A systematic review of Phase 1-3 clinical trials from 2014 to 2024 found no breakthrough in pharmacotherapy for chronic primary pain conditions including fibromyalgia, complex regional pain syndrome, and chronic low back pain. The lack of progress may stem from unsuccessful approaches to reveal pathophysiological mechanisms, lack of translational preclinical animal models, and patient population heterogeneity with comorbidities. Most trials focused on repurposing antidepressants, antiepileptics, psychedelics, and immune modulators. Promising candidates targeted cannabinoid, glutamate, GABAergic, neuroinflammatory, and immune mechanisms. Only cannabidiol (CBD) and (es)ketamine were tested for all three conditions despite similar etiological factors.
Replacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.