Scientists look at everything from genetics and trauma to personality and social traits
The complexities of addiction have stumped scientists for decades. Today, with 48 million Americans suffering from a substance use disorder, and alcohol and drugs combined resulting in over a quarter of a million deaths annually, the urgency to find answers has only risen.
At the University of Colorado Anschutz Medical Campus, researchers are looking for genetic links, studying personality traits and seeking new therapies for addiction. Their hope is to someday not only ease the heavy cost addiction places on individuals, families and communities, but to possibly prevent it.
"Drugs of abuse tap into normal brain functioning, sabotaging normal brain circuits that are critical for adapting our behavior to our environment," said Susan Ingram, PhD, professor, vice chair of research and the Richard Traystman endowed chair in the Department of Anesthesiology. "Understanding how drugs change these circuits help us to find cures and strategies to alleviate pain and drug addiction."
What role does nature play in addiction?
When someone who is prone to addiction - for reasons scientists are still working to understand - experiences an addictive substance, it triggers a cascade of chemicals in the brain. Eventually, they crave the "substance," whether it's alcohol, opioids or the winning pot in a gambling game. The urge for more begins to override everything - obligations, relationships, social activities - despite the destruction it brings to their lives.
There is a physiological basis behind the urge. Ultimately, substances prone to abuse impact the brain's reward center, an essential system for learning meant to encourage survival tactics - such as seeking and consuming water, salt and sugar. Certain substances and drugs can trigger compulsive behaviors and ultimately a substance use disorder, when interacting with the same reward pathways in the brain.
Through her work Ingram hopes to help pinpoint further the biological differences within a brain interacting with pain and chronic drug use. Some of her recent research involves methamphetamine and a specific brain receptor that appears to show the natural aversion some might have to methamphetamine use.
Methamphetamine is a powerful stimulant for the central nervous system that causes feelings of euphoria and increased energy. However, it has significant potential for addiction and serious negative health effects. While it is sometimes prescribed for attention deficit disorder, its primary use is as a recreational drug - 2.5 million Americans currently have a substance use disorder involving methamphetamine. The drug's use has been on the rise and has resulted in an increasing number of psychiatric hospitalizations.
Ingram said methamphetamine is so potent because it quickly crosses the blood-brain barrier. The drug interacts with the reward system and entire body due to its access to the monoamine systems, which govern reward, arousal, emotion and some memory function.
Ingram is studying the trace amine-associated receptor 1, or TAAR1, which is a target for methamphetamine in the monoamine system. In animal models, her team has identified that mutations in this receptor are inheritable and play a large role in aversion (or distaste) to methamphetamine.
In lab results, her findings suggest heritability plays a large role in methamphetamine addiction.
"The impact is huge," she said. "It's 60% of the heritability, which is one of the most impressive single-gene effects in drug addiction that has ever been described. TAAR1 function is associated with aversion to methamphetamine. A single-point mutation in the receptor can be the difference between aversion, or strong rewarding effects and addiction, to a drug like meth."
There is still much to learn, including more about TAAR1 gene mutations in humans and how they affect human behaviors, Ingram said. "We're just tapping the surface of how these TAAR1 receptors work for drug addiction," she said. "We're really trying to understand these receptors and are hoping to look next in specific brain areas that are involved in aversion circuits - like the lateral habenula (a pea-sized part of the brain described as an 'anti-reward center' that scientists have found can play a role in stress responses and decision making)."
Ingram's work comes at a crucial time, given the potency methamphetamine possesses, the health impacts it can cause and that it ranks second - behind synthetic opioids such as fentanyl - in drug deaths in the country.
One insidious aspect of AUD: heritability
In his lab across campus, Joshua Gowin, PhD, an assistant professor in the department of radiology, is doing similar work, but exploring a different substance taking an increased toll on the country lately: alcohol. The Centers for Disease Control and Prevention noted a 29% increase in alcohol-related deaths over a four-year stretch - totaling 178,307 in 2020-2021, and alcohol use has become a leading cause of liver transplant in the U.S..
Similar to methamphetamine, alcohol and alcohol use disorder (AUD) creates challenges for patients, providers and researchers, given its chemical structure. It starts with its molecular nature, Gowin said.
"It's this tiny molecule, compared to caffeine or THC (the psychoactive portion found in cannabis), which are much larger molecules," he said. "Because of this, alcohol gets in your bloodstream and then gets distributed all around your body - there's no part that is immune from being affected."
That extends - in part - to one of the more insidious aspects of AUD and other substance use disorders - heritability. The heritability for AUD is around 50%, which Gowin notes comes from years of studies involving twins.
"The genes that affect metabolism are the most important genes for determining someone's risk for alcohol use problems," he said. "We've determined this because the metabolic pathway is so well characterized, specific to the liver and the time course of the metabolism."
Gowin said a genetic predisposition can be seen in certain populations. The gene is more common in people of East Asian ancestry, for example, who experience a flushing of the skin when they drink due to the rate of alcohol processing by enzymes in the liver. It's unpleasant, and as a result, people with this genetic variant tend to be at lower risk for developing AUD.
While metabolism and heritability aspects have become better understood, Gowin has also seen the conversation change around alcohol and health.
"We've seen an improved understanding of alcohol's role in promoting cancerous tissues and other health impacts," he said. "Specifically, alcohol has both acute and chronic effects on the brain. From short-term memory impacts to longer-term consequences of a reduction in gray matter - a tissue in your brain and spinal cord that helps govern things such as emotions, movement and memory. Everything else being equal, the more someone drinks, the less gray matter they will have."
Discoveries such as these have led to a growing conversation among healthcare providers - who have also connected alcohol to risks for diabetes and cancers, in addition to being in a vehicular accident - about the need to move away from recommending any alcohol consumption to patients.
How does environment enter the picture?
While biology is critical to understanding addiction - with genetics accounting for roughly 50% of the risk for developing a substance use disorder - that still leaves a pressing question: What about the other half?
At CU Anschutz, researchers like Drew E. Winters, PhD, are exploring the impact of environmental factors. A research faculty member in the Department of Psychiatry, Winters focuses on the intersection of cognitive control, social cognition and neuroscience, asking how our relationships - and our ability to understand and navigate those relationships - can shape the trajectory of substance use.
Changing attitudes
