Professor Anders Fink-Jensen

Studying anatomy as a medical student led Anders to an interest in psychiatry. Training in this specialist field involved a fair amount of work in pharmacology. What started out as a collaborative research opportunity at Novo Nordisk, the Danish pharmaceutical company renowned for innovations in diabetes healthcare, turned into almost a decade devoted to developing compounds for mental health conditions such as schizophrenia. Longing to return to work with patients, Anders took up a clinical role where he could help patients and carry out research. Years later he became Professor and Head of Clinic at Mental Health Centre Copenhagen and University of Copenhagen, Denmark, continuing this balance between treating and researching mental health conditions.

In this interview, we speak to Professor Anders Fink-Jensen who is a clinical psychiatrist. His work with patients has furthered the study of a particular group of compounds, called GLP-1 receptor agonists, most commonly used in the treatment of people living with type 2 diabetes and/or obesity. This research is encouraging for the future development of anti-addiction drugs.

Millions of people around the world are suffering from alcohol, tobacco and substance use disorders. The figures are staggering; approximately 35 million people live with substance use disorders worldwide (United Nations Publication, 2020) and 280 million people live with alcohol use disorder (AUD) (World Health Organization, 2018). In this interview, we speak to Anders Fink-Jensen, Clinical Professor of Psychiatry at the University of Copenhagen, Denmark who tells us that: “Despite decades of research, treatment options are sparse or missing.” Current U.S. Food and Drug Administration (FDA) approved drugs for patients with AUD only work for a small percentage of people. Since the 1980s, there have been no new compounds available to test or develop for the treatment of addiction. Only repurposed drugs, like an injectable version of naltrexone that was approved for AUD in 2006, have been used in the last 40 years.

That is until the discovery of glucagonlike peptide 1 (GLP-1), a hormone that is produced in the gut that monitors appetite and blood glucose levels. The GLP-1 analogue receptors are used for diabetes healthcare and people living with obesity.

Since the 1980s, there have been no new compounds available to test or develop for the treatment of addiction

Semaglutide

You have most likely come across the group of GLP-1 compounds, in the form of the popular type 2 diabetes drug Ozempic and weight management drug Wegovy. Both are brand names of the active ingredient semaglutide. These drugs have been stealing the limelight in the media with celebrities and members of the public alike talking about their role in weight and blood sugar management.

“Semaglutide is the most potent GLP analogue because it binds more tightly to the GLP-1 hormone receptor.” This is why it is the active ingredient in the popular drugs, Ozempic and Wegovy, both of which have been changing the landscape of diabetes and obesity treatment. Ozempic is approved by the FDA for use by adults with type 2 diabetes, while the FDA approved Wegovy, a drug specifically designed for chronic weight management for people living with obesity. Wegovy has a higher dose of semaglutide than Ozempic.

There have been a series of reports and studies documenting the effects of semaglutide for weight loss. One study showed people living with obesity lost more than 15% of their body weight whilst taking regular doses of semaglutide (Weidling et al., 2021), propelling semaglutide into fame. However, whilst there seems to be an appeal of using semaglutide as a weight management strategy, the downside is that its popularity could mean less access for those who need it for managing their health. In addition, there have been several warnings from medical professionals of its use for those not living with type 2 diabetes or obesity – the two conditions that it is currently licensed for.

Weight loss is not the only effect making the headlines. There have also been anecdotal reports from patients who report drinking less alcohol. “This has created much hype over the potential clinical applications of semaglutide and other GLP-1 analogues for alcohol and substance use disorders. However, we don’t yet have the hard scientific data and evidence to support this use to curb alcohol cravings,” warns Anders, concerned how people could interpret and act on speculative evidence.

Semaglutide: A promising drug to treat those with addition?

