Integrative Pharmacology in the Treatment of Substance Use Disorders

by Selleckchem | Feb 05 2024

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Comments:

It sounds like you've delved into an extensive review of the complexities surrounding substance use disorders (SUDs) and the need for innovative approaches in their treatment. The multifaceted nature of these disorders, involving various neurobiological mechanisms, presents a significant challenge in finding effective treatments.

Your emphasis on the limitations of monotherapy and the potential benefits of combination treatments is crucial. Substance use disorders often involve a convergence of dysregulated pathways, neurotransmitters, and receptors. Targeting multiple mechanisms simultaneously, as you suggest with the KYNA-NMDA-α7nAChRcentric pathophysiology approach, seems promising. This approach could act as a "command center" for neuropsychiatry, orchestrating treatments for different SUDs.

The focus on KYNA as a potential regulatory element within various pathophysiologic mechanisms is intriguing. Achieving KYNA homeostasis might indeed offer a more comprehensive therapeutic avenue. Moreover, the mention of medications like memantine, galantamine, and N-acetylcysteine that target these pathways underscores the potential of integrative pharmacology in treating SUDs.

As you've mentioned, conducting future randomized controlled trials (RCTs) that explore these novel combination treatments in a multicenter setting is essential. These trials could pave the way for more effective therapeutics that consider the intricate interplay of neurobiological mechanisms involved in SUDs.

It's exciting to see research pushing boundaries to develop more nuanced and effective treatments for such complex disorders. What inspired your interest in this area?