Is Use of Psychedelic Drugs a Risk or Protective Factor for Late-Life Cognitive Decline?

Cultural Perspective

Psychedelics have an extensive history of cultural and ritual use (Nichols, 2016). Psilocybin mushrooms have been consumed by humans for thousands of years. In ancient India, a hallucinogenic substance called “soma” (a plant extract) was consumed in rituals and praised frequently throughout Rigveda, the oldest sacred book of Hinduism (Britannica, 2020; Nichols, 2016). In an ancient village outside of Athens, there was an annual ceremony involving the ingestion of a hallucinogenic brew for more than 2,000 years (Nichols, 2016). Aztec shamans used psilocybin mushrooms for healing and divinatory rituals (Nichols, 2016). “Mescaline” derived from peyote cacti has been consumed by Native Americans during church services for millennia (Nichols, 2016). There are many other examples of the historical usage of psychedelics throughout various cultures. The historical consumption of psychedelics indicates that there are benefits to consuming psychedelics.

Although history and various studies indicate that psychedelics have positive impacts on well-being, psychedelic research lacks government support and funding from agencies, such as the National Institute of Health and the National Institute of Mental Health (Nichols, 2016). This is primarily due to political influences in the 1960s and 1970s because lysergic acid diethylamide (LSD) and marijuana users (often referred to as hippies) rejected social norms by protesting the Vietnam War, which was thought to be caused by drug use (Nichols, 2016). Mainstream culture thought that psychedelic use resulted in younger people rejecting social norms and war, and these substances have no established medical value (Tupper et al., 2015). This widespread false belief about psychedelics quickly led to the passage of the Controlled Substances Act of 1970, which placed all known psychedelics into Schedule 1, the most restrictive category of drugs (Nichols, 2016). This Act made clinical research on psychedelics impossible and terminated ongoing research regarding the useful properties of psychedelics (Nichols, 2016).

Since the 1960s, recreational psychedelic use in Western societies has been increasing regardless of the drug classification. Over 30 million people in the United States have consumed classic psychedelics, such as psilocybin, LSD, or mescaline (Krebs & Johansen, 2013). Research suggests some other substances also produce similar hallucinogenic effects and considered as atypical psychedelics, such as marijuana/cannabis (Wolinsky et al., 2024). Further, it is evidenced that some antidepressants, such as St John’s wort (Ferrara et al., 2017; Gurok et al., 2014) and Fluoxetine (Webb & Cranswick, 2003), and some tranquilizers (Kadriu et al., 2021) also produce some hallucinogenic effects. Psychedelic therapy for treating various mental health disorders is gaining popularity, and people are beginning to become more open-minded about psychedelic therapy. For example, in Canada, many people support legal access to psilocybin therapy, and the Canadian government recently began allowing physicians to use psilocybin therapy in patients with terminal medical conditions (Canadian Psychedelic Association, 2021). The increasing championship for psychedelic therapy from governments and societies may promote human longevity by benefiting individuals’ cardiometabolic health (Simonsson et al., 2021).

Psychedelic Therapy

Current treatment options for neurocognitive and mental health disorders are limited to some medications and psychotherapies, such as antidepressants and cognitive-behavioral therapy, respectively (Craighead & Dunlop, 2014). Medications are typically the preferred treatment, but these drugs are usually prescribed for longer periods and often cause adverse health effects (Craighead & Dunlop, 2014). When medications and psychotherapy are not effective in treating neurocognitive and mental health disorders, alternative therapeutic options should be taken into consideration. Psychedelic therapy is the clinical administration of psychoactive compounds in a controlled setting. Psilocybin and LSD are two psychoactive compounds being increasingly researched regarding their health benefits (Yehuda & Lehrner, 2023). Psilocybin is a chemical compound produced naturally by hundreds of fungi species. LSD is a synthetic chemical compound discovered and synthesized by Albert Hoffman in 1938 (Pallardy, 2022).

Multiple studies have shown that classic psychedelics (e.g., psilocybin and LSD) and atypical psychedelics (e.g., cannabis) may be useful in treating mental and neurocognitive disorders due to their ability to stimulate neurogenesis, produce neuroplastic changes, and reduce neuroinflammation (Vann Jones & O’Kelly, 2020; Vollenweider & Preller, 2020; Wolinsky et al., 2024). Neuroinflammation is significantly associated with the development of Alzheimer’s disease and is considered the most common form of dementia (F. Zhang & Jiang, 2015). In this context, neurogenesis is the formation of neurons in the brain, which is important for learning and memory (Maharjan et al., 2020; The University of Queensland, 2021), and neuroplasticity refers to the brain’s ability to adapt to new stimuli and control how neurons communicate (Maharjan et al., 2020; The University of Queensland, 2018). Neurotransmitters are chemicals that communicate signals between neurons and from neurons to muscles (The University of Queensland, 2017) and are essential for maintaining homeostasis and adequate brain functioning. Psychedelics, also called serotonergic hallucinogens, are non-addictive substances that affect the central nervous system by acting as agonists on serotonin (5-HT2A, 5-HT1A, and 5-HT2C) receptors (Psiuk et al., 2021). Serotonin (5-HT) is a key neurotransmitter that affects mood, emotion, sexuality, breathing, stress, addiction, sleep, and digestion (Watson, 2021).

