Pherines in Psychiatry: A Potential New Paradigm for the Treatment of Mental Disorders


Pherines, also known as vomeropherines, are synthetic, odorless, neuroactive steroids designed to engage human nasal chemosensory receptors. The development of pherines as psychotropic agents is rooted in a series of foundational research studies that have progressively unraveled the neurochemical pathways of the human olfactory system. Seminal investigations into the human vomeronasal system by Monti-Bloch et al. (4) and Berliner et al. (5) uncovered the existence and function of the vomeronasal organ in humans.


Subsequent research delved into the neurochemical mechanisms underlying the vomeronasal system’s influence on behavior and mood regulation. Similar to pheromones, pherine chemical signals are detected by nasal chemosensory receptors, facilitating rapid neuronal transmission to the amygdala, the hypothalamus, and the prefrontal cortex (PFC) (3). Certain pheromones, specifically androstenol, an odorless steroid that modulates γ-aminobutyric acid (GABA) receptors, can activate nasal chemosensory cells and affect the experience of fear and anxiety (6–8). Androstenol’s effect on the autonomic nervous system played an important role in explaining the broader implications of synthetic neuroactive steroids, such as pherines, in major depressive disorder (1, 9). Although the true mechanism of action for pherines has not been fully established, the theory behind their efficacy is based on the understanding of GABA and catecholamine release in mood regulation. Pherines are thought to modulate GABAergic neurons in the PFC, reducing dendritic inhibition of glutamatergic pyramidal neurons and regulating the excitability of serotonergic neurons in the dorsal raphe nucleus via the GABA-glutamate balance (10). Notably, because the serotonergic neurons are activated via the olfactory system, no systemic absorption is necessary (11, 12). Interestingly, chronic stress affects local networks that regulate activity within the medial PFC, leading to changes in local excitatory-inhibitory balance, a potential target for pherines’ therapeutic effect (10).


This proposed mechanism of action provides insights into the complex neurobiological processes involved in mood regulation and the potential therapeutic benefits of manipulating these circuits without the need for systemic absorption, presenting a unique mode of influencing brain activity and behavior. Despite the unique mechanism of action of this emerging drug class, pherines have received only limited attention in the psychiatric literature (2, 3, 13).


Itruvone, also known as PH10, is administered via nasal spray and influences neural brain circuits by acting on nasal chemosensory receptors, particularly affecting the limbic amygdala and basal forebrain structures, thereby exerting antidepressant effects (14). A pilot phase 2 study demonstrated a therapeutic dose-dependent improvement in symptoms among patients with major depressive disorder after 1 week of treatment (15). This study was followed by a larger phase 2a double-blind randomized controlled trial with 30 patients, in which patients treated with self-administered intranasal itruvone showed significant improvement in depressive symptoms compared with those who received placebo, as measured by reductions in scores on the 17-item Hamilton Depression Rating Scale (HAM-D) after a 9-week parallel group trial at a single site (14). Notably, both the high-dose (3.2 µg twice daily) and low-dose (1.6 µg twice daily) groups showed mean reductions in HAM-D scores of 17.8 and 16.3, respectively, versus 10.9 in the placebo group (with a Cohen’s d effect size of 0.74 for the low-dose group and 0.95 for the high-dose group). The study reported minimal adverse effects and a rapid onset of effects within the first week. The responder and remission rates were also higher in the itruvone groups. However, some adverse events, such as increased appetite, sleepiness, nasal dryness, headache, and bitter taste, were more common with itruvone than with placebo. Of note, one limitation of this study was the small sample size of 30 participants. Additionally, PH10 appears to lack benzodiazepine-like adverse effects or addictive potential while still providing acute relief of depressive symptoms. However, its mechanism of action is not fully understood, and further study is required (16).


Fasedienol, also known as PH94B, is a therapeutic agent currently in development for the acute treatment of social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder (17). Similar to other pherine compounds, fasedienol is a neurosteroid that modulates the olfactory-amygdala neural circuit and is administered intranasally in microgram doses with rapid onset (18).


In 2016, a randomized double-blind, placebo-controlled crossover study with a 2-week trial of treatment with intranasal fasedienol was successfully completed (18). This phase 3 clinical trial was designed to evaluate the efficacy and safety of intranasal fasedienol in real-world social and performance situations encountered in daily life by patients with social anxiety, extending findings from previous laboratory-based challenges. The trial revealed a statistically significant decrease (15.6 points for fasedienol vs. 8.3 points for placebo, Cohen’s d=0.66) in the average Subjective Units of Distress Scale (SUDS) score during a public-speaking challenge for patients treated with fasedienol compared with those receiving a placebo. The design of the study allowed participants to serve as their own control subjects, reducing the impact of interindividual confounding variables. Of note, the study had a small sample size of 22 participants, limiting its statistical power. Adverse effects reported for intranasal fasedienol were similar to those for placebo. However, a significant therapeutic carryover effect was found when participants were switched from treatment to placebo (i.e., individuals who started with treatment, when switching to placebo, experienced reduced anxiety compared with the group that started with placebo).


In 2023, a multicenter randomized double-blind, placebo-controlled phase 3 trial revealed a significant difference between fasedienol and placebo groups in the proportion of responders assessed by clinicians using the Clinical Global Impressions–Improvement scale. The study yielded statistically significant results comparable to those of the first trial but with greater statistical power due to a larger sample size of 141 participants (19). Fasedienol-treated patients had a statistically significantly greater change in mean SUDS score (least-squares mean=–13.8) compared with those who received placebo (least-squares mean=–8.0), for a difference in SUDS score between groups of –5.8 (p=0.015). The trial found that fasedienol was well tolerated, with no severe or serious adverse events reported (19). The findings of this study indicated statistically significant improvements in both the primary end point (change in mean SUDS score during a public-speaking challenge) and secondary end point (proportion of clinician-assessed responders), suggesting fasedienol’s potential efficacy in reducing anxiety symptoms. However, because of the trial’s short-term assessment, any generalizability and comprehensive evaluation of long-term effects remains limited.


Recent advances in psychiatric pharmacotherapy have shown promise for the use of pherines such as itruvone and fasedienol to modulate mood and anxiety, representing a novel therapeutic approach targeting nasal chemosensory receptors with rapid onset at single-digit microgram doses and without the systemic absorption associated with traditional oral medications. This innovative mechanism promises an onset of therapeutic effects that is significantly faster than those for SSRIs and TCAs (20).


Moreover, pherines’ targeted action aims to circumvent the common systemic adverse effects and drug-drug interactions seen with SSRIs and TCAs, addressing a significant limitation of these older drug classes (20). In contrast to benzodiazepines, which are effective for rapid anxiety relief but burdened by increased risks for sedation, dependency, and cognitive impairment, fasedienol exhibits an efficacy profile potentially devoid of these issues, because it does not bind directly to the GABAA receptor. Additionally, itruvone’s ability to target catecholamine release from the brain indirectly through the olfactory system is a mechanism of action unlike those for all currently approved oral antidepressants and rapid-onset ketamine-based therapy, including both intravenous and intranasal ketamine. Therefore, both fasedienol and itruvone may offer a safer alternative for certain patients.


Although the treatment concept is promising, the comparative efficacy and safety of pherines relative to established treatments remain to be comprehensively evaluated in head-to-head clinical trials. Such research is crucial to delineate the therapeutic window, optimal dosing strategies, and the long-term safety profile. As the field awaits more robust data, preliminary findings suggest that pherines may offer a valuable addition to the psychiatric treatment arsenal, potentially providing a more rapid well-tolerated option for managing acute episodes of depression and anxiety.