Pherines are a novel class of synthetic neuroactive steroids formulated to engage human nasal chemosensory receptors (nongenomic effect). They are administered intranasally and detected by olfactory afferents wired directly to the limbic amygdala. Due to this mechanism, they have rapid and potent effects on behavior and the autonomic nervous system (e.g., decreased sympathetic tone, decreased cardiac and respiratory rate) (Figure). Connections between the olfactory bulb and amygdala are compatible with the neural circuits involved in the pathophysiology of social anxiety disorder, specific phobias, generalized anxiety disorder, and depression. Thus, pherines are being studied for the treatment of anxiety and depression. Androsta-4,16-dien-3β-ol (PH94B), a neuroactive steroid from the androstane family of pherines has been shown to be more effective than placebo in reducing both performance and social anxiety in individuals with social anxiety disorder. Furthermore, compared to placebo, PH94B has been shown to significantly decrease peak anxiety during social and performance events in the daily lives of patients with social anxiety disorder. Notably, anxiolytic effects of PH94B have been observed as early as two weeks after first dose and are comparable to effects seen after 12 weeks of FDA-approved medications for social anxiety disorder. A different neuroactive steroid pherine molecule from the pregnane family, pregn-4-en-20-yn-3-one (PH10), has been shown to reduce symptoms of depression more than placebo in individuals with major depressive disorder. Similar to PH94B, separation of PH10 and placebo appeared during the first week of treatment. The rapid onset of action of pherine molecules can be explained by their mechanism of action (Figure). Finally, pherines have a favorable safety profile, as their administration bypasses systemic administration and the blood-brain barrier. Pherines may be a novel and safe option for treating psychiatric conditions that require acute intervention, such as anxiety and depression, but additional human investigation is needed.
Figure. Hypothesized mechanisms of pherine activity. PH94B may induce a rapid decrease of sympathetic tone and rapid improvement of anxiety by stimulation of olfactory bulb neurons projecting to medial amygdala and basolateral amygdala that, in turn, trigger the forward inhibitory GABAergic and-PKCδ-positive OFF-neurons in the centrolateral (CeL) and centromedial (CeM) amygdala. These actions then lead to downstream effects on hypothalamus and bed nucleus of the stria terminalis to regulate innate defense responses, as well as on locus coeruleus (release of neuropeptide S) and midbrain (ventral tegmental area, raphe nucleus) to decrease sympathetic system tone. On the other hand, PH10 may induce rapid changes in sympathetic tone and dose-dependent improvement in depression via activation of glutamatergic neurons in the basolateral amygdala that, in turn, trigger GABAergic-PKCδ-negative ON-neurons in the CeL, with downstream effects on bed nucleus of the stria terminalis and prefrontal cortex.
Reference:
Monti L, Liebowitz MR. CNS Spectr 2022;27(1):66-72. Abstract