The Coin Toss of Psychosis Risk: Psychosis Proneness, Menopause and Psychedelics
In the lore of psychedelic substances lies the “never-ending trip”, rooted in a somewhat common fear that if you opt to have a psychedelic experience, you might have a psychedelic-induced psychotic break and never feel normal again; doomed to a life-long ‘bad trip’. Although this myth was partially the result of occasional frightful media publications around the time psychedelic substances were deemed illegal in the 1960s, this fear has taken hold in the collective idea around what risks psychedelics can pose to an individual. However, psychosis risk is a complex issue and is still in its scientific infancy, with the psychosis continuum only having been introduced in the 1990s. The truth is that some individuals do have a higher chance of developing psychosis over the lifetime, and that this experience is not a binary, which is known as having higher psychosis proneness. Being aware of this truth of mental ill health rather than scoffing at an old myth such as the “bad trip” is vital to create a conscientious field of psychedelic science, as we look at some psychoactive substances potentially being approved for psychological therapy soon. Adding psychedelics to the already complex cake batter that is psychosis risk will make for an even more complicated cake. Researching the connection between psychedelics and psychosis risk is an important endeavour to decrease risk and user ignorance, and looking to individuals who might be more at risk for psychosis such as women above 45 can help us create more meaningful and safe psychedelic experiences for individuals who opt for psychedelics as a therapy.
The psychosis-proneness–persistence–impairment model of psychosis theorises that the experience of psychosis is a continuum, meaning healthy individuals can experience temporary symptoms of psychosis without needing clinical care. (1) Research suggests that mean lifetime prevalence of having a psychotic experience (PE) is around 5% in the general population (2, 3), with analyses suggesting that 75-90% of these were transitory expressions and disappeared over time (3). PEs have been organised in a three-factor model based on phenotype – positive, depressive and negative (4). Although most PEs never lead to clinical impairment, the model theorises that clinical impairment ensues when subclinical PEs remain constant over time (3). In an 8-year long cohort study, 38.3% participants who developed clinical psychosis had experienced at least 1 incidence of PE prior to diagnosis, and 19.6% had more than two occurrences. (5) These findings suggest that development of clinical psychosis is a rare negative outcome of a more common and less invasive experience of psychosis. Clinical psychosis and psychosis proneness in turn have similar symptomology and risk factors, and understanding psychosis proneness can help define environmental risk factors that contribute to clinical impairment and thus improve early detection of high-risk individuals (6, 7).
The current dominant understanding is that late-adolescent males are most at risk for developing clinical psychosis (8, 9). However, more recent exploration shows that later age of onset (first age of onset after 40 years of age) (10) is more common than previously thought (11, 12), with studies showing that 66-87% of individuals who develop first-episode schizophrenia after 40 years of age are women (13). Yet, due to large epidemiological studies often applying an upper age limit of 45 to 55 years, females over 45 are excluded from vital research. This creates a clear gender bias in the data available, as there are higher incidence rates in the females over 45 group (14); information lost due to age-biased recruitment. When looking at data pertaining to development of psychosis over the lifetime within female only groups, there is a second peak of first-time episodes in the 45-55 age bracket which is not seen in male only groups (15, 16), an occurrence that is speculated to be caused by the hormonal changes tied to menopause (17).
The menopausal transition marks the end of the female reproductive years and is characterised by the disruption of the menstrual cycle due to senescent biological changes, such as a decline in oestrogen levels (18). Menopausal women experience both psychological (e.g. anxiety, depression) and physiological symptoms (e.g. sleep disturbances, hot flashes) most likely due to the deficiency of oestrogen at this time (19), negatively affecting quality of life (20). Furthermore, menopause impacts neurocognition as oestrogen regulates metabolism and increases cerebral blood flow (21). Animal models demonstrate how neurobiological changes can leave women particularly vulnerable to psychosis due to changes in dopamine sensitivity (22); a key mechanism in context of psychosis risk (23) and use of psychedelics which is suggested to act on the same receptors (5-HT2A/B). Depletion of circulating oestradiol (the main component of oestrogen) during menopause has been associated with an increase in psychiatric symptoms by disrupting the mesolimbic reward system, which can trigger psychosis (24). Studies suggest oestradiol treatment can reduce psychotic symptoms in postmenopausal women (25, 26), an effect replicated in individuals with postpartum psychosis (27) – a disorder in which the abrupt withdrawal of oestrogen is speculated to be at the centre of its aetiology (28). Oestradiol treatment is also widely used for reducing menopause symptom severity (29-31). These effects are thought to be induced by the changes oestrogen causes the receptors involved in mood regulation and serotonin production, namely 5-HT2A, which are also found to be activated by a range of psychedelics often used for therapeutic purposes (32). This similarity means that although there might be potential unique benefits in psychedelics for menopausal women, there might also be unique risks. Studies have found that activating dopaminergic neurotransmission (i.e. via psychedelic compounds) can potentially cause a pathological overactivation of the 5-HT2A receptor which could lead to psychosis (34). Unfortunately, due to the lack of exploration of estrogenic effects on cognition, it is difficult to know who would be at risk and who would benefit from further activation of these receptors as research indicates both outcomes are possible.
The lack of studies limits comprehension of the complex relationship between influencing factors and female-specific psychosis risk. For clinicians giving mental health recommendations and in turn the general population, increasing understanding is imperative to decrease risk and increase early prevention of psychosis, as well as making sure individuals approach the experience of psychedelic use with caution and full awareness of their own personal situation. Currently, both psychosis proneness in females over the lifetime and psychedelic effect in female neurocognition is underexplored scientifically, causing women to be underinformed when making decisions around their health. Psychedelics can both be of great benefit but also of great risk, and with further investigation we can create better guidance for women and eliminate the coin toss. Furthermore, cognizance of personal psychosis risk has been shown to increase overall quality of life for at-risk persons, a consideration that should be extended to female populations over 40.
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