Battling Addiction

By Sheba AJ October 14, 2023 Neuroscience and Cognition, Psychology, Space science 0 Comment

Addiction is a neurological disease that affects millions. How can we help them?

From the desk of Dr. Teresa Franklin

I earned my PhD in 1999 from Hahnemann University in Phila, PA, USA. Since then, I have worked mainly at the Center for the Studies of Addiction in the Department of Psychiatry at University of Pennsylvania, Phila, PA. USA. My research focus is addiction – specifically, the study of conditioned drug responses – otherwise known as drug cue-induced craving, which we can study now in real time with magnetic resonance imaging – MRI. Nowadays, most of us have had an MRI so we know what type of information it can provide; the basic idea is that it can provide images that reveal structure based on the water content of the materials that make up our brain and body. Functional MRI means that we can visualize what is going on in real time. So, we can ‘task’ the brain and take pictures of what the brain does during the task. In our lab, we use visual/audio and tactile ‘reminders’ of drug use to stimulate the brain.

WHAT IS ADDICTION?

Disclaimer: The mechanisms I describe are incredibly more complex – but this is enough information to get a general understanding.

First of all, why do people take drugs? Why not? Depending on the type or quantity of drug, they can make us feel happy, relaxed, energized, sexy, cognitively enhanced, etc. Simple answer. We consume drugs because they make us feel good. The final common pathway of all psychoactive (acts within the brain) drugs is the dopamine system. There are multiple neurotransmitter systems in our brains – and they are all very similar in structure while being different in the neurotransmitter (chemical that defines the system) that is released (e.g., dopamine, serotonin). There are 3 major ‘ingredients’ needed for information to be transmitted in the brain, regardless of which neurotransmitter system we are talking about. The center player is the synapse – a space between two neurons (brain cells). On each ‘side’ of a synapse is a neuron. One of these neurons is the pre-synaptic neuron – that brings the message to the synapse and one of these neurons is the post-synaptic neuron – that sends the message to other parts of the brain. An electric signal travels down the pre-synaptic neuron that causes a chemical (dopamine, in this case) to be released into the synaptic space. Dopamine then attaches to receptors (that act like gates) on the post-synaptic neuron, which results in the transmission of the electrical signal to other parts of the brain. The release of dopamine is what makes us feel ‘good’. Importantly, for two reasons, the dopamine that is released, must be swept out of the synapse immediately after its release – first, to put a stop to the transmission of the signal and second, to recycle the materials to make more dopamine. The component within our brain that does this job is called the dopamine transporter. It transports the released dopamine back into the pre-synaptic neuron. There, it is recycled and fresh dopamine is made, ready for the neuron to fire again.

Dopamine release is necessary as it motivates us to ‘act’. Without dopamine we would not even want to get up in the morning, brush our teeth, eat, work, enjoy relationships, none of it. The dopaminergic system is often referred to as the motivation system. Addictive drugs activate this system to extremely unnatural levels. We call it a ‘supraphysiological’ dopamine response. When that happens, the components of the system react to compensate; there are changes in the number of available receptors and or transporters or their ability to function properly. This also happens when we take a psychiatric medication, the brain adapts to the changes. It compensates. And then, to feel the same effects of either the medication or the psychoactive drug, you need more of it to feel its effects. That is why the dose of any psychotropic medication you may be taking has to be adjusted. With addictive drugs, the changes to the brain happen in at least two major areas – the deep limbic motivational or ‘emotional’ brain and the higher level cognitive control ‘cortical’ regions of the brain. The result is a strong, and sometimes even uncontrollable urge to find and use the drug. We call it craving. The limbic portions of the brain become highly attuned to finding a way to feel good again, or at least normal, while the cognitive control regions exert less energy in determining what strategies are used to find the drug and what consequences could occur. A consistent finding in brain imaging labs is that regardless of the drug, including alcohol, nicotine and cannabis, there is a reduction in dopamine receptors in the brain. Further, in some labs, including ours, we have shown that people who crave more intensely also have differences in the function of their dopamine transporter. This is a very simplified version of the mechanisms underlying addiction.

IS THERE A HEREDITARY OR OTHER COMPONENT TO ADDICTION?

Why is it that 90% of people can use drugs and not become addicted? Most of us can have a few drinks every so often and not even think about using alcohol for weeks or months. Or, substitute another drug for alcohol. But some of us cannot. What is different about the approximately 10% of our population who do become addicted?

