Psychedelic interventions for major depressive disorder in the elderly: Exploring novel therapies, promise and potential

Abstract

The global population is ageing rapidly, with the number of individuals aged 60 and older reaching 1 billion in 2019 and expected to double by 2050. As people age, neuropsychological health often deteriorates, leading to a higher prevalence of age-related depression. Symptoms may include anxiety, apathy, mood instability, sadness, and, in severe cases, suicidal thoughts. Depression in the elderly is a widespread concern, and conventional treatments such as antidepressants are often limited by side effects, reduced efficacy, and complications arising from polypharmacy. In response, novel therapeutic approaches are being explored, including psychedelic interventions. Recent clinical and preclinical studies suggest that psychedelics could offer a promising treatment for major depressive disorder (MDD) in older adults. These compounds, known for their profound neurobiological effects, have gained attention for their potential to address depression where traditional therapies fall short. This review aims to examine the therapeutic promise of psychedelic substances, focusing on those that show potential for treating MDD in the elderly. We also explore the underlying mechanisms through which psychedelics may exert their effects and highlight the preclinical models that support their use. Finally, we address safety considerations and propose strategies to enhance the effectiveness and safety of psychedelics in future clinical trials, offering new hope for treating age-related depressive disorders.

Keywords: Psychedelic-assisted therapy; age-related comorbidities; ageing and depression; mental health care.

Figure 1.

Activation of 5HT receptors by psilocybin and LSD: Implications for neuroplasticity and therapeutic potential in major depressive disorders. The activation of 5-HT2A receptors by psilocybin and LSD induces a cascade of neuropsychological changes in both humans and rodent models. A key advantage of this receptor-mediated mechanism is the enhancement of brain neuroplasticity. The neuroplasticity model of depression posits that disruptions in the brain’s self-regulatory mechanisms occur at various levels, including cellular, molecular and psychological domains. Psychedelics appear to counteract these disruptions, thereby restoring neuroplasticity. LSD administration has been shown to elevate serum levels of BDNF, a finding corroborated by a clinical study conducted on healthy human subjects, where significant increases were observed at 4- and 6-hour post-administration. BDNF binds to TrkB receptors, activating intracellular signalling pathways critical for neuronal survival and differentiation. Additionally, the activation of 5-HT2A receptors expressed on glutamatergic pyramidal neurons, particularly in cortical layers V and VI, mediates the effects of both LSD and psilocybin on serotoninergic and glutamatergic neurotransmission. Psilocybin has demonstrated potential in promoting synaptogenesis in patients with mild cognitive impairment. Furthermore, both LSD and psilocybin enhance neurogenesis and synaptogenesis, positioning these compounds as promising therapeutic candidates for neurodegenerative conditions, particularly in elderly populations. Finally, the psychological effects induced by psychedelics have been extensively observed in both clinical settings and preclinical models of depression. These findings highlight their multifaceted therapeutic potential, encompassing neuroplasticity enhancement and psychological symptom relief (Artin et al. ; de Vos et al. ; Kozlowska et al. ; Song et al. 2023). Abbreviations: brain-derived neurotrophic factor- BDNF; tropomyosin receptor kinase B- TrkB; lysergic acid diethylamide-LSD; 5-hydroxytryptamine receptors-5HT.