Patented formulation of MDMA receives federal “Investigational New Drug” status; Intravenous ketamine outperforms esketamine
Plus: The role of ego dissolution in ancient empires and Psychedelic hallucinations compared to those experienced in dementia
Happy Friday and welcome back to The Microdose, an independent journalism newsletter brought to you by the U.C. Berkeley Center for the Science of Psychedelics.
Patented formulation of MDMA receives FDA’s Investigational New Drug status
This week, “empathogen” company Arcadia Medicine announced that AM-1002, its patented formulation of MDMA, has received Investigational New Drug status from the U.S. Food and Drug Administration. The designation allows researchers to more easily study controlled substances that are not yet approved by the FDA by granting approval for the drug to be transported and distributed across state lines.
MDMA is what is called a “racemic mixture”: it contains an equal proportion of two molecular structures, known as R-MDMA and S-MDMA, which are mirror images of each other. Arcadia’s AM-1002 is a non-racemic MDMA; according to its patent application for the drug, it contains a mix of nine parts R-MDMA to one part S-MDMA. Previous research has suggested that while S-MDMA is associated with strong visual effects and higher blood pressure, R-MDMA provides more stimulation of serotonin receptors. The company calls its drug a “non-neurotoxic form of MDMA with an improved therapeutic profile,” and plans to start a clinical trial investigating its use in treating generalized anxiety disorder.
Arcadia said it has raised $9.25 million from investors including OpenAI’s Sam Altman and cryptocurrency platform Coinbase co-founder Fred Ehrsam. Meanwhile on the MDMA front, Lykos Therapeutics, known for their clinical trials using MDMA to treat PTSD, has yet to announce their next steps in response to the FDA’s recommendation that they conduct another Phase 3 clinical trial. Earlier this year, the company raised $50 million from its new majority stakeholders, billionaires Antonio Gracias and Christopher Hohn.
Racemic ketamine outperforms esketamine
While the definition of “racemic” is fresh in your mind: a study published in The Journal of Clinical Psychiatry investigated the therapeutic effect of intravenously administered generic racemic ketamine versus that of nasally administered esketamine (or S-ketamine, also known by the brand name Spravato).
In the study, researchers looked at racemic ketamine’s and esketamine’s effectiveness in reducing symptoms in people diagnosed with treatment-resistant depression. Over the course of 4 to 5 weeks, participants traveled to a clinic to receive either 8 sessions of intravenous racemic ketamine or 8 doses of nasal esketamine. Before the study, researchers measured participants’ depression symptom severity; during each session, researchers also monitored their vitals. Overall, both groups showed improvements in their depression symptoms, but intravenous racemic ketamine outperformed esketamine: intravenous racemic ketamine was associated with a nearly 50% reduction in depression scores, while participants who received esketamine showed a 40% reduction. Moreover, the therapeutic effect appeared earlier in the intravenous racemic ketamine group; the decrease in depressive symptoms reached statistical significance after just one treatment in this group, whereas it took the esketamine group two treatments to show a significant decrease in depressive symptoms.
The researchers point out that though the difference in response between the two groups is statistically significant, “the degree to which this difference translates into meaningful improvements in daily functioning, quality of life, and long-term treatment trajectories remain uncertain.” Overall, they write, it’s important to note that intravenous racemic ketamine — currently approved as an anesthetic drug, but used off-label to treat depression — performs as well if not better than esketamine. Whereas generic, injectable racemic ketamine can cost under a dollar per dose, Spravato nasal spray (esketamine) costs upwards of $500 per treatment session. (Currently, esketamine can only be administered under clinical supervision.)
Want the latest psychedelics news? Subscribe! (It’s free!)
Ego dissolution in ancient empire-building
Recent archaeological discoveries suggest that ancient peoples consumed psychedelics, often as part of communal ritual. A new paper published in the Spanish language archaeology journal Revista de Arqueología Americana speculates that the “afterglow” of these substances “could have helped rebuild communities after the disruptions of imperial expansion.” For example, the Wari people who lived in what is now Peru from 600 to 1000 CE, ground seeds of the Anadenanthera colubrina tree into a powder known as vilca, and mixed it with beer made from Schinus molle, an evergreen tree. Vilca contains bufotenin, a chemical cousin of DMT. This brew could have engendered feelings of openness and empathy at feasts where it was consumed.
