Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring clinical efficacy, and unique therapeutic potential for use in acute, psychiatric emergencies. This narrative presents an alternative framework for understanding depression, as mounting evidence supports a neuronal atrophy and synaptic disconnection theory, rather than the prevailing monoamine depletion hypothesis. In this context, we describe ketamine, its enantiomers, and various metabolites in a range of mechanistic actions through multiple converging pathways, including N-methyl-D-aspartate receptor (NMDAR) inhibition and the enhancement of glutamatergic signaling. We describe the disinhibition hypothesis, which posits that ketamine’s pharmacological action ultimately results in excitatory cortical disinhibition, causing the release of neurotrophic factors, the most important of which is brain-derived neurotrophic factor (BDNF). BDNF-mediated signaling along with vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) subsequently give rise to the repair of neuro-structural abnormalities in patients with depressive disorders. Ketamine’s efficacious amelioration of treatment-resistant depression is revolutionizing psychiatric treatment and opening up fresh vistas for understanding the underlying causes of mental illness.

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases.

The human brain is an extraordinarily complex organ responsible for all aspects of cognition and control. Billions of neurons form connections with thousands of other neurons, resulting in trillions of synapses that create a vast and intricate network. This network is subjected to continuous remodeling that adapts to environmental and developmental changes. The resulting neuroplasticity is crucial to both healthy states and many forms of mental illness and neurodegeneration. This narrative review comprehensively examines N,N-dimethyltryptamine (DMT), a naturally occurring hallucinogen and psychedelic compound, focusing on its implications in promoting neuroplasticity via neuritogenesis. We examine DMT’s pharmacology, including its interaction with serotonergic, sigma-1, and trace amine-associated receptors and their associated signaling pathways. The therapeutic potential of DMT in both animal models and clinical trials is discussed with impacts on perception, cognition, emotion, and consciousness. We uniquely focus on current directions centered on unveiling the direct mechanisms of DMT’s therapeutic effects that demonstrate transformative effects on mental well-being, particularly for conditions like depression, anxiety, and post-traumatic stress disorder. We discuss the connection between DMT and neuroplasticity, offering the potential for forming new neural connections, improving learning, memory, and aiding recovery from brain injuries, including neurorehabilitation and neuroregeneration. The ultimate potential of DMT’s therapeutic efficacy to enhance neurogenesis, especially for neurodegenerative conditions, is also discussed.

The pandemic highlighted the need for alternative, more accessible access to mental health interventions that can be readily administered remotely. The purpose of this pre-post-interventional study was to evaluate the effectiveness of a virtual mind-body medicine training course on stress, anxiety, and depression levels. University employees and members of the Las Vegas community were recruited via self-selection and snowball sampling and subjected to online mind-body practice sessions in December of 2020. Stress, anxiety, depression, and quality of life were assessed pre- and post-intervention using standardized psychometric valid tools. The paired t-test and related samples marginal homogeneity tests were used for continuous and categorical outcomes, respectively. Depression and stress scores were significantly decreased (p < 0.001). Mean scores of professional quality of life improved post-intervention compared to pre-intervention (p = 0.03). A significantly larger proportion of participants reported no depression or stress post-intervention compared with pre-intervention (p < 0.001, p = 0.003, respectively.) This study suggests that virtual mind-body practices had a pronounced impact on stress and depression levels during the pandemic. These findings support virtual, online-guided mind-body medicine training as an effective intervention that can be administered virtually to reduce stress and depression symptoms.