From drugs to food: Gold traces his career in addiction research | Addiction Professional Magazine Skip to content Skip to navigation

From drugs to food: Gold traces his career in addiction research

July 7, 2014
by Mark S. Gold, MD
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My career as an addiction researcher started with memory research. In the 1970s I was studying the effects of amphetamines on memory1, and this early work led to an exploration of drug-related new learning and recall. It appeared that memory was not the problem in amphetamines' “on during learning” and “off during recall” condition. State dependency of memory helps explain why one slip can re-ignite a long-quiet drug personality and memory. Addicts become like their old selves so fast that a slip quickly becomes a relapse. State dependency of learning means that all the things addicts learn in order to survive on the street and interact with others can be locked away once they are clean and sober for a sufficient length of time. They can learn new ways of living and coping and interacting with others—what we call “recovery.”

Neuroscience was an emerging discipline at this time, and we had a limited understanding of what the brain looked like. The neurotransmitter anatomy of the day included only norepinephrine, dopamine, serotonin and acetylcholine. We knew that certain cell groupings could clearly be seen in the brain in the gross anatomical lab. Most notable were the substantia nigra and the nucleus locus coeruleus.2,3 The substantia nigra was a dopamine-rich area with an important role in Parkinson’s disease, but the noradrenergic nucleus locus coeruleus (LC) did not have a clear function at the time. I had the good fortune to work in a translational neuroscience lab and tried to stimulate and also lesion the LC. I also did some work on human LC during neurosurgery rotations, and heard stories of functional studies done at Washington University.

For most of the next decade, I worked on the LC's connection to opiate action, opiate withdrawal and relief of withdrawal symptoms. This work began with a theory for where and how opiate withdrawal symptoms and signs occur. We tested and ultimately translated this theory into a new therapy and therapeutic approach.4.5 With the LC inhibited by opiates, repeated inhibition would be thought to be the state of the LC in the opiate addict. Chronic inhibition would reverse itself when the opiates were removed slowly, abruptly or after administration of naloxone (Narcan). Withdrawal signs and symptoms would follow the rebound hyperactivity and they would be correlated. Morphine or methadone would reverse the signs and symptoms of withdrawal and return the LC to the chronic inhibition state. This early hypothesis and subsequent tests clearly showed the LC's connection to opiate action, opiate withdrawal and relief of withdrawal symptoms.

This theory remains how opiate withdrawal is understood today. In 1978, it allowed us for the first time to try non-addicting antihypertensive agents that had LC inhibitory actions through a parallel system to the opiate system that inhibited the LC: the alpha-2 receptor system. Production of opiate withdrawal-related LC hyperactivity could be turned off by opiates and reversed by naloxone. Similarly, opiate withdrawal-related LC hyperactivity could be turned off by clonidine, and that inhibition reversed by yohimbine or piperoxane.6 Once a dose was found in the translation from rodents to non-human primates to man, we gave human addicts in withdrawal either clonidine or placebo. Clonidine effectively reversed opiate withdrawal and could help detoxify human addicts without giving them an opiate taper. Clonidine could be given as part of a rapid detox protocol, and patients could switch from methadone or opiate maintenance to naltrexone or opiate antagonist maintenance.

Cure remained elusive

At this point (1978-1980), we thought we had a cure for opiate addicts. Unfortunately, we only had a cure in the lab model for addiction. Adherence to long-term naltrexone treatment was low; relapse after clonidine detoxification became the rule rather than the exception. Clearly, we confirmed what many had thought before—that detoxification is not recovery.

The invention of injectable naltrexone has helped, but generally in the context of mandated treatment. We found that placing employment in jeopardy helped adherence, and that outcomes of physicians managed in impaired physician programs were best with clonidine detoxification followed by naltrexone maintenance.7 Along with Robert L. DuPont, I have continued to champion physicians health programs.8,9

These high-income addicted patients often used more than one drug, and with opiates the combination with cocaine was very popular. This co-occurring use gave me to opportunity to see patients with access to cocaine, even though it was very highly priced. Regular use, self-administration, loss of control and binge use seen in the lab were also seen in people. It was clear to me that the champagne of drugs, “non-addicting” cocaine, was actually highly addictive, despite having a mild to variable withdrawal syndrome compared to alcohol or opiates.

So I started thinking about cocaine addiction and how to understand the drive for the drug and withdrawal.10 Rather than thinking acutely, with cocaine increasing dopamine release, we thought about the chronic and continuous state. Cocaine would increase dopamine release in anticipation of its use in the presence of cocaine or cues, but in chronic use would deplete the nucleus accumbens of available cocaine. There would be a relative or possibly an absolute dopamine deficiency in chronic use, making the users need the drug simply to exist—chasing the high rather than getting it again.


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Hey Mark, thanks for sharing your story here. You have chosen an unique career. I guess it would be tough to make research on drug addiction. Lots of thing needed to watch carefully. Great that you got success at this point. Transition Coaching. It was really awesome reading your article. Keep sharing more about the research you made. Thank you.