Summary

There are currently no disease-modifying drugs for Alzheimer's disease (AD) or other dementia subtypes. The renaissance of research on psychedelic substances in recent years, particularly studies on psilocybin and lysergic acid diethylamide (LSD), combined with anecdotal reports of cognitive benefits from microdosing, suggest that they may have a therapeutic role in a variety of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, induce neuroplastic changes and reduce neuroinflammation. This mini-review will present the scientific basis and current clinical evidence on the role of psychedelics in the treatment of dementia, particularly early AD, with a focus on the microdosing of the classic psychedelics LSD and psilocybin.

Introduction

Globally, an estimated 50 million people are diagnosed with dementia and the prevalence in the population continues to rise. Alzheimer's disease (AD) accounts for approximately 50-70% of dementia cases.

AD is a progressive neurological disorder characterised by the deposition of extracellular amyloid proteins and aggregates of tau proteins (called tangles), which, along with their accumulation, are associated with various pathological processes, including microtubule damage, impaired axonal transport and, ultimately, cell death. The hippocampus, a key structure responsible for the ability to learn and remember information and the site of neurogenesis, is particularly susceptible to AD pathology and is one of the earliest affected brain areas.

There is currently a renaissance of research into the use of psychedelic substances, powerful 5HT2A receptor (5HT2A-R) agonists, in psychiatric and neurological disorders. The 5HT2A receptor is found in high concentrations in areas of the brain prone to dementia, such as the prefrontal cortex and the aforementioned hippocampus. Psychedelics induce brain plasticity and modify connections between brain areas, and there is ample anecdotal evidence of cognitive benefits from microdosing, i.e. dosing that does not cause perceptual changes or functional impairment. There are also many reports of greater productivity after taking a microdose of psilocybin and no noticeable subjective or objective differences after taking five micrograms compared to placebo.

This mini-review will explore the role of classic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), in the treatment of AD, focusing on subliminal or 'micro' dosing. Stimulating 5HT2A receptor-mediated neuroplasticity and neurogenesis in areas such as the hippocampus could theoretically help protect this and other brain structures, which could open up treatment options for AD.

Effects on cognitive functions

A high dose of psilocybin reduces attention to both clinical and electrophysiological parameters. However, this may be due to increased awareness of sensory stimuli that are normally filtered out (cos

For younger adults, the only controlled studies of LSD microdosing (n = 20 and n = 24, respectively), both based on a single-subject design, found no effect, either positive or negative, on cognitive function in healthy volunteers at various subthreshold doses (Bershad et al., 2019; Hutten et al., 2020). Participants had previous experience with psychedelics. The first study used placebo, 6.5, 13 and 26 μg, and the second study placebo, 5, 10 or 20 μg. In the second study, there was an objective increase in psychomotor alertness (and subjective feelings of happiness and mood), but at the same time a paradoxical reduction in concentration and a reduction in the ability to change approach on the highest microdose (20 μg) a few hours after ingestion. Participants also reported greater subjective productivity at 10 micrograms and no noticeable subjective or objective differences at five micrograms compared to placebo. It is important that participants were aware that they were taking the active substance at the two higher doses and had experience of using the substance recreationally.

In 2018, an uncontrolled, open-label naturalistic study was conducted, which showed increased cognitive fluency, flexibility and originality among 33 participants after taking various microdoses of psilocybin (Prochazkova et al., 2018). However, the results should be interpreted with a degree of caution due to the risk of selection bias (the study was organised by the Dutch Psychedelic Association), the lack of a placebo control group, the risk of practice effect bias and the lack of analysis using intention to treat.

For older adults, a recent double-blind, placebo-controlled study of older adults (n = 48) who had not taken LSD for at least 5 years showed no difference in adverse events (including cognitive impairment

in those taking placebo, doses of 5, 10 or 20 μg every 5 days for 28 days (Family et al., 2020). Headaches were reported more frequently in those taking LSD, but the small number of participants and non-linear dose response make interpretation of these results difficult. Overall, the drug was well tolerated, with no serious side effects or withdrawals.

