Table of Contents

Introduction

Today we make jokes about the use of tapeworms for weight loss, but that was a real fad in the early 1900s. Some rich and famous people use them to stay thin.[1] Then, in the 1930s, a drug was developed that increased metabolism, dinitrophenol (DNP). The FDA shut that down because of over a hundred deaths in 1938.[2] (You can still get it, but don’t!)

Then came the amphetamine craze in the 1930s to the 1970s[3] (you can still get these, too – but don’t even think about it!) People lost weight, but it made their obesity worse when they stopped. Though used since the late 1800s, in the 1960s weight loss clinics popped up all over the United States that were giving high-dose thyroid hormones.[4] The problem was, they had terrible side effects and didn’t work very well.

Then came the resurgence of an amphetamine stimulant, phentermine, coupled with an appetite suppressant drug, fenfluramine, known as Fen-Phen in the 1980s, which exploded in the 1990s. After losing some big lawsuits, the company withdrew fenfluramine.[5]

Next, the world was buying ephedra (Ma huang) with caffeine and aspirin to lose weight.[6] This stimulant worked for some, but it caused strokes, heart attacks, and deaths so the FDA banned it from supplements. In the early 2000s, Acomplia was introduced to do the opposite of marijuana by blocking cannabinoid receptors. It caused depression and suicides, so it was also taken off the market.[7]

None of these were adequately tested before being sold. The fad is in the marketing of them, so the company makes billions of dollars knowing that they will have to pay out millions to the patients and families of those who are maimed or die. It’s just the cost of doing business.

Now we have a new fad with lots of great marketing: peptides.

Peptide Hormones

Let’s talk about peptides, which are hormones. Peptide hormones (Insulin, glucagon, GH, ACTH, oxytocin, ADH, GLP-1, and many more) are quick and easy. They are stored in cells and released immediately when needed, and they only last for minutes. They are released quickly and gone quickly.

On the other hand, steroid hormones (cortisol, aldosterone, testosterone, estrogen, progesterone, vitamin D) have a completely different function. They go through membranes, are made more slowly on demand to be a long-term signal.

Peptide hormones are like a text message, and steroid hormones are like an email with attachments.

We’ve been using steroid hormones for many years, such as cortisone injections for inflammation and allergic reactions, testosterone to build muscles, and estrogen/progesterone to help menopause and fertility.

Our use of peptide hormones has been limited to insulin for diabetes mellitus type 1, and occasional growth hormone and vasopressin in children. Only in the last twenty years or so have we begun to see the huge effects of peptide hormones used to regulate functions of the body. Part of this is because peptide hormones don’t survive the stomach so they must be injected. (There is a nasal spray for some of them)

How Tirzepatide and Semaglutide Work

One more recent advance is the use of GLP-1 to regulate blood glucose and appetite. Drug manufacturers found a way to extend the life of this hormone that normally lasts about 2 minutes to around a week. That means instead of needing multiple injections daily with natural GLP-1, semaglutide and tirzepatide only require one injection per week.

Semaglutide (Wegovy and Ozempic):

Lowers blood sugar by stimulating the pancreas to release insulin when blood sugar levels are high.
Slows down the rate at which food leaves your stomach
Reduces appetite.

Tirzepatide (Mounjaro / Zepbound): Same as Semaglutide but also stimulates another receptor called GIP which increases insulin production in the pancreas. Studies indicate that this works better for both diabetes and weight loss.

The problem is that the natural system is made for brief spurts of GLP-1 that disappear in minutes. Now, with constant stimulation for a week with each injection, the system becomes overwhelmed in time. Have you ever gotten a ten-page text? I skim through it, or don’t even read it. Your cells will do the same, becoming insensitive to GLP-1 over time.

Gastrointestinal Side Effects

What do you think would happen if you normally have 2-10 minutes of slowed stomach and intestines, so you are no longer hungry, but then change it to constant stimulation so things don’t move through. (Pregnant women know about this – called “morning sickness”)

Nausea
Vomiting
Diarrhea
Constipation
Abdominal Pain
Dyspepsia
Acid reflux
Gastroparesis

Gastroparesis and Delayed Gastric Emptying

Gastroparesis means “paralyzed stomach” so your stomach empties food more slowly than normal. Designed to slow stomach emptying, Tirzepatide and Semaglutide help you feel full longer, but in some people, it can cause the following problems.

