April 29, 2024

Are GLP-1’s the answer for weight loss?

Is the obesity drug, semaglutide, also known as ozempic or wegovy, beneficial for weight loss or do its side effects outweigh its benefits?

Is the obesity drug, semaglutide, also known as ozempic or wegovy, beneficial for weight loss or do its side effects outweigh its benefits? I have had a few patients in my practice ask me about using this medication for weight loss and also a few cold calls to my practice asking if I prescribe this medication for weight loss. First of all, I am not a big fan of quick fixes when it comes to weight loss. What I have historically seen, is quick weight loss fixes end up with less than desirable outcomes for most people over time such as muscle loss, gallstones, constipation, fatigue, insomnia, rebound weight gain after stopping the diet or drug and skin laxity. But is semaglutide different? Let’s explore the research….

What is Semaglutide?

Semaglutide is a GLP-1 agonist. For those of you who don’t know, GLP-1 is stimulated by the intestines after eating and sends signals to the brain that we are essentially full and this results in a reduced desire to eat further and tells us we are no longer hungry. GLP-1 agonists potentiate this effect by stimulating the release of insulin, suppressing glucagon secretion, slowing down gastric emptying, and promoting satiety causing a reduction in appetite which leads to weight loss. Sounds great, right?…

Semaglutide is used for diabetes control at 1mg dosages once per week. For weight loss this drug is being administered at 2.4 mg once per week. Does that make a difference for weight loss or side effects seen? Let’s keep reading…

What are other side effects of Semaglutide when used for weight loss?

Some well known side effects of Semaglutide (identified as this drug was previously used at lower dosing for diabetes) are related to what the drug is doing in the body i.e. slowing gastric emptying which leads to nausea, vomiting and abdominal discomfort. This can also cause constipation and gallstones. This can occur even after stopping the drug. Pancreatitis and thyroid cancers are also more serious, but rare side effects.

Sometimes the nausea can be severe as well as the constipation as noted by some taking the drug for weight loss. I personally feel this is a severe side effect as bowel movements are a very important aspect of detoxification. Remember these injections are given 1 time per week with the effects lasting for 1 week. I.e. delayed gastric emptying is occurring for the entire week! If we are not having at least 1 daily bowel movement we are not ridding the body of toxins we come into contact with on a daily basis. This alone can lead to the development of chronic disease later on.

What about muscle loss? It should be mentioned that GLP-1 agonists not only have an effect on fat loss but may have a greater effect on loss of muscle which may be accounting for some of the weight loss experienced11. Most weight loss programs that have a rapid decline in weight also show a loss of muscle or fat free tissue but the muscle loss with GLP-1 use at the dosage used for weight loss is much higher. It is important to be eating enough nutritious foods and enough protein to prevent this muscle loss as well as doing resistance training.

How does Semaglutide effect the brain and contribute more serious side effects noted like suicidal ideation?

According to the STAR study done at Oklahoma State University, 10“Semaglutide binds to receptors in the brain involved in dopamine signaling, particularly in areas like the ventral striatum, which includes the nucleus accumbens. These brain regions play a significant role in making us want and enjoy things that make us feel good. They are critical for motivating us to seek out and enjoy rewarding experiences.” In other words, GLP-1 agonists alter this pathway reducing the pleasure we once got from say, eating.

How??

Centrally acting dopamine controls cognition, motor control, mood and reward.

“The holistic view is that dopamine is a powerful energy sensor, being triggered by glucose ingestion and acting through unknown neuroendocrine mechanisms in a two-way fashion: in brain centers, to control feeding behavior and positive energy balance and, in the periphery, to prime adipose reservoirs to optimize energy storage and expenditure”8.

GLP-1 alters dopamine signaling and subsequent food intake by altering the mesolimbic reward system associated with dopamine synthesis1. Food intake and the gut -brain peptide, GLP-1, elevate dopamine turnover in the amygdala activating certain receptors which change feeding behavior1. The mesolimbic reward system or mesolimbic dopamine system is associated with the pleasurable effects we get from food and drugs of abuse6.