As a clinical psychiatrist, Anders has devoted many years to working with patients with schizophrenia and other mental health disorders. Some of the most effective medications for schizophrenia can have unfortunate side effects, such as weight gain, metabolic issues, prediabetes and type 2 diabetes. The GLP-1 receptor agonists manage blood glucose levels by helping the pancreas make more insulin and thus lowering blood sugar levels. It mimics the naturally occurring hormone response to food, signalling to brain that you are full, reducing your appetite, and it slows down the movement of food in your gut. When food takes longer to leave your body, you stay full for longer, so you eat less overall.

The use of GLP-1 receptor agonists against type 2 diabetes was first approved by FDA in 2005 and over the following years some of Anders’ colleagues started to notice an interesting side effect.

“The patients who had type 2 diabetes began reporting that they no longer seemed to desire alcohol. Those who enjoyed drinking with friends and going on wine tastings asked if they could temporarily stop taking the medication to enjoy alcohol again,” shares Anders, slightly amused when remembering this request. “This gave us hope after several years of searching for a new anti-addiction drug.”

The use of GLP-1 receptor agonists against type 2 diabetes was first approved by the FDA in 2005 and over the following years some of Anders’ colleagues started to notice an interesting side effect

An unexpected finding

The observation that patients who were treated with GLP-1 receptor agonists reported a lack of interest in alcohol piqued Anders’ interest. He and a global team of researchers began investigating why GLP-1 reduced alcohol consumption, carrying out the first randomised control trial on the effects of GLP-1 in AUD patients. This study was a six-month double blinded, placebo-controlled clinical trial (Klausen et al., 2022) testing 127 patients. All the participants went through behavioural therapy to encourage them to drink less, and 62 patients received weekly injections of a form of GLP-1, called exenatide. Exenatide is less potent than semaglutide, but semaglutide was not available for clinical use when the study was initiated.

Anders reports: “We measured and compared the activity of three brain structures in the reward centre using functional magnetic resonance imaging (MRI). The reward centre was activated in both the placebo and exenatide groups when shown photographs of alcoholic drinks. However, one brain structure, the ventral striatum, showed less activity in the patients who had been treated with exenatide.”

He was surprised that both groups (placebo and exenatide) cut their alcohol intake by roughly the same amount and the number of days on which they drank heavily by 50%. To unpick this inconclusive finding, they carried out a statistical analysis, which revealed that the most dramatic reduction in alcohol intake was for people with a BMI over 30 (indicating obesity).

To investigate the link between GLP-1 and alcohol in a larger sample, Anders and colleagues also carried out a nationwide register-based cohort study of new users of GLP-1 (38,454) and comparing alcohol events to those who were new users of dipeptidyl peptidase 4 inhibitors (n = 49,222). They found that use of GLP-1 receptor agonists was associated with a lower risk of a subsequent alcohol-related event compared with use of DPP-4 inhibitors after adjustment for covariates (Wium-Anderson, 2022).

Cutting back on alcohol

Most research on the effects of GLP-1 analogues has been carried out in rodents and monkeys (Klausen et al., 2022a). When exenatide is directly injected into different regions within the reward centre of the brain, rodents significantly reduce their alcohol consumption. These inhibitory effects are reversed when the GLP-1 receptors are knocked out in the brain. “This suggests that the effects on alcohol intake are most likely to be controlled centrally by the brain and spinal cord rather than nerves at the periphery of the system,” he explains. Similar findings have been found in monkeys, specifically African vervet monkeys (Thomsen et al., 2018), a species with a known preference for alcoholic beverages and long-term exposure to alcohol. They reduced their intake of alcohol after treatment with exenatide.

Studies have also reported a decrease in the rewarding effects in the brain (Shirazi et al., 2013; Sirohi et al., 2016; Klausen et al.,2022a). Anders says, “These give us clues as to the drug’s mechanism and how it could affect brain circuits.”

We still don’t know the precise neural mechanisms. There is also no guarantee at this point of the research that the same pathways will be activated in the same manner in both animal models and humans

Clues in the brain’s reward centre

Researchers believe the effects of GLP-1 analogue receptors are regulated by the brain and central nervous system. Several structures in the brain produce the GLP-1 hormone or carry receptors for the hormone, including areas that are involved in our reward pathways. Dopamine can activate the reward centre of the brain. GLP-1 appears to be operating in the same regions where dopamine is released.

