Knowing is not enough; we must apply. Willing is not enough; we must do. —Johann Wolfgang von Goethe

The Harvard Review of Psychiatry has recently chronicled important advances in understanding mental health disorders and, to a lesser extent Substance Use Disorder (SUD). This clinical review highlights the important contributions of Harvard experts over the past 25 years.

Addiction Research: What Have We Learned

Through my nearly 40 years of work in translational research and through the work of my colleagues, I have seen tremendous advances that changed how we understand the etiology and pathophysiology of SUD. Specifically, establishing the neurobiological basis of SUD, and the development of new and novel evidence-based pharmacologic and behavioral treatments including the discovery of the game changing and lifesaving drug, naltrexone, and thus establishing the neurobiological foundations for Medically Assisted Treatment (MAT), which resulted in important changes in the DSM.

As research established risk factors for SUD, we discovered that this disease is largely determined (40-60%) by genetic factors. Certainly, the Human Genome Project has unlocked the door to the field of epigenetics and the recognition that subtle variants in genetic transcription and coding are associated with numerous diseases, including SUD. The neuro-mechanisms and environmental stressors that conspire to “switch on” particular genes that increase the risk for SUD are not well established. Yet, our understanding of how specific neuronal circuitry mediates substance-induced reward, drug craving, compulsions and withdrawal is becoming clear. For example, when hedonically driven dopaminergic and opioidergic systems are disrupted, via the chronic use of intoxicants, neuroadaptation results in drug seeking, craving, anhedonia, depression, and chronic deficits in mood, memory and self-control. In other words, addiction.

Most recently, the discovery of ketamine’s efficacy in acute suicidality and treatment resistant depression represents a new and novel direction for research and the development of new therapeutics via the NDMA system. This discovery may supplant the 50-year-old catecholamine hypothesis for understanding addiction, mood disorders, pain and perhaps more.
But knowing is never enough in medicine—we must do.

So, in spite of all we have learned in the past few decades, the neurobiology and epigenetic risks for addiction remain underestimated and virtually unaddressed in current clinical guidelines for treating SUD. For example, we now know that early childhood trauma produces potentially heritable epigenetic changes that are highly correlated with SUD and other psychopathologies in adolescence and early adulthood. In addition, survey data reveals that approximately 70% of women in SUD treatment have suffered trauma, yet only a few of the top centers are professionally equipped to treat trauma as a comorbid disorder. Unaddressed, trauma almost always results in relapse.


The increasing prevalence and severity of SUD and the lack of available treatment is a formidable gap that is widening. By treatment, we do not mean SUD CPR or Naloxone, but rather prevention and when that fails, treatment that is safe and effective for five years. Efforts to close this gap involve many nonclinical variables (cost, access, harm reduction vs. medical model, politics, etc.), over which we have little control–but this is not to say we don’t have influence.

These are exciting times, as there is much to be learned about addictive disease and its numerous comorbidities. But, unless much more of the 23+ million currently addicted people in the US get help, research will remain simply academic.