There seem to be 3 factors that increase one’s vulnerability.

Yes, genetics play a huge role. Cigarette addiction, for example, has been shown to be 85% genetic. If something is genetic, it means it has a neurobiological component – something is different about the underlying biology of the brain – even before the drug has ever been used. Prevailing theory is that the drug normalizes the brain – makes the person feel better than they ever have in their life. Most likely, but we don’t have definitive proof yet, the problem lies in the dopaminergic system. We all know people who just don’t seem to experience that much joy out of life or don’t seem motivated to get off the couch. Perhaps, at least partially, the fault is in their dopamine system.

A second factor that enhances one’s vulnerability to addiction is experimenting with psychoactive substances at an early age. The younger one is, the more malleable the brain is. Pathways within the brain are more easily manipulated. That supraphysiological burst of dopamine received from early experimentation might even permanently affect the brain. We don’t know that yet either. And, it could be both – a faulty system to begin with and one that has been damaged from the drug itself. There is a huge ongoing Adolescent Brain Cognitive Development (ABCD) study funded by the NIH that is delving into the age old question of ‘What came first, the chicken or the egg?’

A third factor is whether or not one has experienced trauma, especially but not confined to childhood trauma. This could be sexual, physical, emotional trauma or any combination thereof. Trauma damages the brain and can predispose one to addiction

SO, IF ONE HAS ALL 3 OF THESE FACTORS, THEY WILL BECOME ADDICTED?

Not necessarily, there is no simple, or even complex biomarker to identify who will and who will not become addicted. This is a big problem in the field, but it also makes sense – I have vastly simplified the process of becoming addicted while human beings have vastly different genetics and experiences that shape their brains.

We talk about addiction as if ….we know what we are talking about. The problem of addiction is that it is individual and heterogenous – meaning even within an individual it can be hard to pin down. A person might say, have a heroin addiction that they manage to overcome but no matter how hard they try, they can’t put down their cigarettes. So, this is my disclaimer – I may make statements about addiction that are generally applicable but each person is a study unto themselves and that treatment can only work when the patient and the people assisting with recovery treat each person as an individual case.

HOW DID YOU GET INTO THIS FIELD?

I grew up in a family that was topped with a heavy dollop of addiction. But, my brother’s travels down the road of substance use was the stick that broke the camel’s back and made me passionate about the study of addiction. My brother had the genetics, he experienced early childhood trauma and he experimented with drugs while young – let’s call it the vulnerability triad. [YOU COULD SHORTEN THIS PART] I watched him become sick with addiction at an early age. I found him sniffing airplane glue out of a paper bag when he was 13. From there he began smoking cigarettes, drinking beer, smoking pot and by his early 20s his drug of choice was crystal meth. Like many held in the grips of addiction, he tried to stop using drugs and failed. He ended up in the hospital in his early 30s – his entire body including his heart and lungs were infected with a deadly bacteria from using a contaminated needle. At this time, cocaine was his drug of choice. I visited him nearly every day. For the first few weeks he was delirious and during that time he relayed to me how he spent his days. His entire day consisted of using and selling drugs. He sat on his couch and his clients came to his house to buy drugs. Sometimes they would bring him food. He couldn’t walk because his leg was so badly infected, so it was the only way he got food. He weighed about 85 lbs when he was admitted to the hospital and half of that weight was from his swollen leg. The inside of his ankle and his knee had large open wounds. This is where he injected. He kept a bottle under the couch to urinate in and used his elbows and chest to climb the stairs every few days to defecate. While in the hospital and after he became lucid something very strange happened. [BUT, THIS PART IS IMPORTANT] I was visiting and we were talking and he started to become very agitated. Watching the clock. Visibly sweating and screaming for the nurse to bring him his medication. This didn’t make any sense to me – I was completely naïve as to what was happening – but now, after my training in addiction, I know. His medication was an IV pump that slowly dripped antibiotic into a vein in his hand. The cold liquid entering his vein was a reminder of drug use. This is a good place to segue into a description of what I now study: conditioned drug responses. What is a conditioned drug response? The big rush of dopamine that occurs in response to addictive drugs is a learning tool. The dopamine washes over the brain ‘teaching’ it that when certain events happen in a particular order, at a particular time, with certain people or at a particular place, the brain gets a dopamine rush. These people, places and things, such as friends that one uses drugs with, the environment in which one uses and the things surrounding drug use, such as a syringe in an IV user, or the smell of a lit cigarette in a person who smokes cigarettes….all of these things come to take on properties of the drugs themselves. In other words, they can lead to a large release of dopamine AND get you the buzz you seek. These are conditioned responses. My brother was getting high off of the cold liquid ANTIBIOTIC dripping into his veins. I watched it myself or I might not believe it – his eyes glazed over, his voice changed in pitch and tone – slowing down, smoothing out, he got a big loopy smile on his face and began slurring his words. I watched this happen every day. Each day he got a little less high. About 4 weeks after the first time I saw him get visibly high, it stopped. The brain relearned that the IV needle was no longer associated with his drug of choice and the dopamine rush was subsiding. In the field, we call this extinguished behavior. The next day I came to see him and he had left the hospital. He died a year later. This changed the trajectory of my life. I was a stay-at-home Mom of 3. I decided I had to learn more about why one would exchange living a full life of exciting and wonderful activities, yes, and also with disappointments and hardship, to living a life that was concerned only with seeking and using drugs. I had to understand how an antibiotic drip could lead to such a profound change in behavior. Seeing my brother in that state was terrible, and incredible at the same time. I thought if I knew more about it, I could stop the disease of addiction. Yep, pretty naïve.