“We need to explore the influence of the brain–gut axis. Interestingly we’ve seen an overlap with all GLP-1 treatments affecting appetite. We know that the GLP-1 hormone is an appetite regulator that is released when we eat, so calorie value could be playing a role with alcohol.”

Activities or food our brain perceives as pleasurable can dominate our behaviour and actions. Overriding this reward pathway could be the key to suppress cravings to help tackle addictive behaviours.

“We still don’t know the precise neural mechanisms. There is also no guarantee at this point of the research that the same pathways will be activated in the same manner in both animal models and humans,” cautions Anders.

Treating addiction – the difference between “wanting” and “liking”

No-one is certain how addiction develops, but the most dominant theory is based on excessive “wanting”. A process termed “incentive sensitisation”, where the desire is triggered by reward cues in the brain of addicted individuals. Wanting is believed to be generated by dopamine, while “liking” is controlled by hedonic hotspots in the brain rather than controlled by dopamine. As an individual becomes more addicted, the “wanting” overshadows “liking” (Berridge and Robinson, 2016).

This could lead to impulsive and compulsive behaviours. “This is a dark and powerful driver for people who use alcohol as a coping mechanism or form of self-medication to alleviate anxiety, depression or to avoid a deeply unpleasant thought or feeling. We could see very different results for the use of exenatide between an individual who is addicted to alcohol compared to someone who enjoys the taste and sensation of alcohol,” says Anders.

Most research has focused on acute effects rather than the long-term effects. As AUD can be a chronic and relapsing illness that typically requires long-term treatment, the acute findings won’t adequately predict the effectiveness of the drug with repeated or chronic usage.

So far studies have been based on modest quantities of alcohol. More research is needed to understand the effects of high levels of alcohol consumption. We also need to study its effects for people living with a dependence on alcohol to alleviate their mood or negative thoughts. Both avenues need to be explored further to examine brain adaptations and pathways.

Studies in rodents and primates have supported that GLP-1 treatments diminish the desire for substances such as alcohol and nicotine. Only a few clinical trials have been completed in humans.

Human clinical trials

Studies in rodents and primates have supported that GLP-1 treatments diminish the desire for substances such as alcohol  and nicotine (Klausen et al., 2022a). Only a few clinical trials have been completed in humans.

“We have two clinical trials underway to investigate the effects of GLP-1 receptor agonists on alcohol intake in “heavy drinkers” or patients diagnosed with AUD. Both are double-blind, randomised, placebo-controlled studies. The first is to investigate reduction in heavy drinking days after patients diagnosed with AUD receive a once-weekly dose for 26 weeks. The findings could offer insight into the potential neurobiological changes.”

GLP-1 analogues could also help reduce smoking. Only one clinical study (Yammine et al., 2018) to date has suggested that GLP-1 analogues could control nicotine addiction. In this study, they found that 46% of patients stopped smoking following weekly injections of GLP-1, in the form of exenatide alongside nicotine patches. This is compared to 27% who stopped smoking out of the group only given the patches. Studies in animals have started to explore the effects on opioids and cocaine, but no human studies have been performed.

Risk of unwanted side effects

Whilst animal and some human studies seem promising, Anders is concerned about the potential side effects of GLP-1 analogues. “We are still not sure if GLP-1 affects an individual’s mood. There have been cases linking GLP-1 to a condition called anhedonia that lowers an individual’s ability to enjoy life’s experiences. It can be a common symptom of depression and other mental health disorders.” A couple of cases have also reported suicidal thoughts among users. This prompted the FDA and the Europeans Medicines Agency to investigate the link, finding no higher risk at this time (Chiappini et al., 2023; EMA, 2023).

