Altered States: Rewiring cravings (Part two)

Semaglutide's potential impact on substance use disorders and brain plasticity

In the first of this three-parter, I explored the role of semaglutide in appetite and hunger (part one). Here in part two, I am going to examine potential roles for semaglutide in addiction (substance use disorder; SUD), and brain plasticity, more generally. And in part three, I am going to elaborate on the claim that this class of drugs may come to be at least as important for the individual, society, and the economy as the wild talk asserts about LLMs/AI (please be sceptical; three links) or Elon’s Neuralink (nope, and nope; two links). Hit the subscribe button please!

For background, I recommend reading my previous pieces on metabolism and on exercise:

• Burn, baby, burn: Metabolism Matters - Eating, Exercise, and Evolution Impact Our Energy Burn

• 'Eat less, exercise more' is useless advice; Our activity levels are up -'Toy models' of metabolism and exercise don't work... Something else is going on...

• Too hot to handle: Thermal strain - are you cool-headed or warm-hearted?

• Hypersleep in Aliens, torpor in animals: Slowing your metabolism, energy conservation, and other metabolic marvels

• In Praise of Walking: Chapter 2

  

  Photo by Julia Nastogadka on Unsplash

Semaglutide and substance use disorder

Soon after the approval of semaglutide as a treatment for obesity, press and other reports appeared suggesting that semaglutide was having unexpected and positive side effects on substance use disorders (the now-preferred term for addiction). These were and are very surprising, but very important, if true.

A few of the reports

Did Scientists Accidentally Invent an Anti-addiction Drug? People taking Ozempic for weight loss say they have also stopped drinking, smoking, shopping, and even nail biting. By Sarah Zhang

“As semaglutide has skyrocketed in popularity, patients have been sharing curious effects that go beyond just appetite suppression. They have reported losing interest in a whole range of addictive and compulsive behaviors: drinking, smoking, shopping, biting nails, picking at skin. Not everyone on the drug experiences these positive effects, to be clear, but enough that addiction researchers are paying attention.”

Scientists hope weight-loss drugs could treat addiction and dementia: Medications with semaglutide such as Ozempic and Wegovy are being studied to see if they can help other conditions - Nicola Davis

The weight-loss drug Wegovy may also help treat addiction: Researchers see promise in semaglutide drugs, which may tap into the brain’s reward circuits - Laura Sanders

“Some people taking drugs such as Wegovy and Ozempic, two brand names for the drug semaglutide, have reported surprising — and welcome — side effects: Their constant thoughts about food quiet; their desire for alcohol diminishes; their need for nicotine dissipates.”

Hot weight loss drugs tested as addiction treatments: Clinical trials will gauge whether GLP-1 analogs curb drug, alcohol cravings - Mitch Leslie

“Studies in rodents and primates have supported that mechanism and confirmed the drugs diminish the desire for substances such as alcohol, fentanyl, nicotine, and heroin. Clinical psychiatrist Anders Fink-Jensen of the University of Copenhagen and colleagues even demonstrated that the drugs work in an incorrigible group of drinkers, the monkeys living on the islands of St. Kitts and Nevis in the Caribbean. These rowdy primates are notorious for heavy consumption of alcoholic drinks, which they often swipe from tourists.”

Amazing, if true. A compound that turns down the clamour of cravings would be a remarkable achievement - even if an unintended and accidental one. We now have a few studies available that test if this is true in humans and in animals (specifically, rats).

Let’s look at a few of these studies

The first is a small-scale study of six (yes, just 6!) patients: this case study series examined six patients undergoing semaglutide treatment for weight loss, all of whom initially screened positive for alcohol use disorder (AUD). Remarkably, all six patients displayed notable improvements in AUD symptoms post-semaglutide therapy.

These findings seem compelling, but this case study series is very limited: it was retrospective; uses a very small sample size of six patients, restricting the generalizability of the results; it was no double-blinded, and was not a randomised controlled trial; there was no control group.

Takeaway: Conclusive evidence requires large-scale randomised, placebo-controlled clinical trials to validate semaglutide's efficacy in treating AUD. We’re not there yet. Nonetheless, this is hopeful.

Another report encompasses two distinct studies. The first study analysed of approximately 68,250 social media posts related to GLP-1 or GLP-1/GIP agonists on Reddit. Employing machine-learning techniques, this analysis identified of eight major themes; these included discussions on medication effects, diabetes, weight loss, and obesity. Alcohol-related posts accounted for 1,580 instances. The majority (71%) of these posts indicated reductions in cravings and a decreased desire to drink. (Make of this what you will: it’s a self-selected group, subject to all of the usual errors of self-reporting, where people forget, misremember, and misreport.)

The second study enrolled 153 participants who were current alcohol drinkers and had a BMI ≥ 30. These individuals self-reported the use of either semaglutide (GLP-1 agonist), tirzepatide (a GLP-1/GIP combination), or served as a control group with no medication for diabetes or weight loss management. This study examined both within-subject (prior to starting medication) and between-subject (control group comparison) effects. The findings suggested:

• a significantly lower self-reported alcohol intake

• reduced drinks per drinking episode

• decreased odds of binge drinking

• lower Alcohol Use Disorders Identification Test (AUDIT) scores

• attenuated stimulating and sedative effects in the semaglutide and tirzepatide groups, compared to their pre-medication status and the control group.

This is some initial, real-world, evidence suggesting a substantial reduction in alcohol consumption among individuals with obesity who are taking semaglutide or tirzepatide.

Takeaway: Conclusive evidence requires large-scale randomised, placebo-controlled clinical trials to validate semaglutide's efficacy in treating AUD. We’re not there yet. Nonetheless, this is very hopeful as well.

Human trials can be difficult for all sorts of reasons, so studies in animals can be useful. This study examined the effect of semaglutide on alcohol-related responses in rodents. Rats do like alcohol, and will consume it to excess - just like humans. This study used an intermittent access to alcohol model (variations on access to choices between one alcohol (20%) bottle and one water bottle), semaglutide was tested to see if it could reduce alcohol intake, and prevent relapse-like drinking. Additionally, this study examined if semaglutide gets into the brain (i.e., is brain-penetrant), by fluorescently marking semaglutide and examining if it gets into a key part of the brain’s reward circuitry (the nucleus accumbens; NAc).¹

Findings:

• Male and female rats showed reduced alcohol intake and relapse-like drinking following acute and repeated administration of semaglutide.

• Fluorescently labeled semaglutide was detected in the NAc.

Semaglutide seems to reduce alcohol consumption, potentially through a reduction in alcohol-induced reward and mechanisms linked to the dopamine release NAc.

Finally, another study suggests a different glucagon-like peptide-1 agonist, liraglutide, reduces cue- and drug-induced heroin seeking in high drug-taking rats. This study suggest that these compounds appear to be ‘strong candidates for the non-opioid prevention of relapse to opioids’. Again, if this result generalises to humans this is a most amazing finding - a safer and alternative route to reducing drug dependence. Of course, treatment will need to go beyond merely reducing dependence. Paths back to productive living will need to be developed as well.

What’s happening in the brain? And to behaviour? And to intrusive thoughts?