Understanding the FDA's Breakthrough Therapy Designation for CYB003
The News: The FDA granted Breakthrough Therapy Designation (BTD) – a fast track for FDA approval - to CYB003 (Cybin), a psilocybin analogue being investigated as an adjunctive treatment for major depressive disorder (MDD) in clinical trials.
My Reaction: What?!
Okay, let's take a step back and try to understand how the active ingredient of magic mushrooms (deuterated psilocybin) is entering Phase III clinical trials for major depressive disorder. First of all:
From Magic Mushroom to Psilocybin, how?
Psilocybin (Figure 1), a tryptamine alkaloid, is naturally found in a family of mushroom-forming fungi (e.g. Liberty Cap – Psilocybe semilanceata) that (can) cause hallucinations when ingested. The most potent varieties belong to the genus Psilocybe. For centuries, Mexican Indians have used psilocybin for medicinal and religious purposes. If you are interested in the traditional use of this powerful mushroom, I highly recommend "Shroom: A Cultural History of the Magic Mushroom" by Andy Letcher.
Figure 1. Illustration depicting the Liberty Cap mushroom, the chemical structure of psilocybin, and its metabolic conversion to psilocin during digestion.
In 1958, Albert Hofmann at Sandoz Laboratories identified psilocybin and its primary active metabolite, psilocin (2), as the psychoactive compounds in Psilocybe mushrooms. A year later, Hofmann synthesized psilocybin, which Sandoz marketed as Indocybin for basic psychopharmacological and therapeutic clinical research. Clinical studies in the 1960s and 1970s showed that psilocybin induces an altered state of consciousness characterized by significant changes in perception, mood, thought, and the experience of time, space, and self.
Psilocybin was used in experimental research to understand the cause and development of certain mental disorders, showing promising psychotherapeutic potential. However, its growing popularity as a recreational hallucinogen led to its classification as a Schedule I drug in 1970, significantly curtailing research until interest was revived in the 1990s. Today, psilocybin is one of the most widely studied psychedelics in human research due to its relative safety, moderately long duration, and good absorption.
By the way: In the Netherlands, psilocybin-containing mushrooms were made illegal in 2008 due to concerns over their recreational use. However, psilocybin remains legally available in the form of "magic truffles," a subterranean structure known as sclerotia that contains psilocybin. The Dutch government distinguishes between mushrooms and truffles in its legislation, allowing the sale of truffles through regulated smart shops. This legal loophole has made the Netherlands a popular destination for those seeking the therapeutic and recreational benefits of psilocybin.
What is major depressive disorder and how many people are suffering today?
Depression, also known as major depressive disorder (MDD) or clinical depression, is a mood disorder that causes persistent feelings of sadness and a loss of interest in activities. It affects how you feel, think, and behave, leading to various emotional and physical problems. Treating depressive symptoms in MDD and life-threatening cancer (LTC) can be challenging. In the United States, an estimated 21.0 million adults experienced at least one major depressive episode in 2021, representing 8.3% of all U.S. adults. In Europe, the overall prevalence is 6.4%, with significant variations between countries, ranging from 2.6% in the Czechia to 10.3% in Iceland. Those who do not respond to two or more adequately dosed and timed antidepressant trials are considered to have treatment-resistant depression (TRD). The high prevalence of TRD highlights the urgent need to reassess and improve current therapeutic strategies for depressive symptoms.
For more information, see our previous article on Ketamine: "Depression: What is it in a Nutshell?
What are the new therapeutic approaches for treating various psychiatric disorders?
Psychedelic-assisted psychotherapy (PAP) is an emerging intervention for various psychiatric disorders. In PAP, supportive psychotherapy is combined with classic psychedelics such as psilocybin or lysergic acid diethylamide (LSD). PAP has been investigated for mood disorders, obsessive-compulsive disorder, and alcohol and tobacco use disorders. Studies have primarily focused on the therapeutic efficacy of PAP in patients with depressive symptoms. PAP has shown a significantly greater antidepressant effect at the primary endpoint compared to the control, regardless of diagnosis or type of control. Additionally, response and remission rates were significantly higher in the psilocybin group compared to the control. Recent studies add to the growing evidence of psilocybin's therapeutic benefits, showing superior results compared to several placebo drugs (e.g., very low dose psilocybin, escitalopram, niacin). Different research groups and companies suggest that psilocybin, combined with supportive psychotherapy, may be an effective intervention for acutely reducing depressive symptoms in LTC and MDD. Long-term results were also more positive for participants in the psilocybin group compared to control. Thirteen clinical trials have evaluated the antidepressant effects of psilocybin, consistently demonstrating robust antidepressant effects.
Molecular mechanism of psilocybin?
There is increasing evidence that serotonergic psychedelics, particularly psilocybin, act as fast-acting and long-lasting therapeutic agents after a single administration. However, the role of the psychedelic experience and the activation of serotonin receptors in these effects is debated. 5HT2AR (serotonin 2A receptor) is known for its role in mediating psychedelic effects, while 5HT2CR (serotonin 2C receptor) and 5HT1AR (serotonin 1A receptor) are involved in regulating mood and anxiety.
Psilocybin produced a dose-dependent increase in the head twitch response (HTR), a rapid head movement in rodents used as a behavioral marker of serotonin receptor activation. Higher doses showed a decrease in HTR, resulting in an inverted U-shaped dose-response curve. This suggests that different doses of psilocybin may activate or inhibit various serotonin receptors, resulting in a complex response profile.
Recent studies show that psilocybin's rapid antidepressant effects correlate with increased brain plasticity, partly independent of 5HT2AR-mediated HTR. The complex interplay of 5HT2AR canonical and non-canonical signaling pathways may explain these effects. It seems that a careful balance between 5HT1AR and 5HT2AR mechanisms explain the varied effects of psilocybin, highlighting the need for precise pharmacokinetic strategies to study the roles of serotonergic receptors in psilocybin's effects.
What is this CYB003 and why deuterated?
Unlike traditional psilocybin therapies, CYB003 is engineered through deuteration, a process that enhances predictability and longevity of the treatment. Although the company has not yet revealed the exact structure, they affirm that there are two elements of the molecule that differ from traditional psilocybin. Psilocybin itself is a prodrug that the body converts to psilocin, but this metabolism varies among patients, making the molecule less than 100% efficient. By deuterating the active agent, this metabolic step is eliminated, leading to a faster onset of action.
Preclinical studies show that deuteration also increases bioavailability and brain penetration, with about a 40% increase in the brain-to-plasma concentration ratios. This suggests that more of the drug reaches the brain, its site of action, rather than staying in the periphery. Cybin attributes deuteration to improve efficacy at considerably lower doses than conventional psilocybin. At 10 mg of CYB003, two-thirds of subjects scored 100% on the visual analog scale, demonstrating a robust psychedelic effect comparable to about 25 mg of psilocybin.
CYB003 has demonstrated robust and sustained antidepressant effects, with both 12 mg and 16 mg doses providing significant improvements in MADRS scores over a four-month period. The 16 mg dose led to a remarkably high remission rate of 75% at the four-month follow-up, suggesting a potent and long-lasting therapeutic benefit. The proportion of patients responding to treatment and achieving remission increased over time, highlighting the durability of CYB003’s antidepressant effects. The trial results support the progression of CYB003 to a pivotal Phase 3 study, bringing this innovative psilocybin-based therapy one step closer to potentially transforming the treatment landscape for MDD.
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Article written by Lorenzo Cianni and edited by Christien Bowman