Let me explain a little more about craving and conditioned responses. At one time there was a prevailing view in the field that relapse is motivated by withdrawal – the wish to alleviate the misery that one feels when there is no more drug fueling the release of dopamine. But then, why can someone relapse months or even years after symptoms of withdrawal have ceased? Years of research has revealed that the other major motivation to relapse is exposure to conditioned reminders. These can be internal cues like stress (this could be good stress, such as an upcoming wedding or bad stress such as a rough day at work), or just a smidgen of the drug itself, or as I discussed above, people places and things previously associated with using the drug. All of these things tickle the dopamine system because they are conditioned reminders of past drug use – when, why and how one used the drug. The addicted brain does not easily let go of these reminders and also does not seem to have the machinery to put them in check. ‘Just say no’ doesn’t work.

LET’S TALK ABOUT YOUR RESEARCH

My early research in human fMRI showed that the limbic system was highly activated in people who smoke cigarettes when they watched a video of smoking reminders. This brain response was observed in people who had smoked right before their fMRI. This was the first study to show that the brain regions involved in motivated behavior respond to these cues even when the individual is NOT in withdrawal. But, even within this study we noted that there was a lot of variability in how individual’s brain’s responded to the cues. Why? This is when we began looking at the dopamine components. There is a genetic variant in humans that may affect the number of, or function of, the dopamine transporter. We grouped the participants by this variant and remarkably, much of the variance in our data was accounted for by this genetic variant. We replicated this finding prospectively. We have also shown that sex and hormonal status (in women) and endorsing prior trauma can affect responses to drug cues. We have also examined the mechanisms of pharmacological manipulation (medications) on the brain’s response to drug cues. An overarching goal of contemporary medicine, is to use the variability in brain, behavior and genetics to ‘type’ an individual to a particular treatment strategy (or strategies); to tailor the treatment to manage individual vulnerabilities to aid in conquering addiction.

ARE THERE MEDICATIONS TO TREAT ADDICTION?

Yes, for some of the addictions and for some people. For example, several medications have been shown to be effective for opiate or opioid use disorder (OUD). Like, methadone, Buprenorphine or Naltrexone (Suboxone). But they don’t always work. Why? Because they are not available to everyone. Most medical professionals are not trained to prescribe these medications or manage the treatment in people with OUD. Also, people can’t afford them. And, there is stigma associated with their use – many people STILL think treating with an agonist, such as methadone is exchanging one addictive drug for another. That is a whole topic unto itself and we could easily do an entire We Talk Science on that one. To touch briefly on the stigma issue; there are many forms of stigma attached to substance use disorder, including stigma attached to users by medical professionals, internal stigma by those who use substances and even stigma within the research community. The stigma of addiction could be another We Talk Science topic unto itself.