Longer lasting effects

In rat models, activation of the 5HT2A-R receptor with a mid-dose of psilocybin (0.13 mg/kg) increases both prospective and retrospective learning, and the effects are smaller at a low dose (0.06 mg/kg; Buchborn et al., 2014; Cini et al., 2019). Daily administration of further doses reduces the benefits, and older rodents benefit from a rich environment, which enhances their learning ability (Buchborn et al., 2014).

An observational study of 89 recreational microdosing users of psychedelic substances showed self-reported improvements in a number of psychological areas, including creativity and attention, sustained over 6 weeks (Polito and Stevenson, 2019). Studies of recreational microdosing, which are prone to bias but select long-term users, report improvements in concentration and cognitive attention (14 to 61% of users; Anderson et al., 2019; Hutten et al., 2019; Lea et al., 2020b). However, only one of these studies reported data on length of use, where 60.5% of respondents used microdosing for 3 months or longer (Lea et al., 2020b).

No adequately controlled studies have been conducted on microdosing in cognitively impaired patients or on the effects on cognitive function and mood beyond the caution phase. However, studies on high doses of LSD and psilocybin have shown long-term benefits for mood. A study of 16 healthy participants showed subjective benefits from a single dose of 200 μg LSD after 12 months, with 10 participants ranking the experience as one of the 10 most important in their lives (Schmid and Liechti, 2018). In 10 patients with a life-threatening illness, therapy with LSD significantly reduced anxiety, and this effect persisted in 77.7% of them for 12 months after therapy. Two-thirds of respondents also reported an improved quality of life as a result of the experience (Gasser et al., 2015).

Similar results were observed following high-dose psilocybin in both patients with life-threatening cancer-related anxiety and cancer-related depression and anxiety (n = 51 and 29 respectively, both crossover designs; Griffiths et al., 2016; Ross et al., 2016). Both studies showed that approximately 60-80% of participants had a clinically meaningful response that lasted approximately 6 months. The second study also conducted follow-up 4.5 years later and found that these results persisted, with 71-100% of participants stating that this experience was one of the most important in their lives (Agin-Liebes et al., 2020).

In the treatment of treatment-resistant depression, the administration of 10 mg and 25 mg psilocybin 1 week apart (n = 20) led to a clinical response or remission in 14 participants, sustained at assessment after 5 weeks. This effect was also maintained at 6-month follow-up, despite no further treatment (Carhart-Harris et al., 2018).

These promising results led in part to the approval of a high-dose trial of psilocybin, specifically targeting depression in early Alzheimer's disease (Clinicaltrials.gov, 2020).

Neurobiological effects

Specific 5HT2A-R receptor polymorphisms impair verbal memory and object recognition, and reduced 5HT2A-R receptor concentrations in brain areas responsible for key memory processes are associated with poorer cognitive performance (Schott et al., 2011). Activation of 5HT2A-R prior to a task enhances long-term synaptic potentiation in the hippocampus and enables the reconsolidation of fear conditioning in the amigdala, confirming a key role for neuroplasticity (Catlow et al., 2013; Zhang et al., 2013). This effect can be reproduced in rats and rabbits using very low doses of the substance

psychedelics, but is inhibited by higher doses (Romano et al., 2010; Cameron et al., 2019). In rats, activation of 5HT2A receptors stimulates neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the neocortex, but appears to simultaneously inhibit the same process in the hippocampus (Vaidya et al., 1997). This may be dose-dependent, with higher doses inhibiting neurogenesis above a certain threshold. Activation of 5HT2A receptors also stimulates proliferation and growth of dendritic spines in rat neuronal cultures (Jones et al., 2009; Yoshida et al., 2011). In a mouse model taught conditioned fear, both low and high doses of psilocybin led to complete disappearance of the fear response to the auditory stimulus (Catlow et al., 2013). This process was faster at lower doses, where neurogenesis in the hippocampus was not impaired. In cultures of rat and Drosophila larval cortical neurons, LSD stimulates neurogenesis and synaptogenesis in a dose-dependent manner, suggesting an important evolutionary interspecies pathway for this effect and the possibility that the optimal dose could be used therapeutically for this purpose (Ly et al., 2018).

