The Long Term Effects Of Taking The Drug

By Dr. Henry Mahncke and Jamie Bussin

We know that Ozempic, and other GLP-1 agonist drugs are effective at maintaining blood sugar levels for those with Type 2 diabetes and for those trying to lose weight. But do we know how these drugs actually work? I interviewed brain scientist Dr. Henry Mahncke recently on episode #327 of The Tonic Talk Show/Podcast. This article is a digest of our discussion. 

When the scientists were inventing Ozempic, and other drugs in the GLP-1 agonist class of drugs, their belief was that the drugs would act in the gut. Our body releases a peptide, a sort of signal that you’ve eaten. The scientists thought that if they could make a drug that mimicked the effect of this naturally occurring peptide, people would feel like they were full and wouldn’t eat as much and they’d lose weight.

But the initial reports from people who were taking Ozempic was that they were noticing other effects that didn’t seem related to the gut. People started talking about how they were drinking a little bit less, or the drug was having effects on other sorts of lightly addictive behaviours such as drinking alcohol or gambling. According to Dr. Mahncke, that set off a lot of interest in warning bells at the same time among brain scientists. Because, what was being reported actually suggested that the drugs weren’t just working on the gut. It also suggested that the drugs were working on the brain, says Dr. Mahncke; “…and it’s always interesting and exciting and scary when you have a drug that starts to work through the brain in this way, in a way that perhaps wasn’t anticipated.”

How does the brain work to curb appetite?  According to Dr. Mahncke; “The brain controls just about everything we do, including appetite. It both sets a goal for us, which is, ‘we’d like to eat’, because we need to eat to stay alive. Also it is responsible for figuring out well, maybe we’ve eaten enough.” 

Our ancestors lived and evolved in an environment which is very different from today as fats and sugar were not prevalent. Both fat and sugar were necessary for our survival. So our brains released dopamine into our system whenever we ate those nutrients. Dopamine is a “learning signal” in the brain. It serves to reinforce behaviour – in this case encouraging our ancestors to eat more fat and sugar. It is because we live in a modern environment where sugar and fat are more readily accessed that causes problems for our eating behaviour. Our brain rewards us for eating donuts and potato chips by releasing dopamine.

According to Dr. Mahncke; “What’s happening is Ozempic and the other GLP-1 agonists are working in the brain to interact with the reward systems that normally encourage us to eat fats and sugar and food in general. It’s damping those down a little bit. So our brain doesn’t find eating is rewarding, so we eat a little less and we lose weight, which I guess sounds good in the first pass, doesn’t it?”

Our Executive Functions: In cognitive science and neuropsychology, executive functions are a set of cognitive processes that are necessary for the cognitive control of behaviour: selecting and successfully monitoring behaviours that facilitate the attainment of chosen goals. Executive functions include basic cognitive processes such as inhibitory control. According to Dr. Mahncke, it seems that these drugs are in our brains, interacting with our executive function systems to make it easier to resist the temptation to eat a second donut, for example.

We know we’re not supposed to eat a lot of donuts but once they’re in our hands, we can’t stop ourselves from consuming. Ozempic may be working with our executive function to both dampen the dopamine reward and help us pause and think about what we really want to do. 

The long term effects: For the purpose of weight loss, GLP-1 agonists are meant to be taken for the rest of our lives. And that may be problematic, because at this point we don’t know what the long term effects of a drug that impacts dopamine and executive functions will be. Says Dr. Mahncke; “If the way the drug is actually working in our brains and by interacting with the very systems that help us figure out what we want in the world and what is rewarding to us in the world, one has to ask the question these chronic changes to what we find rewarding in the world, is that going to have some other effects upon our health, our lives, our personality, our sense of self? It’s an unknown. We’re all sailing on this journey together into the future. We don’t know yet. We can’t know what the 10-year effects of Ozempic are, because this drug hasn’t been around for 10 years.”

What are the risks or rewards? According to Dr. Mahncke, the reward and dopamine systems are incredibly important. Dopamine is associated with risk tolerance and risk avoidance. There are mutations in dopamine receptors that actually affect our interest and our tolerance of risk, and there’s a strong belief that that is probably related to addictive behaviour. So the people who seem like they get more of a reward out of risk-taking are also the people who are probably a little bit more inclined to get involved in substance abuse and become addicted to it. It may be that this class of drugs will help people curb their addictive behaviours. 

But risk tolerance and aversion is a double-edged sword. Risk tolerance might also spur someone to explore or invent. As a society we want a spectrum of risk taking behaviours. Dr. Mahncke stresses that if we’re going to chronically take drugs that change our brain chemistry, we need to be aware of both the risks and the rewards.