REFERENCES

Batra, Vikas, Ashwin A. Patkar, Wade H. Berrettini, Stephen P. Weinstein, and Frank T. Leone. “The Genetic Determinants of Smoking.” Chest 123, no. 5 (May 2003): 1730–39. https://doi.org/10.1378/chest.123.5.1730.

Franklin, Teresa R, Ze wang, Jiongjiong Wang, Nathan Sciortino, Derek Harper, Yin Li, Ron Ehrman, et al. “Limbic Activation to Cigarette Smoking Cues Independent of Nicotine Withdrawal: A Perfusion FMRI Study.” Neuropsychopharmacology 32, no. 11 (November 2007): 2301–9. https://doi.org/10.1038/sj.npp.1301371.

Franklin, T. R., K. Jagannathan, R. R. Wetherill, B. Johnson, S. Kelly, J. Langguth, J. Mumma, and A. R. Childress. “Influence of Menstrual Cycle Phase on Neural and Craving Responses to Appetitive Smoking Cues in Naturally Cycling Females.” Nicotine & Tobacco Research 17, no. 4 (April 1, 2015): 390–97. https://doi.org/10.1093/ntr/ntu183.

Franklin, Teresa R., Joshua Shin, Kanchana Jagannathan, Jesse J. Suh, John A. Detre, Charles P. O’Brien, and Anna Rose Childress. “Acute Baclofen Diminishes Resting Baseline Blood Flow to Limbic Structures: A Perfusion FMRI Study.” Drug and Alcohol Dependence 125, no. 1–2 (September 2012): 60–66. https://doi.org/10.1016/j.drugalcdep.2012.03.016.

Franklin, Teresa, Ze Wang, Jesse J. Suh, Rebecca Hazan, Jeffrey Cruz, Yin Li, Marina Goldman, John A. Detre, Charles P. O’Brien, and Anna Rose Childress. “Effects of Varenicline on Smoking Cue–Triggered Neural and Craving Responses.” Archives of General Psychiatry 68, no. 5 (May 2, 2011): 516. https://doi.org/10.1001/archgenpsychiatry.2010.190.

Franklin, Teresa R., Ze Wang, Nathan Sciortino, Derek Harper, Yin Li, Jonathan Hakun, Susan Kildea, et al. “Modulation of Resting Brain Cerebral Blood Flow by the GABA B Agonist, Baclofen: A Longitudinal Perfusion FMRI Study.” Drug and Alcohol Dependence 117, no. 2–3 (September 2011): 176–83. https://doi.org/10.1016/j.drugalcdep.2011.01.015.

Franklin, Teresa R, Falk W Lohoff, Ze Wang, Nathan Sciortino, Derek Harper, Yin Li, Will Jens, et al. “DAT Genotype Modulates Brain and Behavioral Responses Elicited by Cigarette Cues.” Neuropsychopharmacology 34, no. 3 (February 2009): 717–28. https://doi.org/10.1038/npp.2008.124.

Franklin, Teresa R., Ze Wang, Yin Li, Jesse J. Suh, Marina Goldman, Falk W. Lohoff, Jeffrey Cruz, et al. “Dopamine Transporter Genotype Modulation of Neural Responses to Smoking Cues: Confirmation in a New Cohort: DAT Genotype Effects on SCs.” Addiction Biology 16, no. 2 (April 2011): 308–22. https://doi.org/10.1111/j.1369-1600.2010.00277.x.

Maurer, John J., Mathieu E. Wimmer, Christopher A. Turner, Rae J. Herman, Yafang Zhang, Kael Ragnini, Julia Ferrante, et al. “Paternal Nicotine Taking Elicits Heritable Sex-Specific Phenotypes That Are Mediated by Hippocampal Satb2.” Molecular Psychiatry, May 20, 2022. https://doi.org/10.1038/s41380-022-01622-7.

McCabe, Susan. “Substance Use and Abuse in Trauma: Implications for Care.” Critical Care Nursing Clinics of North America 18, no. 3 (September 2006): 371–85. https://doi.org/10.1016/j.ccell.2006.05.002.

Franklin Teresa F.,Nathaniel H. Spilka, Heather Keyser, Melanie Maron, Kanchana Jagannathan, Reagan R. Wetherill “Impact of the natural hormonal milieu on ventral striatal responses to appetitive cigarette smoking cues: A prospective longitudinal study.” Drug and Alcohol Dependence Reports. https://doi.org/10.1016/j.dadr.2022.100119.