3,4-Methylenedioxymeth
-amphetamine (MDMA)

Commonly known as ‘ecstasy’, one compound is seeing a resurgence not on the dancefloors, but rather in the clinics of researchers who have identified its value in treating a number of psychiatric disorders. With a Phase III trial now underway, many anticipate MDMA to be the first psychedelic-like drug to be approved by the FDA for the treatment of PTSD.

Now, ATAI has launched EmpathBio to develope derivatives of 3,4-methylenedioxy-methamphetamine (MDMA) for the treatment of post-traumatic stress disorder (PTSD) and other indications.

From party drug to promising therapeutic

Despite its recent popularity, MDMA was first synthesized in the search for hemostatics at the pharmaceutical company Merck KGaA in 1912 and patented in 1914. Dr. Walter Beckh, head of Merck’s laboratory, alongside his co-worker Dr. Otto Wolfes, developed a method to synthesize and use 3-methyl-hydrastinine as a replacement for hydrastinine (alkaloid used for antihemorrhagic drugs); the company was interested in the new antihemorrhagic 3-methyl-hydrastinine, not the precursor MDMA.

However, even before the advent of MDMA, its metabolite MDA was well known. In the 1950s and 1960s, MDA was tested for select medical indications – such as depression – by pharmaceutical companies, but it was abandoned due to unwanted “central side-effects”.  MDA’s hallucinogenic effects were discovered in 1955, leading to its reputation as “The Love Drug”. Indeed, Claudio Naranjo and Alexander T. Shulgin conducted initial testing of its therapeutic potential, consequently leading psychotherapist Leo Zeff to adopt MDA in his sessions in the 1960.

In 1985, against the backdrop of increased use and a corrective PR campaign by Rick Doblin’s first non-profit venture Earth Metabolic Design Laboratories, MDMA became a Schedule I controlled substance – against the recommendation of an appeals committee – in the United States and banned in most others soon thereafter. In 1986, recognizing that the most effective means of ensuring access to MDMA lay through established regulatory pathways, Rick founded the now renowned Multidisciplinary Association for Psychedelic Studies (MAPS) with the primary goal of making MDMA an FDA-approved medicine. 

Today, MAPS has raised more than $100 million — $30 million of this in just a few months in 2020 via its Capstone Challenge — allowing it to advance its Phase 3 clinical trials in the U.S., Canada, and Israel.

 

 

From party drug to promising therapeutic

On the pharmacological level, MDMA is distinct from both LSD-type hallucinogens and amphetamines. 

MDMA itself is an amphetamine derivative that possesses complex pharmacology and is believed to act by increasing the release of monoamines like serotonin, norepinephrine and dopamine in the brain, as well as stimulating neurohormonal activity. These effects are thought to result in the anxiolytic, prosocial and empathic responses seen with MDMA administration in humans. As a result, MDMA is often classified as an entactogen rather than a typical psychedelic.

More specifically, MDMA’s “stimulant” and emotional effects are produced by the acute release of 5-HT, while the “hallucinogenic” effects are elicited by direct interactions with postsynaptic 5-HT2A receptors. Meanwhile, MDMA’s euphoric effects result from increases in dopamine. Finally, increases in norepinephrine/noradrenaline cause increased heart rate and blood pressure while increases in the serotonin system cause changes in mood, appetite, sexual arousal, and sleep cycles. Spikes in serotonin after taking MDMA likely account for the common feelings of emotional closeness and empathy.

MDMA also has weak agonist activity at postsynaptic serotonin receptors 5-HT1 and 5-HT2 receptors, and its more efficacious metabolite MDA likely augments this action. Cortisol, prolactin, and oxytocin quantities in serum are increased by MDMA. Finally, a number of studies in humans have demonstrated that MDMA increases plasma levels of oxytocin.

 

 

From party drug to promising therapeutic

The Multidisciplinary Association of Psychedelic Studies (MAPS) recently published results from their phase II clinical trials, which demonstrated that after MDMA-assisted psychotherapy, 56% of participants no longer met the criteria for PTSD two-months after the final session. Additionally, researchers followed up with 91 participants twelve months later and found that 67% still did not meet PTSD criteria, with many reporting substantial improvements in many areas in their life, including relationships, sleep quality, and general wellbeing.

The prosocial effects of MDMA could play an important role in its therapeutic potential by increasing openness and facilitating a therapeutic alliance between patients and therapists. Indeed, one of the most reliable behavioural features of MDMA is that it reduces aggression across species, along with reduced anxiety, lowered defensiveness, and a feeling of “closeness” with other persons.

It is hypothesized that the effects of MDMA allows a person to voluntarily navigate difficult emotions when recalling traumatic memories due to a reduction in activity in the amygdala, a region of the brain activated during fear responses. This reduction in fear allows for a decreased defensiveness about revisiting painful experiences, making room for new perspectives and different responses towards deep-rooted traumatic memories.

 

Conclusion

With the success of MAPS’ Capstone Campaign, as well as progress in its phase III clinical trials, focus has shifted to the eventual rollout. As part of this effort, ATAI has recently announced the launch of EmpathBio to develop derivatives of 3,4-methylenedioxy-methamphetamine (MDMA) for the treatment of post-traumatic stress disorder (PTSD) and other indications.

EmpathBio is focused on developing MDMA derivatives with different pharmacological profiles than MDMA. The company believes that such changes may permit the entactogenic effects of MDMA to be separated from some of the known adverse effects.

If successful, such an approach could help minimize some of the transient physiological changes caused by MDMA, potentially expanding the pool of PTSD patients who will be medically eligible for the therapy.

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