Entrevista em inglês com Nora D. Volkow, M.D

1. What does drug addiction represent for the brain?

Drug addiction is the end result of an iterative process whereby the brain habituates to a pharmacologically induced rewarding experience (the addictive drug) that is far more potent than any natural reward could possibly deliver or compete with. Not everybody has the same risk of engaging in that initial experience nor does every first-time user end up repeating the experience to become a regular/chronic user or develop a drug use disorder. But some people with certain genetic, psychological, and/or socioenvironmental vulnerabilities are at higher risk of entering a vicious cycle of reinforced conditioned learning that increasingly shifts the drug-using behavior from goal-oriented to automatic and increasingly uncoupled from the control of inhibitory circuits.

2. How can the rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits impact in the addicted?

At the neurobiological level, repeated exposure to drugs of abuse trigger epigenetic changes that modulate synaptic strength and remodel neural circuits throughout the mesocorticolimbic pathways disrupting reward processing, engendering craving, and weakening inhibitory control of prepotent responses.    

3. What are the brain responses due to the negative emotional, dysphoric and stress states related to drug addiction?

The brain stress response system appears to become activated by acute excessive drug intake, to be sensitized during repeated withdrawal, and to persist in an activated state during protracted abstinence, contributing to the development and persistence of addiction

As drug taking becomes compulsive-like, the factors that motivate behavior are thought to shift to drug-seeking behavior that is driven not only by positive reinforcement but also by negative reinforcement.

But the negative emotional state that drives negative reinforcement has been hypothesized to derive from the dysregulation of key neurochemical circuits that drive not just brain stress systems (i.e., corticotropin-releasing factor, dynorphin) within the extended amygdala and that mediate anxiety-like states, but also of incentive-salience/reward systems (dopamine, opioid peptides) in the ventral striatum.

Excessive drug taking also engages CRF activation in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system.

4. What might mediate initial vulnerability, maintenance, and relapse associated with addiction?

Most individuals who use drugs do not develop addiction. Epidemiological and clinical studies have shown that an individual’s risk of becoming addicted is influenced by many different and interacting biological, psychological, developmental, and environmental factors. For example, genetic studies have shown strong complex genetic contributions to the overall risk of abuse of and addiction to multiple addictive substances. These effects can be mediated through allelic differences operating at different phenomenological levels, including enzymatic, synaptic, neurophysiological, and psychological or behavioral processes.

The developmental stage is also a critical variable affecting vulnerability: epidemiological data clearly demonstrate that adolescence is a particularly high risk period not only because adolescents have a natural predisposition to novelty seeking and risky behaviors (including drug experimentation) and adapt their behaviors to social pressures but also because drug exposure during this active phase of brain development is significantly more vulnerable to the addictive properties of drugs of abuse.

Finally, there is a growing list of environmental factors (e.g., adverse childhood experiences, chronic stress, sleep deprivation, deviant affiliation, poverty, etc.) that play major and modifiable roles in dialing up interindividual differences in risk.

The important think to understand is that such genetic, developmental, and environmental factors do not operate in isolation but are highly interactive such that the overall individual risk reflects the complex result of their dynamic combination.   

5. Can marijuana damage a forming brain?

The specific effects of prenatal marijuana exposure remain unclear and warrant further research. The larger number of neuropsychological domains that exhibit decreased versus increased psychological and behavioral functions suggests that exposure to marijuana may be harmful for brain development and function. And animal studies suggest, among others, that in utero exposure to THC, the main psychoactive ingredient in marijuana, increases the general responsiveness of the mesolimbic dopamine system.

With regards to the effects of cannabis use during childhood and adolescence, a protracted period of active brain development, neuroimaging studies provide some evidence of compromised frontoparietal structure and function, however, it remains unclear whether the observed effects are specifically attributable to adolescent onset of use or general cannabis use-related factors such as depressive symptoms. The relative contribution of adolescent onset of cannabis use and use chronicity will have to be more comprehensively examined in prospective, longitudinal studies with more rigorous measures of cannabis use (dosage, exposure, dependence, constituent compounds such as the relative cannabinoid levels), like the ABCD and HBCD studies.

