Similarities in alcohol and opioid withdrawal syndromes suggest common negative reinforcement mechanisms involving the interoceptive antireward pathway.

Alcohol and opioids are two major contributors to so-called deaths of despair. Though the effects of these substances on mammalian systems are distinct, commonalities in their withdrawal syndromes suggest a shared pathophysiology. For example, both are characterized by marked autonomic dysregulation and are treated with alpha-2 agonists. Moreover, alcohol and opioids rapidly induce dependence motivated by withdrawal avoidance. Resemblances observed in withdrawal syndromes and abuse behavior may indicate common addiction mechanisms. We argue that neurovisceral feedback influences autonomic and emotional circuits generating antireward similarly for both substances. Amygdala is central to this hypothesis as it is principally responsible for negative emotion, prominent in addiction and motivated behavior, and processes autonomic inputs while generating autonomic outputs. The solitary nucleus (NTS) has strong bidirectional connections to the amygdala and receives interoceptive inputs communicating visceral states via vagal afferents. These visceral-emotional hubs are strongly influenced by the periphery including gut microbiota. We propose that gut dysbiosis contributes to alcohol and opioid withdrawal syndromes by contributing to peripheral and neuroinflammation that stimulates these antireward pathways and motivates substance dependence.