Substance use disorders (SUDs) are a major global health burden, and psychedelic-assisted therapies are now gaining scientific interest, with ibogaine being considered as a candidate for anti-addictive effects across multiple substance classes. Ibogaine is a multi-target indole alkaloid acting on opioid, glutamatergic, serotonergic, and sigma systems with potential to rapidly reduce withdrawal and cravings after a single administration. Ibogaine is metabolized into noribogaine, which has a longer half-life and contributes to sustained pharmacological effects. These compounds act on multiple neurotransmitter systems including NMDA receptors, serotonin receptors, and opioid receptors, which allow it to have a broad neurobiological effect. It also has anti-addictive properties linked to neuroplasticity, dopamine modulation, and opioid receptor activity. Additionally, iboga has use in African rituals, with modern interest increasing in the twentieth century. Ibogaine now is an unregulated or semi-regulated substance with increased interest in controlled clinical development as well. Clinical evidence for ibogaine comes from observational studies and case reports, e.g., particularly in opioid use disorder. Ibogaine carries significant risks, particularly cardiotoxicity, neurological adverse effects including hallucinations, and reported fatalities. Safer derivates such as noribogaine and tabernanthalog (TBG) are being developed to retain anti-addictive efficacy and reduce toxicity. Ibogaine induces prolonged oneirogenic states involved in autobiographical memory processing, and outcomes are influenced by setting, integration therapy, and psychotherapy. Current research is largely observational, and studies are small, which highlights the need for standardized protocols and clinical trials. Overall, ibogaine represents a therapeutic candidate for SUDs, with broad anti-addictive potential. In this review, we provide an overview of ibogaine’s history and pharmacology, critically examine its therapeutic potential in multiple SUDs, and discuss current limitations, emerging alternatives, and future directions.

Chronic musculoskeletal pain remains a leading cause of disability worldwide, driven by progressive degeneration of cartilage, bone, tendon, intervertebral discs, and peripheral nerves. Conventional interventional approaches primarily address symptoms without restoring structural integrity or tissue homeostasis. Regenerative strategies, including platelet-rich plasma, mesenchymal stem cells, and biomaterials, have demonstrated potential but are limited by variability in outcomes, poor cellular survival, and lack of standardization. Exosomes and extracellular vesicles are key mediators of intercellular communication in tissue repair, reproducing many of the paracrine effects of parent cells while offering improved safety and scalability. These nano-sized vesicles regulate inflammation, angiogenesis, extracellular matrix remodeling, and cell survival across musculoskeletal and neural tissues. Importantly, growing evidence suggests that mechanical cues such as compression, shear stress, and tensile loading not only regulate cellular behavior but also shape exosome biogenesis, cargo composition, and functional effects through mechanotransduction pathways involving integrins, ion channels, and YAP/TAZ signaling. This mechanobiology–exosome interface is particularly relevant in interventional pain medicine, where therapeutics are delivered into mechanically active environments such as joints, discs, tendons, and perineural spaces. Mechanical loading conditions may therefore modulate therapeutic efficacy by shaping both endogenous repair processes and the behavior of administered exosomes. The present investigation reviews the current literature and knowledge on mechanotransduction pathways and exosome biology, with a focus on their intersection in musculoskeletal regeneration. We further examine preclinical and clinical evidence supporting exosome-based therapies in osteoarthritis, degenerative disc disease, tendon and ligament injuries, and neuropathic pain states, alongside key translational challenges including heterogeneity in exosome isolation, dosing, biodistribution, and clinical standardization. Finally, we discuss future directions in mechanobiology-guided exosome engineering and their potential integration into interventional pain practice.

Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington’s disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood–brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington’s disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy.

Chronic pain is a major cause of disability worldwide, impacting around 20% of adults globally. Conventional mu-opioid peptide (MOP) receptor agonists provide effective analgesia; however, their prolonged use is restricted by severe dose-limiting toxicities such as opioid-induced respiratory depression, analgesic tolerance, hyperalgesia, physical dependence, and addiction. The goal of this narrative literature review was to compile the available data on NOP receptor-targeted analgesics, with a focus on dual NOP/MOP agonists and cebranopadol. The pharmacological mechanisms, preclinical and clinical evidence, safety profile, and potential therapeutic role in pain management were all highlighted. The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor system has been identified as a new pathway for managing pain through mechanisms that differ from those of classical opioid signaling. The NOP receptor is a Class A G-protein-coupled receptor (GPCR) that preferentially couples to inhibitory G(i/o) proteins. Upon activation, it suppresses adenylyl cyclase activity, lowers intracellular cyclic adenosine monophosphate (cAMP) levels, blocks voltage-gated calcium channels, and activates G-protein-gated inwardly rectifying potassium channels, thereby hyperpolarizing neurons and decreasing excitatory neurotransmitter release. NOP receptors are anatomically distributed throughout the peripheral and central nervous systems, including primary afferent sensory neurons, dorsal root ganglia, spinal dorsal horn, periaqueductal gray, rostral ventromedial medulla, central amygdala, ventral tegmental area, and nucleus accumbens. NOP activation via these pathways offers significant pain relief in acute nociception, as well as in chronic inflammatory and neuropathic pain conditions. Supraspinal activation of NOP within the mesocorticolimbic pathway influences the emotional aspect of pain by reducing corticotropin-releasing factor signaling and decreasing mesolimbic dopamine release. NOP agonism effectively provides analgesia while also attenuating drug reward and reinforcement. The development of pharmaceuticals utilizing NOP agonism has progressed from endogenous peptide analogues to selective non-peptide agonists, and more recently to bifunctional NOP/MOP (dual NMR) agonists, such as the dual NOP/MOP agonist cebranopadol, which has passed Phase I–III clinical testing. There are still significant questions about long-term safety, comparative efficacy, and the interpretation of unpublished or preliminary Phase III results, despite the fact that available clinical trials indicate analgesic efficacy with perhaps decreased respiratory and abuse-related effects. This drug achieves equianalgesic efficacy through potent dual NOP/MOP activation while significantly reducing the risk of respiratory depression and drug-liking. However, clinical translation of NOP receptor agonism is hindered by several challenges, including supraspinal pronociceptive paradoxes, species-specific pharmacology, dose-dependent sedation, and regulatory complexities associated with mixed-mechanism ligands. NOP-targeted therapies represent a promising approach for the development of next-generation, opioid-sparing analgesics in pain medicine.