It should be emphasized that the negative impact suggested by the existing clinical evidence is consistent with seminal animal research directly linking prenatal and adolescent exposure to THC with protracted effects on adult neural systems relevant to psychiatric and substance use disorders.

6. What works in the prevention of substance abuse?

Just as addiction is a complex multifaceted phenomenon so one needs to think about effective prevention as the result of multipronged, evidence-based strategies that must adhere to four basic principles that state that prevention programs should:

1. Enhance protective factors and reverse or reduce risk factors,
2. Address all forms of drug abuse, alone or in combination, including the underage use of legal and illegal drugs; and the inappropriate use of legally obtained substances, prescription medications, or over-the-counter drugs,
3. Address the type of drug abuse problem in the local community, target modifiable risk factors, and strengthen identified protective factors, and
4. Be tailored to address risks specific to population or audience characteristics, such as age, gender, and ethnicity, to improve program effectiveness.

7. What is the latest news in the field of drug addiction science?

Addiction research covers a vast range of disciplines and there have been very exciting developments in the recent past. But the findings that are still fresh in my brain with a huge translational potential include the research published by Marco Venniro and NIDA colleagues in 2018, which found that positive social interaction in rats prevents drug self-administration. These NIDA investigators found that, when given a choice between interacting with another rat or taking heroin or methamphetamine, the rats consistently chose the social reward.

This study has far reaching clinical implications, with several researchers initiating human studies on brain mechanisms of choice between rewarding social interactions and addictive drugs. These new findings should stimulate more human research into how social-based treatment approaches might help restore normal reward and emotional regulation, resulting in reduced relapse risk.

Another discovery that is worth-highlighting stems from the recent molecular and functional study using computational modeling that shed new light on the mechanism by which cannabinoids inhibit glutamate release in certain areas of the brain and that the process is controlled by the neurotransmitter adenosine operating via complexes (heteromers) of receptors for both cannabinoids and adenosine. This research represents a significant conceptual advance in the field of the G protein coupled receptor (GPCR) physiology and pharmacology and suggests the possibility of using A2A receptor antagonists to counteract the adverse effects of cannabinoids, including cannabis use disorder, for which no pharmacotherapies are currently available.  

8. What motivates your working in the field of drug addiction?

As a medical student I volunteered in a laboratory, whose purpose was to discover a medication for pain based on opioids that would not be addictive. Immediately, because I was working with opioids, I became fascinated with the concept of an animal working compulsively in order to get a very small amount of drug injected into them – how the animal (at the time I was working with both rats and monkeys) would forgo everything else. I observed with fascination how one chemical can so profoundly disrupt someone's behavior.

I was struck by how we, as humans, are so vulnerable to the effects of drugs, how they change us in such profound ways, and how that leads people to actually isolate themselves and others to reject them.

In my own family, my uncle was an alcoholic, and as a medical student I would see patients coming into the hospital with cirrhosis or varicose veins, or with cancer because they've been drinking or smoking all of their lives.

But it was also very frustrating to see as a physician, and as a student, how stigmatized addicted individuals were – doctors didn't want to treat them, they dismissed them. That really bothered me because it was antithetical to what they're supposed to do as physicians. I mean physicians are supposed to have empathy and care for those that are vulnerable, and yet the way we dealt with addicted individuals was exactly the opposite.

Looking back, these were some of the experiences that motivated me to work in the addiction field.

9.         How can Obid can contribute to your work?

One of the main goals of our Institute is to maximize the extent to which research is translated into a) more effective interventions (prevention and treatment) and b) smarter evidence-based drug policies to protect public health. This is why it is so important for us to maintain open and robust channels of communications with international institutions that, like OBID, are in charge of ensuring methodological rigor in activities designed to reduce demand, supply, and the damage associated with drug use; and of advocating for the systematic conduct of studies and research in the area. I consider OBID a natural partner in this challenging endeavor and would very much appreciate to establish an ongoing dialogue to share data, compare notes, and analyze emerging trends.