The Wari were constantly expanding their empire, with several key wealthy families holding land and resources; ensuing power struggles erupted into war and violence. Enormous feasts were a way of getting people to work towards a common goal, and became a “cornerstone of Wari politics,” the authors write. This beer and vilca may have helped create trust and rapport as Wari colonists made themselves welcome in new territory. “Within the context of an expanding empire where violence and animosity was commonplace, the lingering effects after ego dissolution may have been integral to Wari legitimization and consolidation,” the authors write. Perhaps, they posit, the “longer-term impacts of psychedelics may have also significantly shaped the history of other regions.”
Hallucinations in psychedelics users vs. Lewy body diseases
Hallucinations are perhaps the best-known effect of psychedelic drugs. They’re also common among people with Parkinson’s disease or Lewy body dementia, conditions which arise from the overaccumulation of the protein alpha-synuclein in the brain. A review paper published in Schizophrenia Bulletin probes the similarities and differences in visual hallucinations between psychedelics and Lewy body diseases in hopes that it might illuminate more about the neural mechanisms behind both types of phenomena.
There are many different types of hallucinations; in some cases, people may perceive complete scenes that do not exist (complex hallucinations), as opposed to “simple” hallucinations like flashes of light, or geometric shapes. One might also experience an illusion like pareidolia — seeing faces where they are not, like in clouds. Or one might see visual distortions called metamorphopsias, where lines may seem to bend or stationary chairs appear to move. Metamorphopsias and complex hallucinations are common among both psychedelics users and people with Lewy body diseases. Other phenomena are more common with one group versus the other; for example, while people taking psychedelics often report experiencing synesthesia, such as seeing colors while listening to music, there is no mention of the phenomenon in studies of people with Lewy body diseases.
In looking at similarities between brain activity of people with Lewy body diseases and people on psychedelics, the researchers identified that reduced activity in some visual cortical regions was accompanied by increased activation in other areas of the visual cortex. The mechanisms through which this works could be different for psychedelics versus Lewy body diseases, the authors posit. Hallucinations in psychedelics users could be driven by overall greater excitability among visual neurons in response to serotonergic drugs, whereas in people with Lewy body diseases, which often is accompanied by declining eyesight and therefore less sensory input, the brain becomes more prone to hallucination. “Insights into these mechanisms may clarify the fundamental sensory effects of [serotonergic psychedelics] administration and guide novel interventions for Lewy body hallucination, potentially improving clinical management and patient quality of life,” the authors write.
The National Institute on Alcohol Abuse and Alcoholism has awarded two multi-million dollar grants to companies studying the use of serotonergic drugs in treating alcohol use disorder. Küleon Bioscience, a Seattle-based biotechnology company, was awarded $2 million to study the use of its non-hallucinogenic drug KB-128 in rodent models; Psilera was also awarded a $2 million grant to study non-hallucinogenic psilocybin derivatives.
NPR podcast It’s Been a Minute explores the recent rise of ketamine as a party drug.
Tech bros use ChatGPT for everything, prefer grinding in the office to working from home, do “dopamine fasts,” and, of course, trips on psychedelics to generate new ideas, according to The San Francisco Standard.
After MAPS executive director Kris Lotlikar stepped down, longtime staffers Betty Aldworth and Ismail Ali were named as interim co-executive directors while the organization conducted a search for a new leader. But MAPS has decided to keep the two at the helm, and Lucid News interviewed the two about their vision for the future, which includes more resources for psychedelics professionals and expanding its crisis response training, while also reconsidering what role the organization has in the larger psychedelics ecosystem.
Earlier this year, Arizona legislators designated $5 million in research funds for ibogaine studies. Applications are now open for those research grants and will be accepted through mid-November. According to the application criteria, the principal investigator of all grants must reside in Arizona.
You’re all caught up! We’ll be off Monday for Indigenous Peoples Day, but we’ll be back in your inbox next Friday with another news round-up.
If you know anyone who might like the latest on psychedelics in their inbox, feel free to forward this to them, or click below.
Got tips? Email us at themicrodose@berkeley.edu.