disorder poses a formidable challenge to remediation efforts. Effective treatment of PTSD necessitates patients to closely approach or recount traumatic experiences in significant detail. It can be inferred that an individual who has dissociated from a particular experience and is unwilling to access the associated emotional states and memories may face significant challenges in responding to treatment. The administration of MDMA, coupled with the presence of two trusted therapists, one of whom has established a strong rapport, has been observed to create a pro-social and empathic mental environment. This environment enables patients suffering from PTSD to approach their traumatic experiences, engage in discussions about them, and reframe them in a context that often involves empathy for both themselves and others. The aim is to contextualize individuals' experiences of trauma, depression, and anxiety within a broader framework that enables them to perceive themselves as cognizant of the occurrence of these events. By confronting the emotional burden of these experiences and embracing it without fear, while also receiving adequate support, individuals may experience a reduction in the emotional weight of these experiences. It has been observed that individuals experience a reduction in emotional reactivity both during and subsequent to MDMA therapy. These individuals experience a sense of burden. The recollection of the aforementioned experience persists, albeit without causing any disruptive impact on the individual's regular cognitive and physiological processes. The findings and patient testimonials indicate that the use of MDMA in conjunction with talk therapy is not solely attributable to the pharmacological effects of the drug. The drug's impact enhances the motivation and outcomes of talk therapy [42].

Figure 16. MDMA and Empathy [43].

References

42. Nicholas, C.R., et al., The effects of MDMA-assisted therapy on alcohol and substance use in a phase 3 trial for the treatment of severe PTSD. Drug and Alcohol Dependence, 2022. 233: p. 109356.

43. Can MDMA Save a Marriage? Available from: https://www.nytimes.com/2022/02/08/well/mind/marriage-molly-mdma.html

(17): 02:09:47 Side-Effects?, MDMA Efficacy & Legality

In the context of MDMA therapy, there was no observed escalation in the frequency of suicidal attempts among patients, in contrast to the placebo group which exhibited a baseline level of suicidal ideation and behavior. The incorporation of MDMA pharmacotherapy into PTSD psychotherapy does not appear to exacerbate the adverse effects that are occasionally linked to PTSD psychotherapy, as it is reasonable to anticipate side effects when addressing PTSD and trauma. In summary, the current period is highly stimulating for the investigation of MDMA as an adjunct to psychotherapy for addressing PTSD and related disorders. Numerous members of the mental health community express enthusiasm towards these substances due to their historical association with recreational applications. Hence, their comprehension has been inadequate owing to frequent adulteration or amalgamation with extraneous substances or unsuitable administration to certain individuals, particularly the youth, resulting in numerous health complications. When MDMA is administered in conjunction with talk therapy, the results appear to be exceedingly favorable. This intervention cannot be considered a panacea. The triad of behavioral characteristics encompassing irritability, impulsivity, and aggression has been discerned. The constellation of depression, disruptions in sleep patterns, and anxiety has been recognized as prevalent manifestations in clinical contexts. Cognitive impairments related to memory and attention have been identified. There have been reports of a decrease in both appetite and sexual drive. Potential synergistic effects may arise from the concurrent administration of other substances, particularly cannabis. The decrement in the ability to perceive and anticipate motion has significant implications for an individual's cognitive evaluation. An increase in body temperature can lead to the failure of vital organs such as the liver, kidneys, or heart, and in severe cases, may result in death. The potential for unsafe sexual practices may be facilitated by the promotion of trust and intimacy, particularly when used in combination with sildenafil. The presented manifestations comprise involuntary contraction of the mandibular muscles, decreased desire to consume food, mild detachment from reality, incoherent or irrational thought patterns, agitated leg movements, queasiness, variations in bodily heat levels, cephalalgia, sudation, and rigidity in the musculoskeletal system [44].

Figure 17. MDMA Side Effects [45].

References

44. What are the effects of MDMA?; Available from: https://nida.nih.gov/publications/research-reports/mdma-ecstasy-abuse/what-are-effects-mdma.

45. Drug Side Effects & Medical Device Complications. Available from: https://www.drugwatch.com/side-effects/

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