GLP-1 agonists reduce dopamine levels after ingesting food, drugs, and nicotine by blocking the dopamine which negates the “high” that can occur after ingesting these substances. This reduces the “reward” effect seen after using these substances. This is a promising tool for addiction, and the behavioral aspects of obesity may be viewed as an addiction-like syndrome as food stimuli engage dopamine in reward circuits within the brain, in a similar way to mechanisms of drug abuse. 2

But does this same concept apply for other activities that are considered pleasurable other than eating?

What about physical pleasure and motivational drive? GLP-1 agonists alter dopamine signaling in the brain associated with dopamine release with pleasurable activities like eating, addictive drugs and sexual contact6. Alterations in dopamine pathways also affect our motivational drive5. This can lead to complete anehedonia (or lack in the ability to find pleasure in anything) especially in those already affected by depression.

The manufacturer of the drug denies any link between GLP-1 use and suicidal ideation but does warn to stop the medication if thoughts of suicide occur. It is interesting to note, that when studies were done that looked at GLP-1 use and suicide subjects that had a history of depression or mental health disorder such as bipolar or schizophrenia were excluded. This is important to note as a clinician.

When Semaglutide is used for weight loss it is used in higher dosages than for diabetes control and management. There has been some research going into this increase dosage and it’s link to suicidal ideation and behavior. A study done in Diabetes, Obesity, and metabolism8, looked specifically at resting state functional connectivity (RSFC) in brain regions thought to be critical for emotion regulation and impulsivity, such as the amygdala, orbitofrontal cortex and anterior cingulate cortex while subjects were taking semaglutide. Patients with major depressive disorder with suicidal ideation and/or behaviour showed declines in RSCF on MRI imaging. There were no observed adverse effect found in this study, HOWEVER, there were significant changes noted in regions of interest related to suicide. Interesting to note, this study used the dosage to treat diabetes at 1mg NOT the dosage to that is currently being used to treat obesity at 2.4 mg.

What mechanisms are really at play?

It seems that dopamine sensitivity and synthesis is a big target of GLP-1 effects. As mentioned earlier, dopamine affects our reward and pleasure areas of the brain. In peripheral tissues, dopamine regulates pancreatic endocrine function including insulin release and also modulates the effects of insulin action on adipocytes (fat cells) increasing glucose uptake by the cells2.

Peripheral dopamine was initially thought to be exclusively produced at the level of the sympathetic nerves, pancreas, or adrenal medulla, but is nowadays also acknowledged to be secreted by the gut7. Studies show decreased dopamine expression with the onset of insulin resistance7. This is also important to note as diseases like Parkinson’s disease are showing some promise with treatment with GLP-1 agonists as insulin resistance is one cause of dementia.

Dopamine also plays a role in immune functioning. Why is this important? As GLP-1 agonists alter dopamine synthesis the drugs are also altering immune function. Dopamine in the periphery may have an effect an anti-inflammatory effect on mast cells3 which may be another reason why GLP-1 agonists lead to weight loss reduction as GLP-1 increases peripheral dopamine secretion. Quieting down immune, mast cell activation, will reduce systemic inflammation and cause weight loss. This would also suggest an immune component to obesity.

What causes dopamine levels to drop?

Dopamine is produced in the gut through amino acid conversion of tyrosine. So, it is plausible to say that reduced dopamine levels can be attributed to gut dysfunction….

What causes gut dysfunction?

  1. Poor diet
  2. Chronic stress
  3. Medications – antibiotics, acid blockers, etc
  4. Parasites
  5. Fungus
  6. Pathogenic bacterial overgrowth
  7. INFECTIONS
  8. TOXINS
  9. insulin resistance

Once I stop GLP-1’s will the weight come back?

As with any “fad” diet or diet drug as soon as you stop, the weight tends to return and this is not different for GLP-1 agonists. My hypothesis is because the drug does not teach the person how to eat well, how to balance stress, the importance of movement, and the drug can contribute to increase toxin load with constipation and gallstones being common side effects especially at the dosages used for weight loss.

But wait there are positives to this drug!