There is also an optimal frequency of doses. Repeated administration of LSD and/or psilocybin leads to a rapid onset of tolerance to psychological effects, which peaks after only four consecutive daily doses, cannot be overcome even with significant dose increases or switching to another substance (cross-tolerance) and is completely reversed after 5 days of abstinence (Buchborn et al., 2016). In rats, high doses of LSD (0.16 mg/kg) administered every 2 days for 90 days led to symptoms of hyperactivity and antisociality (Martin et al., 2014). The aforementioned double-blind placebo-controlled study in older adults using a schedule of one dose every fourth day (Family et al., 2020). This may be optimal, as cross-tolerance is unlikely to

likely at this frequency and, importantly, side effects were minimal and not significantly different from placebo.

Neurophysiological effects

Human gamma oscillations (30-100 Hz) in neuronal networks are important for communication between brain areas, especially those related to attention and memory (Jensen et al., 2007; Verret et al., 2012; Mably and Colgin, 2018). These networks become disrupted decades before the onset of symptoms in Alzheimer's disease, which may be related to dysfunction of inhibitory interneurons leading to a disruption of the gamma-dependent temporal structure of cortical processing, which enables coherent packaging of sensory information (Weber and Andrade, 2010; Palop and Mucke, 2016).

Studies on mild cognitive impairment and Alzheimer's disease show conflicting results regarding gamma activity levels of sensitive brain areas and networks (König et al, 2005; Van Deursen et al, 2008; Basar et al, 2017; Wang et al, 2017). However, a recent study found that the gamma frequency response slows down in Alzheimer's patients in response to a stimulus, suggesting that the increase in gamma power observed in some studies in Alzheimer's patients may be due to increased use of brain resources to maintain a resting state (Basar et al., 2016). The same researchers also found that, compared to controls, Alzheimer's patients had increased connectivity in the distant gamma frequency (Basar et al., 2017). It is possible that this increase in gamma activity is an initial response to brain damage, but this process may be exhaustive.

In a recent study, increasing the frequency of gamma oscillations with external stimuli reduced amyloid burden, possibly through increased microglia activity, and improved cognitive function

in rodents (Laccarino et al., 2016; Martorell et al., 2019). 5HT2A-R receptor agonists increase the power of recorded gamma oscillations, suggesting a role for the 5HT2A-R receptor in mediating long-distance projects and reducing focal Alzheimer's pathology (Puig et al., 2010; Athilingam et al., 2017).

Neuroimaging

In Alzheimer's disease, global brain glucose metabolism is reduced, particularly in frontal and temporal-occipital areas (Garibotto et al., 2017; Rice and Bisdas, 2017). One PET-FDG study of psilocybin in healthy volunteers showed that acute ingestion of a 15 mg or 20 mg dose increases global brain glucose metabolism by approximately 25 per cent, particularly in the prefrontal and temporal-occipital cortex (Vollenweider et al., 1997).

A 2019 fMRI study showed sustained benefits at 4 months after a single dose of 315 μg/kg psilocybin in a group of 38 meditators (Smigielski et al., 2019). Changes in acute MRI scans - a reduction in connectivity between the medial prefrontal cortex and ventral tegmental cortex centres - were associated with positive changes after 4 months. A 2020 fMRI study of 16 depressed patients who took a single dose of 10 mg psilocybin and 25 mg a week later showed increased functional connectivity between the cortex and the default rim in those who responded the day after treatment, with these changes persisting for 5 weeks after administration (Carhart-Harris et al., 2017b). Increased functional connectivity occurred between areas of high 5HT2A receptor density, suggesting that reorganisation of dysfunctional neuronal networks is an important component of the neuroplastic effects of 5HT2A-R agonists (Tagliazucchi et al., 2016; Deco et al., 2018