Ultra-high dilution medicines can modulate dopaminergic molecular targets and ΔFosB in the Nucleus accumbens preventing morphine reacquisition in rats

Addiction is a recurring disease that constitutes a significant public health issue, particularly evident in the global opioid crisis involving substances like morphine (MORPH). Reestablishing to opioid use poses a major obstacle to successful detoxification treatment, as many individuals return to drug use after withdrawal. Therefore, given that drug addiction involves emotional, social, and physical factors, there is a necessity to explore integrative medicine approaches, including ultra-high dilution medicines such as isotherapic (ISO) and organotherapic (ORG) treatments. This integrative approach holds promising potential in addressing drug addiction, as frequent reinstatement to addictive substances entail comprehensive symptoms. In our study following the MORPH conditioned place preference (CPP) paradigm, rats were treated with ISO or ORG for 14 days during MORPH-CPP extinction and subsequently challenged with the drug to assess MORPH-CPP reacquisition. The findings confirmed the hedonic effects of MORPH in the CPP, which also increased D1- and D3-R, DAT, and ΔFosB immunoreactivity in the Nucleus accumbens (NAc). Conversely, both ISO and ORG prevented MORPH-CPP reestablishing, whereas ORG treatment was associated with increased D2- and decreased D3-R levels. Both ORG and ISO increased DAT levels and decreased D1-R and ΔFosB, thus restoring the molecular neuromodulation induced by MORPH. To our knowledge, this study represents the first demonstration of the beneficial influence of ultra-high dilution medicines as a promising treatment for opioid use disorder. This finding is particularly relevant as these medicines are not associated with toxicity or undesirable side effects. Clinical studies are warranted to validate their efficacy in rehabilitation centers for drug use disorder.