As discussed in this article, there is an immune component at play with obesity. GLP-1 agonists may be inadvertently addressing this highlighting the importance of immune regulation through toxin and infection removal for sustained weight loss. Toxin overload is a driver of many chronic diseases including obesity. The dosages used for weight loss are the primary problem, however…

As I mentioned before, this drug is being used at high dosages for weight loss. Do we need to use that high of a dosage? Maybe lower dosages will be enough to get the immune modulating and anti-inflammatory effects that accompany weight loss without the side effects? This is something I am investigating in my practice as treating complex chronic disease and the infections and toxins that accompany it are the main goal of my practice. The high dosages used for weight loss currently are the cause of the major side effects seen today as well as the rebound weight gain. I think this drug has great potential when used safely, not to the levels advertised and with proper guidance on diet and other lifestyle factors.

We cannot forget that the major factors in complex, chronic disease and symptoms (obesity, insulin resistance, and metabolic syndrome are all complex, chronic diseases) are toxins, infections and gut health. I see this drug as a potential adjunct to the current protocols I use. Addressing detox and getting the gut in line is still the long term approach to sustained weight loss.

If you struggle with weight loss, insulin resistance or metabolic syndrome schedule a FREE consult today.

References;

  1. Anderberg, R., Anefors, C., Bergquist, F., Nissbrandt, H., Skibicka, K.P. (2014). Dopamine signaling in the amygdala, increased by food ingestion and GLP-1, regulates feeding behavior. Physiology and Behavior, v. 136, 135-144. https://doi.org/10.1016/j.physbeh.2014.02.026

2. Blanca Rubí, Pierre Maechler, Minireview: New Roles for Peripheral Dopamine on Metabolic Control and Tumor Growth: Let’s Seek the Balance, Endocrinology, Volume 151, Issue 12, 1 December 2010, Pages 5570–5581, https://doi.org/10.1210/en.2010-0745

3. Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev. 2023 Jan;75(1):62-158. doi: 10.1124/pharmrev.122.000618. Epub 2022 Dec 8. PMID: 36757901; PMCID: PMC9832385.

4. Karlijn L. Kooij, Derek IJsbrand Koster, Emma Eeltink, Mieneke Luijendijk, Lisa Drost, Fabien Ducrocq, Roger A.H. Adan (2024). GLP-1 receptor agonist semaglutide reduces appetite while increasing dopamine reward signaling. Neuroscience Applied, 3; 103925. https://doi.org/10.1016/j.nsa.2023.103925

5. Nestler, E. & Carlezon, W. (2006). The Mesolimbic Dopamine Reward Circuit in Depression. Biological Psychiatry, 59;12, 1151-1159. https://doi.org/10.1016/j.biopsych.2005.09.018

6. Soares-Cunha C, Coimbra B, David-Pereira A, Borges S, Pinto L, Costa P, Sousa N, Rodrigues AJ. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation. Nat Commun. 2016 Jun 23;7:11829. doi: 10.1038/ncomms11829. PMID: 27337658; PMCID: PMC4931006.

7. Tavares G, Rosendo-Silva D, Simões F, Eickhoff H, Marques D, Sacramento JF, Capucho AM, Seiça R, Conde SV, Matafome P. Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue. International Journal of Molecular Sciences. 2023; 24(3):2464. https://doi.org/10.3390/ijms24032464

8. Verovnik, B., & Vovk, A. (2024). Semaglutide, suicidal ideation and behaviour: A resting state functional magnetic resonance imaging perspective. Diabetes Obesity & Metabolism, 26(2).

9. Zhu Changliang , Li Hailiang , Kong Xuerui , Wang Yezhong , Sun Tao , Wang Feng (2022). Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder. Frontiers in Pharmacology, 13. DOI=10.3389/fphar.2022.819470

10. https://news.okstate.edu/articles/health-sciences/2023/osu-chs-researcher-studying-weight-loss-drugs-alcohol-use-disorder-treatment.html

11. https://fox2now.com/news/missouri/ozempic-use-often-leads-to-loss-of-more-muscle-than-fat

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