Vettleson-Trutza, Sara

Background: Substance use disorders (SUDs) are highly prevalent, affecting over 48.5 million Americans. Available treatments for SUD remain insufficient, and many patients do not respond to existing interventions despite adequate adherence to treatments. While novel therapies for SUD are urgently needed, the use of psychedelic drugs for the treatment of SUDs has shown promise. Objectives: This overview of systematic reviews summarizes existing evidence on hallucinogens—serotonergic psychedelics and ketamine—for the treatment of SUD. Methods: A comprehensive search of the literature was conducted to identify relevant evidence for using serotonergic and non-serotonergic psychedelics for the treatment of SUDs. After initial screening (n = 468 studies), 62 studies were retrieved and assessed for eligibility, and a total of 16 systematic reviews were included. Conclusions: Although preliminary, evidence suggests that the use of serotonergic and non-serotonergic psychedelics for the treatment of SUD may provide advantages over traditional therapeutics, and these compounds may eventually become part of the next generation of treatments for SUD under specific circumstances. Research with these drugs has faced significant challenges, though, and caution when interpreting results is warranted, given high risk of bias and several other methodological limitations from the studies to date. Furthermore, risks associated with these drugs are not negligible. For now, the use of psychedelic drugs for the treatment of SUDs remains experimental, and existing evidence is insufficient to support its use in clinical practice.

Background: Invasive and non-invasive neuromodulation in psychiatry represents a burgeoning field that leverages advanced neuromodulation techniques to address substance use disorders (SUDs). Aims: This narrative review synthesizes findings from multiple reviews to evaluate the efficacy of neuromodulation in treating SUDs. Methods: A comprehensive literature search was conducted between December 2024 and April 2025, focusing on systematic reviews and meta-analyses that examined various neuromodulation modalities, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). The selected reviews were analyzed to identify common themes, outcomes, and gaps in the current understanding of these treatments for SUDs. Results: 11 reviews met the final inclusion criteria; 5 focused on non-invasive neuromodulation (rTMS, tDCS) and 6 on invasive neuromodulation (DBS). Non-invasive neurostimulation was associated with modest improvements in craving and cognitive dysfunction in individuals with SUDs. Similarly, invasive neuromodulation (DBS), through high-frequency stimulation of the bilateral nucleus accumbens, appeared to reduce cravings and improve comorbid psychiatric symptoms in both preclinical and human studies. Importantly, small sample sizes, heterogeneity in targets and stimulation protocols, and short follow-up periods significantly limit the generalizability of current findings from both non-invasive and invasive neuromodulation studies. Conclusions: As novel and more effective therapies for the treatment of SUD are desperately needed, procedural interventional psychiatry holds promise. However, despite encouraging results, existing evidence is still preliminary, and larger, rigorously designed studies are warranted to further establish the safety and efficacy of neuromodulatory interventions for SUD treatment.

Abstract Introduction: Opioid use disorder constitutes a significant health crisis in the United States, contributing to high rates of opioid overdose-related deaths. A major driver of these fatalities is fentanyl, a potent synthetic opioid with both sedative and analgesic properties. These properties that make fentanyl clinically effective also increase its addictive potential. Early in opioid addiction, abnormal increases in extracellular dopamine in the nucleus accumbens (NAc) reinforce excessive drug-seeking behaviors which can lead to fatal respiratory depression. Given this mechanism, we investigated whether high frequency stimulation (HFS), mimicking human deep brain stimulation (DBS) of the ventral tegmental area (VTA) could block NAc dopamine increase following an acute lethal dose of fentanyl. We hypothesized that VTA DBS would mitigate these dopaminergic responses and prevent fentanyl-induced respiratory failure. Methods: Multiple cyclic square wave voltammetry (M-CSWV), was applied via a carbon fiber microelectrode in the NAc of urethane-anesthetized male Sprague-Dawley rats. Dopamine levels were recorded at baseline and following acute fentanyl (30 µg/kg, i.v.). HFS (130 Hz frequency, 200 µsec pulse width, and 0.2 mA amplitude) was administered to the VTA before and during fentanyl exposure. Results: Acute fentanyl administration resulted in a 178.2% increase in NAc dopamine levels from baseline, accompanied by a decline in respiratory rates to critically low levels (45 breaths per minute vs. 102 bpm), eventually resulting in 100% mortality. HFS of the VTA did not significantly alter baseline tonic dopamine levels or prevent fentanyl-induced dopamine increase in the NAc but was able to fully rescue fentanyl-induced respiratory failure.