Researchers have for the first time directly compared the physical and psychological effects of the psychoactive drug MDMA and its chemical cousin MDMA in human volunteers. Results show that MDA provides a longer-lasting treatment experience with more visual distortions and side effects. These results suggest that MDA may be less suitable than standard MDMA for therapeutic applications. The study was published in the journal neuropsychopharmacology.
MDMA is a widely known synthetic compound that promotes strong emotions such as empathy, trust, and interpersonal relationships. To reliably induce these emotional states, medical professionals are studying this substance as a psychotherapeutic drug for patients suffering from post-traumatic stress disorder. When a person ingests MDMA, the molecule breaks down into several secondary chemicals.
One of these breakdown products is a molecule called MDA. MDA itself has psychoactive effects, and psychiatric research has been limited to date. Both substances fall into the broad category of drugs known as entactogens. This roughly translates to touch inside.
Pharmacologically, both drugs work by releasing signaling chemicals such as serotonin and dopamine in the brain. In laboratory models, MDA has been shown to target dopamine slightly more aggressively than MDMA. It also exhibits 10 times higher activation of specific serotonin receptors, which are known to cause the subjective effects of classic psychedelics.
Despite these known molecular differences, researchers had never evaluated the two drugs side-by-side in a controlled human setting. Isabelle Straumann, a clinical pharmacologist at the University Hospital Basel in Switzerland, and her colleagues sought to map these differences. Determining how these chemicals act in the body could guide future clinical decisions.
The research team also wanted to test new ways to administer these drugs. Fast-acting stimulants cause rapid euphoria, which increases the risk of abuse. To slow the absorption of the drugs, researchers created special versions of standard MDMA and MDA molecules by chemically attaching an amino acid called lysine.
These bound molecules act as inert carriers, known as prodrugs, that the body must metabolize before the active drug can enter the bloodstream. This sustained-release strategy is already used in prescription drugs for attention-deficit hyperactivity disorder to reduce the potential for abuse.
To conduct the study, Stroman and his colleagues recruited 23 healthy adult volunteers. The group consisted of 12 women and 11 men. Each participant participated in five different 13-hour testing sessions, separated by at least two weeks.
During these sessions, participants received one of five identical-looking capsules. Options included a placebo, a standard recreational dose of MDMA, a chemically equivalent dose of MDA, lysine-conjugated MDMA, or lysine-conjugated MDA. The trial used a double-blind design, meaning that neither the participants nor the observing researchers knew which capsules were administered on any given day.
After taking the medication, each volunteer stayed in a quiet hospital room. Throughout the day, the researchers repeatedly measured the participants’ blood pressure, pupil size, heart rate, and body temperature. The researchers also asked the volunteers to rate their subjective emotional and physical experiences on a numbered visual scale.
In addition, the team took blood samples to track drug concentrations and hormone levels. They specifically looked for oxytocin, a hormone closely related to social bonding and trust. MDMA is known to cause a large release of oxytocin, which scientists suspect is responsible for its therapeutic effects. Because oxytocin can be too volatile to measure, the researchers also tracked a stable carrier protein called neurophysin I.
The data collected showed that MDA produced a subjectively longer and more intense experience than MDMA. The psychological effects of MDMA lasted about four hours for the average participant, while the effects of MDA lasted more than six hours. MDA reached its peak effects in the body in the same two hours as MDMA.
Participants reported that MDA produced stronger excitatory effects and caused more visual distortions than well-known MDA. Volunteers also experienced additional fear and terrible drug experiences while under the influence of MDA. Subacute side effects in the days following the session, such as headache, fatigue, and loss of appetite, were slightly more common after MDA use.
Both chemicals equally increased body temperature, heart rate, pupil size, and blood pressure. As expected, MDMA caused a massive release of oxytocin. The researchers found that MDA also increased circulating levels of oxytocin and its carrier protein, and that the increase was slightly stronger than MDMA.
When testing extended-release prodrug versions, researchers encountered partial success. The lysine-conjugated MDA tablets worked as intended. While maintaining similar physiological responses to standard MDA, it delayed the onset of the drug’s effects by about an hour and further delayed the peak of subjective experience.
Lysine-conjugated MDMA pills caused no physical or psychological effects. Blood tests confirmed that the participants’ bodies were unable to completely separate active MDMA from lysine molecules. Researchers believe that the highly specific chemical form of the MDMA compound may have prevented digestive enzymes from completing the process.
This biological failure inadvertently created a second placebo session for participants, as the researchers had expected the lysine-bound MDMA to work. Volunteers reported a greater subjective drug experience during the second day of this unexpected placebo session than during the scheduled placebo session. They reported feeling high and stimulated simply because they were anticipating taking a mind-altering substance.
This observation highlights the enormous power of expectations in psychiatric research. Physical and emotional changes caused by anticipatory beliefs can easily be reflected in the interpretation of clinical results. The researchers noted that knowing that a placebo could be administered could limit the scientific utility of control groups in psychedelic trials.
The researchers also observed slight differences in how certain groups processed the drug. Female participants reported slightly more extreme visual and temporal changes than male participants. Women also reported more subacute side effects in the days following MDA sessions.
Participants’ genetics also influenced drug clearance rates. People with certain mutations in the CYP2D6 liver enzyme have a slower rate of removing active chemicals from their system. These poor metabolizers had longer drug elimination half-lives than participants with typical liver enzymes and reported more fatigue in the days following the study.
This particular trial has several limitations that should be noted in future studies. The researchers tested only a single dose of each substance. It is still completely unclear how the balance between prosocial and negative effects changes depending on the amount.
This study was also conducted in a sterile clinical setting using healthy volunteers. People experiencing active mental illness may react very differently to the visual and emotional changes caused by these substances. Additionally, this test uses a chemical mixture rather than a single drug variant, which may produce slightly different results based on how it binds to brain receptors.
Future research may focus on fine-tuning the chemical structure of these molecules to maximize therapeutic efficacy while minimizing physical adverse reactions. So far, clinical data shows that standard MDMA holds a more favorable psychological profile than long-acting chemicals.
The study, “Acute Effects of MDMA, MDA, Lysine-MDMA, and Lysine-MDA in a Randomized, Double-Blind, Placebo-Controlled Crossover Study in Healthy Participants,” was authored by Isabelle Straumann, Patrick Vizeli, Isidora Avedisian, Livio Erne, Diana Noorshams, Ina Vukalovic, Anne Eckert, Dino Luethi, and Deborah. Rudin, Matthias E. Lichti.