Persistent nausea or vomiting
Feeling full after eating only a small amount
Bloating and stomach pain
Loss of appetite
Weight loss because you can’t eat

Pancreatitis

Imagine if the normal stimulation of the pancreas to produce insulin lasted a few minutes during a meal, and then you start constantly stimulating them for a week or more. It is hypothesized that this overstimulation is the reason the GLP-1 medications have been associated with pancreatitis. Pancreatitis is inflammation of the pancreas, which is a serious but rare side effect. The pancreas helps digest food and control blood glucose. Symptoms of acute pancreatitis include:

Severe, persistent stomach pain (often radiating to the back)
Nausea and vomiting
Fever

You may be at higher risk if you have a history of pancreatitis, gallstones, high triglycerides, or drink alcohol. Pancreatitis can be life-threatening if not treated promptly.

Gallbladder Disease

Not only do Tirzepatide and Semaglutide slow down the stomach, they also slow the biliary system, increasing the risk of gallstones and gallbladder inflammation (cholecystitis). Normally, this slowing effect would last for minutes, but the injections last for weeks, continuously impairing the bile. Symptoms of gallbladder disease include:

Sharp pain in the upper right side of your abdomen
Pain after eating rich or fatty foods
Fever, nausea, or vomiting
Yellowing of the skin or eyes (jaundice)

The risk is higher if you are overweight, have lost a lot of weight quickly, or have a family history of gallstones.

Thyroid C-Cell Tumors

The FDA includes a black-box warning, meaning if anybody reads the package insert, they will see a black box on the front with the following: “In rodents, [tirzepatide / semaglutide] causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures.” These medications are not tested for this, so we don’t know if it will cause thyroid cancer in humans.

You should not take Tirzepatide or Semaglutide if you or a close family member have had Medullary Thyroid Carcinoma (MTC) or a genetic condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Hypoglycemia (Low Blood Sugar)

Normally, there is no natural GLP-1 around if you aren’t eating. With Tirzepatide and Semaglutide, however, the receptors in the pancreas are constantly stimulated to produce and release insulin. Generally, while the pancreas is producing insulin, it only releases it with a meal, so there is usually no problem with hypoglycemia. Sometimes, however, they may cause both release of insulin and inhibition of glucagon to cause low blood sugar on their own. The risk increases if you use them with insulin or other diabetes medicines. Symptoms of low blood glucose include:

Shakiness or sweating
Fatigue
Dizziness or confusion
Fast heartbeat
Blurred vision

If you have trouble waking up, seizures, or lose consciousness, seek emergency care immediately.

Mental Health Effects

The GLP-1 agonists have affects in the brain as well. In the amygdala and the nucleus accumbens the constant stimulation leads to decreased dopamine reward, and increased sensitivity to stressors. While this is a desired effect to decrease appetite, a small number of people may experience mood changes, depression, or anxiety while taking these medications. Some report a lack of ability to feel good (anhedonia).

Persistent sadness or hopelessness
Loss of interest in activities
Changes in sleep or appetite
Thoughts of self-harm or suicide

Loss of Lean Body Mass

If you go on a diet, just by cutting calories, you will lose both fat and protein. Fat loss is what you want as your abdominal girth decreases, but the protein loss is muscle. Studies indicate about 20% of the weight you lose is muscle when on a calorie-restricted diet.

Tirzepatide and Semaglutide are continuously active for weeks to months. During this time, they inhibit anabolic metabolism and cause muscle wasting. The estimated loss of lean body mass is 45% of the total weight lost! This means that while you want to lose fat, you are also losing almost as much muscle (sarcopenia). If you weigh 200 pounds, your maximum weight loss would be about 40 pounds, and 18 pounds of that is muscle. That means you can only lose about 22 pounds of fat, MAX! This is not good! The longer you get these injections, the more muscle loss you get.

Compare this to fasting, which has no plateau, or tachyphylaxis (loss of effect). During fasting you lose 90% fat and 10% lean body mass, so you could lose 50 pounds of fat, and you would only lose about 5 pounds of muscle. Moreover, because fasting increases anabolic metabolism, you gain back the muscle first upon eating, whereas with the GLP-1 agonists you don’t get it back because they shut down anabolic metabolism.

Weight Regain After Stopping

Since the constant stimulation of receptors causes them to become insensitive, the GLP-1 agonists stop working. The maximum weight loss is about 15% of body weight if you stay on the drug for 2 years. This is heartbreaking for those who need to lose 50% of their current weight. Within a couple of years of using them weekly, weight loss stops.

