Cerebrum Winter 2022

and those already suffering from it are particularly sensitive to stress —a reflection of the intricate links between the brain’s stress and reward systems. Addiction neurobiology is an extremely complex system that involves numerous neurochemicals and interconnected circuits, all of which are influenced by both internal and external stressors. Each phase of addiction—intoxication, habitual compulsive drug-seeking, withdrawal, abstinence—can result in changes to our neurobiology. One of the most important chemicals in our brain’s “reward pathway” is the neurotransmitter dopamine. Most drugs of abuse will directly or indirectly increase dopamine in this pathway. Stress, especially acute or intense stress, boosts dopamine in these same brain areas, via the release of such compounds as corticotrophin-releasing hormone and cortisol. Consequently, stress can heighten reward sensitivity, potentiating the reinforcing effects of drugs. Conversely, drug use can sensitize the brain to stress. In its attempt to protect the brain against the effects of acute stress, the body recruits neurobiological processes that feedback to increase neurochemicals that reduce dopamine levels and normalize other neurobiological systems (e.g., production of stress hormones). With repeated drug use or chronic stress, however, the biological picture changes: the brain is highly plastic and attempts to return neurobiological systems to “normal,” can lead to adverse pathological states. For example, chronic use of drugs can result in reduced baseline dopamine release, decreasing the drug’s rewarding effects and increasing negative emotions. This phenomenon, “tolerance,” can have two effects: the user requires more and more of the drug to achieve the high experienced initially; and now he or she also needs the drug to provide relief of the negative mood state. The result: transition to uncontrolled compulsive drug use. By reducing dopamine levels, chronic stress also increases neurochemicals that promote stress, such as the neuropeptide called dynorphin, in brain areas such as the amygdala, which is involved in emotional regulation and drug-seeking behavior. Negative emotional states induced by these changes also drive compulsive drug-seeking behavior.

Now, fentanyl contamination was being regularly detected in various drugs, including counterfeit pain pills and sedatives, such psychostimulants as methamphetamine and cocaine, and even cannabis. As overdose data started to trickle in during 2020, it soon became clear that all of the gains that had been made from 2017 to 2019 had been lost. Shockingly, overdose death rates in the US skyrocketed higher than they have ever been at any time during the opioid crisis—with synthetic opioids accounting for more than 60 percent. This historic rise in overdose deaths was, of course, multifactorial—besides the turn to addictive substances to cope with Covid-related stress, the disruption in access to drug treatment, and adulteration with toxic synthetic opioids, more people were using drugs in isolation. This meant limited opportunity for others to provide lifesaving help by administering naloxone (an opioid antagonist also known as Narcan) when overdose occurred. As more data became available regarding Covid-19 risks, disparity, and outcomes, it was evident that substance- use disorders were a significant underlying medical condition associated with high risk for severe Covid-19 illness. Not only were individuals with substance use disorders (SUD) at increased risk of Covid-19, but they also experienced significantly worse outcomes than those without SUD. Knowing that they were at increased risk of bad outcomes from Covid-19 further heightened the already elevated anxiety of the addicted, causing more reactive substance use and more death. Overall, a perfect storm. Stress: A Neurobiological Force Though Covid-related stressors increased psycho- pathological states of fear, depression, and anxiety in most people, these were more elevated in individuals with SUD. Numerous factors associated with Covid—from social distancing and lockdown isolation to economic downturn—converge in the state of mental or emotional strain or pressure we call “stress.” Biologically , stress refers to the body’s response to change. Clearly, the pandemic involved profound changes and demands in all aspects of life. This development was not unexpected: It is well documented that individuals at risk for addiction



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