Individuals with bipolar disorder (BD) spend a third of their lives in the midst of a depressive episode. BD is a severe and persistent mental illness with a lifetime prevalence of 2-3%. Bipolar depression remains a significant treatment challenge, with a paucity of evidence-based treatments. Only four pharmacological treatments for acute bipolar depression (cariprazine, olanzapine-fluoxetine combination, quetiapine, and lurasidone) are approved by the US Food and Drug Administration (FDA). Other medications often used for the treatment of BD are those primarily used to treat mania or psychosis (i.e., lithium; antipsychotics) or major depressive disorder (MDD) (i.e., antidepressants). Lamotrigine, which is recommended by international guidelines as a maintenance treatment for BD to prevent depressive recurrence, has limited efficacy for acute BD. Current medication options are also limited by adverse effects, including renal and thyroid impairment with long-term lithium therapy and weight gain and metabolic abnormalities with atypical antipsychotics. Furthermore, treatment outcomes remain poor, particularly for depressive episodes, with over one-third of patients failing to respond to two or more first-line treatments. Hence, there is a clear need for novel and efficacious treatments for BD. However, there is a limited understanding of the neurobiology of BD, which poses as a major barrier to identifying truly innovative treatments.

Psilocybin is a chemical compound that naturally occurs in certain species of mushrooms, (for example, in the psilocybe genus, among others). It belongs to a class of drugs referred to as "psychedelics". Psilocybin is a tryptamine which is chemically similar to the neurotransmitter, serotonin, and the essential amino acid, tryptophan. It is considered a 5-hydroxytrptamineric (serotonergic) psychedelic along with other similar drugs such as dimethyltryptamine (DMT) and lysergic acid dieythamide (LSD). Psilocybin is a product for the pharmacologically active ingredient psilocin, which readily crosses the blood-brain barrier and acts as a potential partial agonist at serotonin 5HT2A and 5HT2c receptors in the brain. Typical effects of psilocybin include significantly altered states of consciousness, experienced through visual and auditory effects, changes in perception, distortions of time; and a range of effects including a sense of awe, novel perspectives, existential and personal insight, dramatically heightened empathy and feelings of compassion, strong emotions, and unitive experience. With proper screening and preparation, psilocybin has a safe physiological and psychological profile. Psilocybin is currently the preferred compound for use in clinical research involving 5-hydroxytrptaminergic psychedelics because it has a shorter duration of action and suffers from less notoriety and stigma than other similar drugs.

Two recently completed clinical trials have assessed the effects of psilocybin on TRD in participants with BDII. The first study was a non-randomized controlled trial that demonstrated a single 25 mg dose of psilocybin with accompanying PAP led to a decrease in MADRS scores in all study participants (n=15) at the 3-week primary endpoint. The second study was a randomized controlled trial that included participants with both unipolar (n=27) and bipolar treatment-resistant depression (n=4), wherein all participants received at least one 25 mg dose of psilocybin with accompanying PAP (with the exception of one participant who dropped out of the study before receiving the study intervention). Participants had the opportunity to receive up to two additional 25 mg doses of psilocybin with accompanying PAP, if they were eligible to receive a repeat dose as per the study protocol. Both trials demonstrated that 25 mg of psilocybin resulted in a decrease of depressive symptoms in participants with treatment-resistant bipolar depression, without increased incidence of manic or hypomanic symptoms.

Beyond the clinical benefits observed, psilocybin has provided several new insights into the neurobiology of depression, with dozens of additional, ongoing mechanistic studies underway. Neuroimaging studies evaluating the effects of psilocybin in treatment-resistant (unipolar) depression (TRD) have provided surprising neurobiological insights that have called into question several assumptions of mood disorders. In an open-label TRD trial evaluating the antidepressant and neurobiological effects of psilocybin, increased activity of the right amygdala was observed in response to fearful and happy faces post-treatment. Psilocybin's antidepressant effects were associated with increased right amygdala responses to negative emotional stimuli, an opposite effect to previous findings with selective serotonin reuptake inhibitors (SSRIs). Wherein SSRIs mitigate negative emotions, psilocybin might allow patients to feel, confront and work through them. These findings also suggest that neurobiological targets and mechanisms required to alleviate TRD, may be different from non-resistant depression, where SSRIs are often effective by reducing amygdala response to negative stimuli. Notably, the impact of psilocybin on amygdala function varies inter-individually depending on baseline mood state. More specifically, in healthy volunteers, psilocybin has been shown to decrease amygdala response to emotional stimuli, whereas in TRD, psilocybin was associated with increased amygdala response. Evaluating the effects of psilocybin in TRBD may improve the investigator's understanding of the neurobiology of bipolar depression by dynamically evaluating altered amygdala function and associated changes in depressive symptoms over time.