Will Ozempic be used to treat addiction?

These GLP-1 RA's are now being touted as reducing cravings and addictive behaviors, possibly finding another future use for this class of drugs.

Now that GLP-1 receptor agonists such as Ozempic have seen greater, more widespread use other uses for these drugs are now coming to light.

Case reports from those taking these GLP-1 receptor agonists have reported that they don’t just lose their hunger cravings, but their cravings for alcohol, smoking, and other addictive behaviors seem to decline as well.

Take a look at a few headlines below for some examples of these reports:

From Insider

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From Daily Mail

In some of these reports, these findings have been met with intrigue and curiosity, with several clinicians wondering how exactly this can be occurring.

Although the attenuation of addictive behavior may seem like a side effect, in reality it likely stems from the neurotropic effects of GLP-1 receptor agonists.

Remember from a prior article that GLP-1 receptors also reside within the CNS, with some evidence suggesting that certain neurons within the brain may produce these incretin hormones, or that GLP-1 produced within the intestines may bypass the blood-brain barrier and bind to these receptors, thus leading to a cascade of events that attenuate hunger and induce satiety.

The latter pathway is the one in question as it relates to these GLP-1 RA’s, as there is some evidence that not all GLP-1 RA’

s can permeate the blood-brain barrier, usually owing to size restrictions. This would suggest that a dose-dependent response in addiction modulation is likely occurring, which again isn’t much of a surprise.

In any case, the fact that GLP-1 receptors reside within the brain and CNS should infer that these hormones may interact with other pathways relating to addiction, either through a broader neurological pathway aside from hunger satiation, or through interactions with other hormonal pathways.

A review from Hayes, M. R., & Schmidt, H. D.¹ notes a possible mechanism in which GLP-1 RAs may attenuate hunger by way of interaction with various parts of the brain (emphasis mine):

To date, studies have shown a physiological and/or pharmacological role for food intake control by GLP-1R activation in a variety of CNS nuclei, including the NTS, paraventricular, dorso-medial, ventral-medial and lateral hypothalamus, as well as the ventral hippocampus, ventral tegmental area (VTA), parabrachial nucleus, and nucleus accumbens subregions [see [20] for review]. While research pursuant to the exploration of GLP-1-mediated effects in all of these nuclei is certainly warranted, of particular interest is research aimed at identifying GLP-1-modulation of food reward-related processing. Indeed, with the growing appreciation that the excessive food intake that contributes to human obesity is not driven by metabolic need, a number of laboratories have made major advances in our understanding of the role that GLP-1 signaling in the mesolimbic reward system has on energy balance control[27-29]. Perhaps most attractive from an obesity treatment perspective is the finding that GLP-1R activation in the VTA and nucleus accumbens core has been shown to selectively reduce intake of highly palatable, energy dense food without producing a significant suppression of intake of a standard bland diet in rats presented with both diets simultaneously[27,30,31]. However, others have reported that GLP-1R activation in the VTA and accumbens can suppress intake of a standard rodent diet in animals not provided with a dietary choice (i.e., only given access to standard chow)[28,29]. Thus, it may be that GLP-1R activation in these mesolimbic nuclei reduces the motivational incentive of the most rewarding stimuli/food available.

Although several animal studies, including studies using non-human primates, have been conducted with respect to GLP-1 RA’s as possible addictive behavior modulators, the actual process by which this occurs is still unclear. That is to say, the actual mechanism of action for these changes in addiction are still yet to be determined.

Most studies have looked at this process from the perspective of reward behavior, and have compared the effects of GLP-1 RA’s to the effects seen in other drugs used for addiction.