Cognitive Health and Psychedelic Therapy in Late Life

Although aging is an individualized process, some degree of cognitive decline is considered to be a normal aspect of aging. Older adults typically experience some decline in receiving, interpreting, transmitting, and processing information (Saxon et al., 2014, p. 85). Relatedly, episodic memory and executive function are two major cognitive domains that have been studied extensively (Glisky et al., 2022). Older adults experiencing normal age-related cognitive declines are still able to perform activities of daily living and instrumental activities of daily living. However, often, older adults experiencing progressive deterioration in their memory, communication, reasoning, judgment, and attention end up with some type of dementia (Bhattacharyya, Andel, & Small, 2021; Lee et al., 2013). Dementia is an umbrella term for neurocognitive disorders that impair a person’s ability to think, remember, and perform activities of daily living (Duong et al., 2017). Dementia is not a normal aspect of aging. The number of dementia cases is increasing significantly due to population aging, which is worrisome because of its expensive management options and non-curable nature. The prevalence of dementia is expected to quadruple by 2050 (Rocca et al., 2011). Persons with dementia require extensive formal and informal support. However, there is a dearth of adequately trained healthcare professionals caring for persons living with dementia (Surr et al., 2017). Globally, dementia costs $1.3 trillion annually and causes a significant decrease in life quality; thus, it is essential to find effective treatment and therapy options for dementia (Alzheimer’s Disease International, 2015, 2020). Ideally, people should aim to preserve their cognitive functions early on by doing mentally stimulating activities, such as meditation, yoga, reading, physical exercise, socializing, and learning a new language. Focusing on the prevention of health conditions can combat the increasing prevalence of age-related diseases like dementia. Health interventions after disease progression are not as effective as preventing diseases altogether.

Purpose of the Study

Nevertheless, there is an urgent need to find effective prevention, treatment, and alternative therapy options for late-life cognitive decline and dementia. Not much clinical research has been conducted considering the impact of classic psychedelics and other hallucinogenic compounds on cognitive functions, particularly episodic memory and executive function, and depression in middle aged and older adults; the current study will examine the above associations in a publicly available national dataset, the Midlife in the United States (MIDUS). In line with the earlier research, we hypothesize that the use of classic psychedelics and other hallucinogens would improve cognitive functions and reduce depressive symptoms in middle-aged and older adults.

Study Sample

We used data from the third wave of the MIDUS study. The MIDUS 3 study was conducted in 2013 to 2014, with 3,294 English-speaking participants from the U.S. households in the 48 contiguous states (Bhattacharyya, Hueluer, et al., 2021; Hughes et al., 2018). In wave 3, participants were aged between 42 to 92 years (M = 64 ± 11, 55% women) (Lachman et al., 2014). MIDUS 3 was conducted through the phone, along with a mailed self-administered questionnaire (SAQ).

Measures and Procedure

Statistical Analysis

We conducted statistical analyses using Stata 18.0 SE (College Station, TX) software. To examine the association between the usage of psychedelic agents and the cognitive functions of individuals, we estimated multiple linear regression models by predicting executive function, episodic memory, and depressive symptoms (dependent variables) in separate models while controlling for covariates (sociodemographic factors and health status). These models only included predictor variables that showed significant group differences associated with psychedelic use. Statistical significance was evaluated at p < .05 (two-sided). We reported unstandardized regression coefficients (β) and standard errors (SE).

Limitations

Multiple limitations should be considered in interpreting the current result. First, psychedelic therapy requires longer time than other therapies (up to 12 hr per session), a properly prepared environment for the therapy session, and monitoring throughout the session (Psiuk et al., 2021). Because of its cross-sectional nature, our study did not consider longer follow-up. Another issue with psychedelic therapy is that the hallucinations caused by psychedelic compounds may be too overwhelming for some patients (Psiuk et al., 2021). Although from the nature of the MIDUS questionnaire it seems that much of the use was as off-label recreational purposes, with little understanding of dosage or safety, side effects and high dosages of certain psychedelics may outweigh the benefits. The most common side effects of psychedelic therapy are short-term anxiety, psychological discomfort, headache, nausea, and vomiting (Psiuk et al., 2021). Micro-dosing (small, reoccurring doses that do not alter perception) psilocybin or LSD may be a useful option for those who want to prevent the hallucinogenic effects. However, from the existing MIDUS data, it is impossible to find out the exact form, frequency, and dosing of psychedelics used by the participants, inducing generalizability concerns. Additionally, given the broad age range of participants, from middle-aged to older adults, a potential generalizability bias in the results may arise from variations in baseline cognitive functions. Finally, even after growing scientific interest in psychedelic medicines in recent years, their usage is limited even by physicians, probably due to hesitancy from its scientific evidence of risks and limited latest knowledge about psychedelics. For example, only a little over 8% of participants used psychedelics (including both classical and atypical psychedelics), as a key limitation of our analysis, posing some concern about our result; however, many participants were hesitant (around 1.5% refused to answer the question) to respond about psychedelic usage, reducing the chance of achieving stronger findings.