The use of GLP-1 receptor agonists is still in its infancy, having only been on the market since 2021. With widespread and ongoing use, we could see new problems emerge. An approved cannabinoid receptor 1 drug was taken off the market after one year because of increasing reports linking it to depression and suicide. However, a very recent register study published in Nature Medicine did not support concerns of increased risk of suicidal ideation with semaglutide (Wang et al., 2024).

Most research has focused on acute effects rather than the long-term effects. As AUD can be a chronic and relapsing illness that typically requires long-term treatment, the acute findings won’t adequately predict the effectiveness of drug with repeated or chronic usage

Promising but unproven treatments for alcohol and substance use disorders

Animal studies and anecdotal evidence from initial human studies have given much promise about the use of semaglutide for alcohol and substance use disorders, but it is clear its use must be regulated until the safety and efficacy have been rigorously tested. “We need to have the data from research and clinical studies to clarify how the drugs work and understand the capabilities and patient benefits. We don’t want individuals using them to help with alcohol-related use based on speculative observations alone (Leggio et al., 2023). However, we are hopeful that in the future we may get another effective tool to help treat alcohol and substance use disorders.” 

References

Berridge KC, Robinson TE (2016). Liking, wanting, and the incentive-sensitization theory of addiction. American Psychologist, 71(8), 670–679. https://doi.org/10.1037/amp0000059

Chiappini S et al. (2023). Is there a risk for semaglutide misuse? Focus on the Food and Drug Administration’s FDA Adverse Events Reporting System (FAERS) pharmacovigilance dataset. Pharmaceuticals 16, 994. https://doi.org/10.3390/ph16070994

EMA (2023). EMA Statement on Ongoing Review of GLP-1 Receptor Agonists. Available at https://www.ema.europa.eu/en/news/ema-statement-ongoingreview-glp-1-receptor-agonists

Klausen MK et al. (2022a). The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. British Journal of Pharmacology 179(4): 625–641. https://doi.org/10.1111/bph.15677

Klausen MK et al. (2022). Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight. 7(19);e159863. https://doi.org/10.1172/jci.insight.159863

Leggio L et al. (2023). GLP-1 receptor agonists are promising but unproven treatments for alcohol and substance use disorders. Nature Medicine 29, 2993–2995. https://doi.org/10.1038/s41591-023-02634-8

Shirazi RH et al. (2013). Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward. PLoS ONE, 8(4), 1–7. https://doi.org/10.1371/journal.pone.0061965

Sirohi S et al. (2016). Central & peripheral glucagonlike peptide-1 receptor signaling differentially regulate addictive behaviors. Physiology and Behavior, 161(2016), 140–144. https://doi.org/10.1016/j.physbeh.2016.04.013

Thomsen M et al. (2018). Effects of glucagon-like peptide 1 analogs on alcohol intake in alcohol-preferring vervet monkeys. Psychopharmacology, 236(2), 603–611. https://doi.org/10.1007/s00213-018-5089-z

United Nations Publication (2020). World drug report 2020, 2. Drug use and health consequences. United Nations Publication, Sales No. E.20.XI.6. Available athttps://wdr.unodc.org/wdr2020/field/WDR20_Booklet_2.pdf

Wang W et al. (2024). Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nature Medicine 30, 168–176. https://doi.org/10.1038/s41591-023-02672-2

Wielding JPH et al. (2021). Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine 384, 989-1002. https://doi.org/10.1056/NEJMoa2032183

Wium-Anderson IK et al. (2022). Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study. Basic and Clinical Pharmacology and Toxicology 131(5), 372-379.. https://doi.org/10.1111/bcpt.13776

World Health Organization (2019). WHO global report on trends in prevalence of tobacco use 2000-2025, third edition. Available at https://www.who.int/publications/i/item/who-global-report-on-trends-inprevalence-of-tobacco-use-2000-2025-third-edition

Yammine L et al. (2018). Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial. Medicine (Baltimore). 97(2): e9567. https://doi.org/10.1097/MD.0000000000009567