The mechanistic divide in psychedelic neuroscience: An unbridgeable gap?

In recent years, psychedelics have generated considerable excitement and interest as potential novel therapeutics for an array of conditions, with the most advanced evidence base in the treatment of certain severe and/or treatment-resistant psychiatric disorders. An array of clinical and pre-clinical evidence has informed our current understanding of how psychedelics produce profound alterations in consciousness. Mechanisms of psychedelic action include receptor binding and downstream cellular and transcriptional pathways, with long-term impacts on brain structure and function-from the level of single neurons to large-scale circuits. In this perspective, we first briefly review and synthesize separate lines of research on potential mechanistic processes underlying the acute and long-term effects of psychedelic compounds, with a particular emphasis on highlighting current theoretical models of psychedelic drug action and their relationships to therapeutic benefits for psychiatric and brain-based disorders. We then highlight an existing area of ongoing controversy we argue is directly informed by theoretical models originating from disparate levels of inquiry, and we ultimately converge on the notion that bridging the current chasm in explanatory models of psychedelic drug action across levels of inquiry (molecular, cellular, circuit, and psychological/behavioral) through innovative methods and collaborative efforts will ultimately yield the comprehensive understanding needed to fully capitalize on the potential therapeutic properties of these compounds.

Mitochondrial respiration as a target for neuroprotection and cognitive enhancement.

This paper focuses on brain mitochondrial respiration as a therapeutic target for neuroprotection and cognitive enhancement. We propose that improving brain mitochondrial respiration is an important future direction in research and treatment of Alzheimer's disease (AD) and other conditions associated with cognitive impairment and neurodegeneration. The central thesis is that supporting and improving brain mitochondrial respiration constitutes a promising neurotherapeutic principle, with potential applications in AD as well as in a wide variety of neuropsychological conditions. We propose three different interventional approaches to improve brain mitochondrial respiration based on (a) pharmacology, (b) photobiomodulation and (c) nutrition interventions, and provide detailed examples for each type of intervention. First, low-dose USP methylene blue is described as a pharmacological intervention that can successfully increase mitochondrial respiration and result in memory enhancement and neuroprotection. Second, transcranial low-level light/laser therapy with near-infrared light is used to illustrate a photobiomodulation intervention with similar neurometabolic mechanisms of action as low-dose methylene blue. Finally, a nutrition intervention to improve mitochondrial respiration is proposed by increasing ketone bodies in the diet. The evidence discussed for each intervention supports a fundamental neurotherapeutic strategy based on improving oxidative energy metabolism while at the same time reducing the pro-oxidant tendencies of the nervous system. Targeting brain mitochondrial respiration with these three types of interventions is proposed as part of a holistic neurotherapeutic approach to improve brain energy metabolism and antioxidant defenses. This strategy represents a promising new bioenergetics direction for treatment of AD and other neuropsychological disorders featuring cognitive impairment and neurodegeneration.