Substance use disorder (SUD) is referred to as a “chronic brain disease” by the National Institute on Drug Abuse (NIDA). The prevailing theory of SUD is that humans are attracted to consuming substances that result in a dopamine surge of satisfaction. For some humans, their brains’ reward systems are hijacked by repeated substance abuse.

Something’s not quite right, however, in this description of the addiction process. It starts with substances being consumed, meaning ingested into the digestive system or into the bloodstream. So why is so much addiction research focused on the brain? Why is SUD considered a chronic brain disease and not a chronic gut disease?

Mapping the relationship of addiction to the gut microbiome yields promising results for the prevention of substance abuse and the treatment of SUDs. Let’s begin our investigation with the most obvious of gut-impacted SUDs: eating addiction.

Eating Addiction

Eating addiction is “a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome interactions,” writes Dr. Emeran A. Mayer, with the Ingestive Behavior and Obesity Program at the University of California Los Angeles (UCLA). Dr. Mayer is the corresponding author on an article on brain–gut–microbiome interactions in obesity and eating addiction for the publication, Nature Reviews Gastroenterology & Hepatology.

Dr. Mayer and his colleagues chart the two-way interactions between the brain and the gut microbiome in response to the hedonic pleasure of eating. Rather than a straight shot of dopamine to the brain, the gut-brain interface involves:

• disruptions in dopaminergic signalling
• vagal afferent function
• metabolic endotoxaemia
• systemic immune activation
• changes to the gut microbiome and metabolome

In an intriguing passage, Dr. Mayer writes, “Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood.” The early life experiences he alludes to include malnutrition and stress. These experiences can be aggravated by “the ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food.”

Cannabis Addiction

Eating addiction isn’t the only addiction that involves the gut microbiome. Research suggests that the gut microbiome is implicated in cannabis addiction, marijuana addiction, and THC addiction. A comprehensive, systematic review of the subject by a team of Thai researchers was published by medRxiv Preprint Server in January 2024.

Their review of 10 studies found that cannabis indeed impacts the microbiome. Exactly how that impacts addiction, however, would require more research. Their conclusion:

Through a meticulous systematic review utilizing comprehensive data, our findings uncover that cannabis consumption in adults with varied clinical conditions leads to [discernible] alterations in the human microbiome.

They state that “21.4% of [marijuana] cigarette users experienced adverse outcomes” in a variety of tests of microbiome health, including “HIV infection, pain/inflammation, systemic aspergillosis, obesity, cognitive deficits, and oral diseases.” However, they do not compare that rate of adverse outcomes with a normal population. It’s possible that 21.4% is a lower rate of adverse outcomes, as marijuana is often prescribed to counter the nausea resulting from chemotherapy.

Alcohol Addiction

The role of the gut in alcohol use disorder (AUD) seems obvious. The gut is where alcohol enters the bloodstream. It’s also the place where people feel cravings for alcohol. An article by Dr. James Schwaber in the scientific journal Progress in Neuro-Psychopharmacology and Biological Psychiatry attempts to explain the role of the gut microbiome in AUD.

Dr. Schwaber says that AUD is associated with a puffy amygdala (neuroinflammation) causing a “disturbance of neural function observed as anxiety and autonomic distress in withdrawal.” The AUD causes an imbalance in the gut microbiome, marked by a loss of beneficial bacteria and overgrowth of harmful, pro-inflammatory microbes. Out of the gut comes the microbiome-brain interface of AUD:

This peripheral response may modulate neuroprotective vagal afferent signaling that permits and exacerbates a neuroinflammatory response in the amygdala.

Dr. Schwaber peers into the future with his suggestion that, “The contribution of the gut to an anxiogenic response is a promising therapeutic target for patients suffering with withdrawal symptoms given the safe and well-established methods of modulating the gut microbiome.” Kaboom! The best treatment for AUD might turn out to be one that targets the gut rather than the brain.

GLP-1 Drugs and Addiction

Dr. Schwaber could not have known that 10 years later, drugs that target the gut would turn out to be treatments for all kinds of addictions. GLP-1 receptor agonists, or GLP-1 drugs marketed as Ozempic, Wegovy, Mounjaro, and Zepbound, were developed from the saliva of a gila monster lizard. An enzyme in the saliva allowed the lizard to digest meals extremely slowly, enabling it to eat very infrequently.

The same enzyme refined in GLP-1 drugs impacts the gut microbiome, with the result that users feel full almost immediately after starting to eat. For many patients, the full feeling results in a near continuous, sub-clinical nausea, which is the leading reason people discontinue use of GLP-1 drugs.

It’s not just the consumption of food, however, that triggers the Clockwork Orange-like nausea. Ingesting alcohol brings the same reaction: I’m full; No more, thanks. People with AUD report not being able to drink nearly as much alcohol as they used to, and people without AUD seem to acquire the habit at a lower rate if they’re using GLP-1 drugs. Those are the results of a massive new trial involving hundreds of thousands of veterans over a three-year period.

It’s not just eating addiction or alcohol addiction that GLP-1 drugs appear to impact. It’s also cannabis addiction, cocaine addiction, opioid addiction, and tobacco addiction. And it’s not even just substance abuse. GLP-1 drugs have shown effectiveness against such behavioral addictions as compulsive gambling, shopping addiction, and pornography addiction.

All addictions and compulsions may, in fact, involve the gut microbiome, the flora of microorganisms that live in the digestive tracts of all animals. The fact that the gut microbiome is involved in behavioral addictions points to A Unified Theory of Addiction, which posits that all addictions have a common source. It’s not a proven theory, yet; let’s call it a gut instinct.

Written by Steve O’Keefe. First published March 23, 2026.

Sources:

“Brain–gut–microbiome interactions in obesity and food addiction,” Nature Reviews Gastroenterology & Hepatology, August 27, 2020.

“Cannabis-Microbiome Interactions in Varied Clinical Contexts: A Comprehensive Systematic Review,” medRxiv Preprint Server, January 21, 2024.

“The role of the gut–brain axis in alcohol use disorders,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, February 4, 2016.

Image Copyright: sfvasco.