Brain Change


One of the core protective traits that all human brains possess is that of neuroplasticity. This means that the brain has the ability to flex and mold based on pressures. These pressures often are chronic ingestion of compounds i.e. drugs. Many of these changes connect to the development of tolerance in the brain and adaptation. Others affect stabilizing structures meant to hold the nervous system in an adequately functioning state. For instance, chronic increases in appetite from cannabis use will lead to compensatory down-regulation in natural satiety. One of the common symptoms of cannabis withdrawal is a loss of appetite. This is because the downward pressure on appetite is ‘unopposed’ now that marijuana is gone.

Advanced Brain Change

More advanced markers of neuroplasticity were initially discovered through the work of Nora Volkow MD, the current director of the National Institute on Drug Abuse (NIDA). Her brain imaging research showed that through chronic cocaine use, there would be dopamine desensitization in the front part of the brain, the prefrontal cortex. A way of thinking about this change in circuitry is through an automotive metaphor of a car cruising the track with the brakes on, effectively burning through those brakes. That car also sequentially is installing a higher and higher performance engine.

Prefrontal Cortex Dysfunction and Healing

Dysfunction in the prefrontal cortex is especially destructive to a person’s life and places them at magnified risk for further drug use. This part of the brain is responsible for executive function. This entails the ability to say “no” to things, the ability to prioritize and plan, and mood regulation components. ADHD is a neurological condition that involves essentially an under-active prefrontal cortex, and hence dysfunction in these above domains.

Another way of thinking about this is that chronic drug use can make someone appear more and more as though they have ADHD. The vicious cycle inherent in this is that ADHD people score at higher rates for drug use, to begin with. ADHD is a large risk factor for drug addiction, repeated drug use worsens symptoms of ADHD.

Healing from this brain change cycle is possible and also dependent on the neuroplasticity of the brain, albeit in reverse. The more amount of clean time the person has, the more the front part of the brain is able to “breathe” and adapt back to homeostasis without substances. This would not apply generally to people with primary ADHD. As that prefrontal dysfunction is more genetic and natural, the brain would be healing back to a position before the drug use began.

Dopamine Sensitization / Desensitization Hypothesis

1954 experiments by researchers Olds and Milner paved the way to a greater scientific understanding of the role of dopamine in reward processing. In initial studies, activated electrodes placed in the rat’s midbrain, specifically regions including the nucleus accumbens (NA) and ventral tegmental area (VTA), would drive the rat to pursue repetitive behaviors at the exclusion of any other behaviors. To describe this in another way, when these parts of the brain activated, other areas of the rat’s life would be put on hold. All that seemed to matter to the rat was the reward sensations of these regions.

We can extrapolate these concepts to human behavior and compulsive addiction. A person’s repetitive drug use happens at the expense of other pro-social activities. You’re at risk of losing your [insert anything you care about here…job, home, children, life] if you use cocaine again and yet you continue to use.

Secondary pathways are also highly involved in this brain change. The mesolimbic pathway involving the way memories are encoded in the brain plays a crucial role in the development of addiction. Advanced rat models today will involve multiple cages for the rats to frequent. Drugs are available to the rat in certain cages but not others. The phenomenon of conditioned place preference is used. This basically says that rats will choose to frequent “drug-cages” over “clean and sober cages.” The pattern recognition by the rat brings introduces a fundamental concept of learning.

Dopamine Sensitization

The process by which dopamine is leading to behavioral repetition is termed dopamine sensitization. Through repeated drug use and dopamine firing, there develops a later phenomenon termed dopamine desensitization. This involves a gradual change to the growth of receptors in the NA and VTA such that more of the dopaminergic firing is required to reach the same responses experienced in the past. These mechanisms are how we describe deep-brain tolerance – a distortion of the pleasure principle as it applies to drug use. Whereas the initial drug use was associated with positive affective states and reward, later use exhibited negative affective states including anxiety, agitation, and dysphoria.

Early Drug Use

In connecting these concepts, early drug use and extreme pleasure would lead to repetitive modeling and repeated use. Through tolerance and desensitization, later drug use would be associated with more hurtful negative emotional states when the substance was absent. Repeated drug use at this time would then potentially only bring the user back to baseline instead of achieving euphoria as in the past.

In Summary
  1. Dopamine is the initial ingredient necessary for reinforcement of pleasurable activities.
  2. Chronic firing of dopamine will lead to brain changes and the development of tolerance.
  3. Secondary pathways imprint memories around the behaviors that triggered dopamine release. The subject learns the behavior associated with the reward.
  4. Conditioned place preference for the rats illustrates the reward-seeking translated into “life choices.”
  5. Continued drug use will lead to tolerance and negative emotional states such as dysphoria, anxiety, and agitation.
  6. Drug use becomes more about reaching baseline emotional states instead of euphoria as initially experienced.

It is also worth noting contrary findings from other drugs of abuse. Over decades of basic science research, there has not been the development of significant animal models for hallucinogen addiction. Interestingly, hallucinogens in the brain act almost exclusively through serotonin pathways instead of dopamine transmission. Hence, it makes logical sense that the drug use for the animal would not have the reinforcement magnitude as compared to dopamine-focused drugs of abuse. Clinically, we see these same brain change patterns play out. The prevalence of hallucinogen addiction is exceedingly rare (0.04% according to an NIH study. [1] Of those with hallucinogen use, the highest rates of any sort of addiction or subthreshold addiction were amongst MDMA (ecstasy) users. This also makes sense in that the MDMA itself has dopaminergic activity and hence greater reinforcement potential than pure serotonergic mechanisms.

[1] Wu L-T, Ringwalt CL, Mannelli P, Patkar AA. Hallucinogen Use Disorders Among Adult Users of MDMA and Other Hallucinogens. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2008;17(5):354-363. doi:10.1080/10550490802269064.

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