Then, without the stimulation of the drugs, weight loss from Tirzepatide or Semaglutide does not last when you stop the medication. Most regain some or all of the weight. On average you gain back 40% in 3 months, and 67% by a year. To prevent this, you must stay on the injections for life – and risk losing more lean body mass, but not lose more fat.

Insulin Resistance and Metabolic Rebound

These medications can improve insulin sensitivity while you’re taking them both because you are losing fat, and because they inhibit glucagon which allows lower fasting glucose. After stopping, however, your body may return to its previous state, and blood sugar or weight can rise again (metabolic rebound).

Cardiovascular Effects

Tirzepatide and Semaglutide may lower your risk of heart attack and stroke, especially if you have diabetes because they decrease blood glucose and allow fat burning. However, after stopping them, your risks will also return.

Renal Impairment (Kidney Problems)

Vomiting or diarrhea as well as nausea and not being hungry or thirsty can lead to dehydration, which may harm your kidneys. People with existing kidney problems should be especially careful. It’s important to make sure you are getting enough water.

Long-Term Risks and Unknowns

Tirzepatide and Semaglutide are relatively new medications. We do not yet know all the long-term risks so it is wise to have a very low threshold for stopping the injections – you can always go back on it if it’s a false alarm.

Another Option: Intermittent Low-Dose Tirzepatide

Some healthcare professionals are exploring the use of low-dose tirzepatide[8] on an intermittent schedule—such as 12 weeks on treatment followed by 12 weeks off—to prevent or minimize the side effects and risks commonly associated with continuous therapy.[9] This approach may help reduce the likelihood of gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, while potentially maintaining the medication’s benefits for blood sugar control and weight management.

The program includes a low-dose initiation of four weeks, followed by the ON-CYCLE of the same dose or higher, depending on the need for 12 weeks, then the OFF-CYCLE with no medication for 12 weeks. The ON-CYCLE and OFF-CYCLE is repeated. It is normal to gain back a little during the OFF-CYCLE, so this is the best time to build muscle that would be lost during the ON-CYCLE.

Phase	Duration	Dose & Frequency	Key Goals/Actions
Initiation (If New User)	Weeks 1–4	0.5 mg weekly (SC injection)	One meal per day, no snacks — 1,500 kcal diet + 150 min exercise/week.
On-Cycle	Weeks 5–16 (12 weeks)	0.5 – 1 mg weekly	Diet: high-protein (1.6 g/kg) and Exercise to spare muscle.
Off-Cycle	Weeks 17–20 (4 weeks)	None (drug holiday)	Reset: Focus on habits; expect mild hunger return—use behavioral tools (e.g., Noom app, intermittent fasting, keto diet, exercise).
Repeat On-Cycle, then Off-Cycle	Weeks 21+ (Indefinite)	Same as above	Semi-annual labs.

Recommended Testing:

Monthly: blood tests (Insulin, glucose, lipids, liver enzymes).
Quarterly: DEXA for lean mass; Consider gallbladder ultrasound if indicated

Evidence and Risks: What the Data Says

Supporting Data:
- Low-dose efficacy: SURPASS trials show 2.5 mg yields ~8–12% loss (scalable down); 2025 real-world studies (e.g., JAMA Network Open) report 5–10% loss at ≤2.5 mg with fewer dropouts.[10] This is almost as good as the full dose, without the side effects!
- Cycling: SURMOUNT-4 (randomized withdrawal) implies short breaks cause ~2–5% regain per month off.[11] It’s OK to gain back some muscle in the time off, that is the purpose.

Recommendations

There is a great deal of excitement over the use of Tirzepatide and Semaglutide for weight loss. People are using them and losing weight. However, just like tapeworms, amphetamines, ma huang, and so forth, they are untested, and there are significant problems with them. Every weight loss fad was stopped or faded out because drugs are not the way to maintain a healthy body weight.

The actual weight loss is moderate, at best, before it stops working, averaging only 15-30 pounds, and then gaining it all back within a couple of years, so you still need to eat less and exercise more. The only way anyone really loses weight is by eating less and exercising more. You would think we would have learned this in over a century of weight-loss fads. The is no magic pill (or injection)!

Plus, nobody knows what will happen in five or ten years. Having already seen some of the side-effects, I do not recommend their use at the current dose, although it may be better to use the low-dose regimen. Still, it seems like turning on this metabolic switch continuously for years will do more harm than good. The fact is, we don’t know – but it seems like the risks outweigh the benefits.