The Small Pharma Team/Courtesy of Small Pharma Inc.
Petite Pharma Inc. develops a new approach to treat major depressive disorder (MDD) without using SSRIs or standard antidepressants. Instead, a clinical trial is underway using DMT, a naturally occurring psychedelic tryptamine found in plants and mammalian brains, in tandem with assisted psychotherapy to potentially retrain the brain. This is believed to be the world’s first trial of DMT-assisted therapy in patients with MDD.
The company believes this approach can address the root causes of depression. “Our hypothesis, based on studies of the mechanism of action, is that it will attack the negative cycle of damaging thought patterns in order to reset the mind,” said Carol Routledge, Ph.D., Medical Director and scientist, at BioSpace.
SPL026, Small Pharma’s proprietary formulation of DMT, is undergoing a Phase I/IIa trial for MDD in the UK in collaboration with Imperial College London. SPL026 holds an ILAP designation — The UK equivalent of the FDA FastTrack — of the Medicines and Health Products Regulatory Agency.
Efficacy data should be available in mid-summer from the phase IIa trial. This phase of the study is evaluating the efficacy of SPL026 versus placebo and the efficacy of one dose versus two doses when followed by psychotherapy. For the Phase I trial, Routledge said, “We recruited psychedelic-naïve healthy adult volunteers because we expect the majority of patients in the Phase IIa study to be psychedelic-naïve.” She explained that there is no upper age limit as SPL026 is no less safe for older people.
Phase I collected pharmacokinetic and pharmacodynamic endpoints of safety, tolerability, and included assessment of the intensity and quality of the psychedelic experience. EEG was also used to better understand the mechanisms of action of SPL026.
Already completed phase I results showed a close correlation between SPL026 dosage levels and pharmacodynamic parameters. It involved 32 healthy volunteers and pharmacokinetic analysis showed that DMT has a very short half-life in the body with virtually undetectable levels in the blood after 60 minutes. The 20 drug-related adverse events were mild (85%) or moderate (15%) and were rapidly self-limiting. Over the following three months, patients showed no statistically significant negative effects on anxiety and well-being. The study found that the richness of the psychedelic experience and the therapeutic benefit of treatment were closely correlated with dosage.
“Psychedelic-assisted therapies have the potential to completely change the treatment paradigm for mental health issues,” said David Erritzoe, MD, Ph.D., of Imperial College London, chief researcher of the phase I/IIa study, when these results were published. published. “Additional insights from Small Pharma’s Phase I study show promising results at this stage of development. Dosing time (including psychedelic experience) of 30 minutes, compared to up to 6 hours seen with alternative approaches, has the potential to offer a real benefit in terms of treatment regimen for patients and providers .
SPL026 is being developed to provide an additional treatment option for patients who find Selective Serotonin Reuptake Inhibitors (SSRIs) — the most commonly prescribed antidepressantsaccording to Medline — inadequate.
In terms of mechanism of action, Routledge explained, “SSRIs increase the concentration of endogenous serotonin in the brain, whereas psychedelics have a different mechanism of action in that we believe they increase overall connectivity and increase plasticity in the brain.” She said evidence suggests that negative and ruminative thought cycles in depressed patients may stem from overactivity of brain networks, particularly the default-mode network, during depression, which creates inflexible thought patterns and neural connections in the brain.
“Psychedelics like DMT are thought to modulate these ingrained neural connections, making them more flexible while increasing connectivity. Additionally, they stimulate serotonin receptors in the brain, which leads to increased brain plasticity and further improves connectivity. We believe that increasing brain connectivity increases a person’s receptivity to therapy, which makes therapy more effective,” Routledge said.
As a potential treatment, DMT has a huge advantage over psilocybin. DMT induces a short psychedelic experience of around 20-25 minutes compared to several hours with psilocybin. Even with therapy, the time spent in the clinic is much shorter, she explained, and so treatments can take place within the existing clinical infrastructure.
During the psychedelic experience, patients typically see various shapes or patterns (visual hallucinations such as balloon shapes or balloon creatures), and may also experience auditory hallucinations, loss of sense of time, and some will have an out of body experience. “Hallucinogenic effects are very subjective,” she said.
Trial participants — even if naive psychedelic — tolerated the psychedelic experience very well, with many saying it was a pleasant experience. “None expressed regret for participating in the trial,” she said.
A therapy session immediately follows the DMT psychedelic experience. “The therapy session serves many purposes. It helps patients make sense of their psychedelic experience and allows them to talk about issues that arose during the experience and cement new neural connections,” Routledge said. The goal is to integrate the ideas of the themes that have arisen during the psychedelic experience into everyday life. “We believe the combination of DMT treatment and therapy points to increased efficacy.”
Upon completion of the Phase IIa study, “Small Pharma plans to commence a Phase IIb study with a larger international multicenter study in patients with MDD in the US, EU and UK. This study will assess safety, tolerability and efficacy in the broader patient population,” Routledge said. “We are also developing a follow-up molecule with an extended profile (SPL028).” Another program (SPL029) involves developing an oral formulation to facilitate administration — currently an infusion — Easier.”
Small Pharma holds four patents, with over 50 patents pending.
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