An overview is outlined in a review from Klausen, et al.² below, which notes 3 possible ways in which GLP-1 RA’s may alter drug abuse behaviors (emphasis mine):

Despite the preclinical research discussed above and a small number of clinical trials, it is still unclear how GLP‐1 receptor stimulation modulates the effects of drugs of abuse and alcohol. At a behavioural level, the focus of most research has been on the rewarding/reinforcing effects. Currently, the FDA‐approved medications to treat AUD, that is, disulfiram, naltrexone and acamprosate, reduce drinking through three different mechanisms of action: (i) unpleasant effects when consuming alcohol, (ii) reduced rewarding/reinforcing effects of alcohol and (iii) reduced negative state when abstinent. In the published reports, it has largely been assumed that GLP‐1 receptor agonists reduce alcohol intake by decreased rewarding/reinforcing effects of alcohol, and the possibility that GLP‐1 receptor stimulation might decrease alcohol intake through additional mechanisms has not been published. Similarly, studies on cocaine and amphetamine have focused on rewarding/reinforcing effects. An alternative mechanism (not mutually exclusive with reward modulation) is suggested by a study on nicotine, namely, that GLP‐1 receptor stimulation may promote satiety and avoidance of aversive effects of the drug, in this case nicotine, via a habenula‐dependent mechanism (Tuesta et al., ²⁰¹⁷). Another study suggested that cocaine produces a GLP‐1‐dependent negative feedback loop through activation of stress circuits including corticosterone, limiting cocaine intake (Schmidt et al., ²⁰¹⁶), which could also be interpreted as a form of GLP‐1‐potentiated cocaine ‘satiety’. Mechanisms involving some form of satiation would be consistent with the known effects of GLP‐1 system stimulation on the regulation of nutrient intake. However, several studies have reported that GLP‐1 receptor stimulation can suppress drug‐conditioned behaviours, in both classical conditioning (CPP procedures) and operant conditioning (drug seeking using reinstatement procedures), that is, tests during which the drug is unavailable (Douton et al., ²⁰²¹; Egecioglu, Steensland, et al., ²⁰¹³; Egecioglu, Engel, & Jerlhag, ^{2013a, 2013b}; Graham et al., ²⁰¹³; Harasta et al., ²⁰¹⁵; Hernandez et al., ^{2018, 2019, 2020}; Shirazi et al., ²⁰¹³; Sirohi et al., ²⁰¹⁶; Vallöf et al., ²⁰¹⁶; Vallöf, Kalafateli, et al., ²⁰¹⁹; Vallöf, Vestlund, et al., ²⁰¹⁹). This would suggest that GLP‐1 receptor stimulation also modulates mechanisms underlying drug and alcohol ‘seeking’ or ‘wanting’, and not only intake and satiation.

I usually try to avoid taking such a large excerpt, but as shown above many of the reviews so far appear to be rather descriptive in nature, usually summarizing what has been researched in the literature. It appears, with the limited data available, that these synthetic incretin hormones may alter behavior by way of reducing the need or want for addictive substances, rather than just providing a quicker sense of “fullness”. This may partially explain some of the revulsion seen by individuals when trying to smoke or drink of Ozempic and the like.

With respect to cocaine use in particular, some arguments have been raised to suggest that GLP-1 RA’s may alter dopamine transporter (DAT) function and reduce dopamine bioavailability, and thus may operate to reduce cocaine seeking and rewarding behaviors by way of influencing dopamine.³

As it stands, it seems like much of this talk is still in the early works. Some outlets seem to think that these initial reports should be used to investigate GLP-1 RA’s as possible addiction therapeutics, likely spurring even more obsession over the use of these drugs for other diseases.

From CNN reposted in MSN

GLP-1 RA’s have been argued to be possible antioxidant and anticancer agents as well, and speaks more to the broader nature of GLP-1 and corresponding receptors in overall health, and may suggest even more possible uses for this class of drugs in the near future.

For me, I’m rather curious if all of this may be suggestive of alterations in GLP-1 and receptor expression. That is to say, are people who show reduced expression of these genes more inclined for addiction, and is GLP-1 likely to explain the relationship between sugar and substance abuse?

It’s apparent that there’s a lot going on with respect to these incretin hormones, and it’ll be interesting to see what revelations may come about how important they are in health and disease.

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1. Hayes, M. R., & Schmidt, H. D. (2016). GLP-1 influences food and drug reward. Current opinion in behavioral sciences, 9, 66–70. https://doi.org/10.1016/j.cobeha.2016.02.005

2. Klausen, M. K., Thomsen, M., Wortwein, G., & Fink-Jensen, A. (2022). 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

3. Zhu, C., Li, H., Kong, X., Wang, Y., Sun, T., & Wang, F. (2022). Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder. Frontiers in pharmacology, 13, 819470. https://doi.org/10.3389/fphar.2022.819470