For several years, Robert C. Malenka, M.D., Ph.D., a BBRF Scientific Council member and a 3-time BBRF grantee and prizewinner, along with some of his Stanford University colleagues, have been pursuing what they call a “circuits-first approach” to research aimed at better understanding psychedelic drugs and their potential to be useful in the treatment of psychiatric illnesses such as depression and PTSD.

They have urged that by using modern neuroscience tools to “define the [brain-]circuit adaptations that contribute to a drug’s behavioral and therapeutic effects, studies can be conducted which could reveal new molecular targets in brain cells or circuits” which can be used as a basis for developing novel versions of psychedelic drugs that have maximum therapeutic impact and cause fewer side effects.

In a newly published paper in Molecular Psychiatry, Dr. Malenka, along with senior collaborator Boris D. Heifets, M.D., Ph.D., and a team that included 2023 and 2020 BBRF Young Investigator Neir Eshel M.D., Ph.D., show some of the fruits of the “circuits-first” approach. They closely studied how the drug MDMA (known on the street as “molly” and “ecstasy”) exerts its principal effects—some undesirable, some potentially therapeutic—and found separate mechanisms that appear to be responsible for each. Taken together, the results suggest how and why MDMA appears to have lower abuse potential than some other psychotropic drugs, and may have potential for use as an “enactogen,” a drug that induces feelings of empathy and emotional openness.

The behavioral effects of MDMA in “assisted therapy” applications tested in small trials in people with PTSD have indicated its characteristic properties: an enhanced sense of emotional connectedness and empathy, along with reduced fear when confronted with aversive stimuli like traumatic memories. But MDMA, an amphetamine analog, is prone to misuse and abuse, which, the team notes, is “an important risk consideration for treating patients with PTSD, many of whom have comorbid substance use disorders.”

At the same time, MDMA is not as widely abused as closely related amphetamine drugs, such as methamphetamine. The question the researchers explored in their study was whether MDMA’s reduced abuse potential is mechanistically linked to its therapeutic behavioral effects. Prior work by the team helped explain how MDMA’s neurochemical mechanism differs from that of methamphetamine. In some respects it is similar: like “meth” and other amphetamines, MDMA has a molecular affinity for the protein that transports dopamine molecules in the brain, called the dopamine transporter (DAT). Like all amphetamines, MDMA amplifies dopamine release in the brain, which generates an intensely rewarding feeling—and is also the reason it can be addictive.

But unlike meth, the researchers were able to show that MDMA also has a high affinity for the protein that transports serotonin in the brain, called the serotonin transporter (SERT). They found that in a major reward center of the brain called the nucleus accumbens (NAc), serotonin release appeared to account for MDMA’s prosocial effects in various mouse experiments. This prosocial effect was the result of an interaction between MDMA and SERT, and subsequent activation of one of the many receptors for serotonin in the brain—the serotonin 1B receptor, in cells in the NAc.

In contrast, their experiments and those of other investigators have shown that the nonsocial drug reward evoked by meth—as well as high doses of MDMA—appear to be traceable to dopamine release, in the same brain structure, the NAc. This raises the question of whether and how the specific dopamine- and serotonin-enhancing effects of MDMA in the NAc might be mechanistically related, and whether this might help explain why MDMA at low doses has been observed to have a lower risk of abuse in humans.

The team conducted their experiments in mice. The form of MDMA administered at various dosages (from low to high), called R-MDMA, is a chemical version that has a structural configuration which gives it distinct properties compared to conventional MDMA. Multiple structural forms of MDMA were administered for comparison purposes, as well as methamphetamine and cocaine. Well-validated tests were performed, revealing the addictive properties of drugs based on conditioned expectation of reward, as well as tests in which the social behavior of the animals could be closely observed before and after drug administration, including in animals with transporters for serotonin or dopamine genetically deleted.

One finding was that serotonin released after MDMA administration had the effect of limiting the release of dopamine through activity observed in the NAc.

Further experiments revealed that MDMA’s activation of a specific receptor for serotonin in the NAc—the serotonin 2C receptor—actively suppressed dopamine release in that brain structure. This action, the team suggested, may account for MDMA’s lower addictive potential: its action lowers the rewarding release of dopamine in the NAc, compared, for example, with the stimulation of dopamine release in an administration of meth.

Other experiments provided evidence for theories about the possible source of MDMA’s prosocial effects. The form being tested as a potential drug, R-MDMA, has prosocial effects because R-MDMA is more active at serotonin transporter molecules (SERTs) than at transporters for dopamine (DATs), especially in comparison with the standard form of MDMA, which affects these molecules more evenly.

Importantly, the precise cellular location of the serotonin 2-C receptors in the NAc linked with the drug’s limitation of dopamine release and thus its lower abuse potential is still unclear, and should be taken up in subsequent research, the team said. They also cautioned that the simple behavioral tests they used in mice to explore addictive and prosocial behavioral characteristics of MDMA “are unlikely to represent the full range of social behavior and patterns of drug misuse” in people.

Still, the results of their study provide, they said, reason to continue exploring the use of R-MDMA (at low doses) in the clinic for therapeutic purposes in patients with illnesses like PTSD that often do not respond satisfactorily, or over the long-term, to current treatments.