The Microdosing Debate

Happy Monday!

I hope your week is off to a great start.

I received the question below over the weekend and want to address it head-on in today’s email.

I actually received several questions like this in my question box over the past week.

In clinical trials, research has only examined once-per-week dosing of tirzepatide and retatrutide, so I understand the confusion.

Nonetheless, what matters most is how your body handles the total weekly exposure and how your metabolism responds to it.

Retatrutide is one of the most impressive tools ever created for metabolic repair and fat loss, but everyone’s protocol will likely be different.

Some people do well with the standard weekly injection, while others feel miserable and perform far better when they divide their doses into smaller and more frequent injections.

Let’s go through exactly what microdosing means, why it works, and when you should or should not do it.

Understanding Microdosing

In this context, I define microdosing as splitting up your total weekly dose into smaller and more frequent injections.

If your protocol calls for 8mg per week (which is a very high dose), you could inject one milligram every day or two milligrams every other day.

The total weekly amount stays almost the same, but the way it is delivered to your body becomes smoother.

Everyone’s ideal dose is different.

I always tell people to start low and go slow.

Some people who simply want longevity benefits may get great results at two milligrams per week, while someone with deeper metabolic dysfunction might need eight milligrams or more to see the same results.

Microdosing is powerful because it allows you to slowly build tolerance while avoiding the shock that can come from taking one large injection all at once.

It gives your gut, brain, and liver time to adapt, and it lets you feel more in control of how the peptide affects your day-to-day rhythm.

The Pharmacokinetics

Retatrutide was designed with a long half life of about six days.

This is because of a fatty acid chain that binds to albumin in the blood, which allows it to stay active for the entire week.

This is the reason pharmaceutical companies tested it as a once-weekly drug.

The goal in clinical trials was to make it as easy as possible for people to stay compliant because most people hate injecting.

The weekly dosing schedule maximizes human compliance, not necessarily biological perfection.

When you take the full weekly dose in one shot, the level of retatrutide in your blood rises quickly in the first 24 hours, stays high for a few days, and then slowly falls until the next injection.

This creates a steep peak and a low trough.

The difference between the high point and low point is called the fluctuation index.

When you microdose, you inject smaller amounts more often and create multiple small peaks that overlap.

The result is a flatter and more even line of activity.

I have included a graph showing this visually so you can see how the concentration curve changes between once weekly and every other day injections.

The graph below shows how 6 milligrams of retatrutide behaves in the body when given once per week compared to splitting that same total dose into every-other-day or daily injections.

The once-weekly injection produces a sharp rise and fall in concentration, while the microdosed approaches create smoother, overlapping curves that keep blood levels steadier throughout the week.

The total exposure over the week stays the same, but the body experiences it in a more balanced way.

You’ll feel the effects faster if you do once weekly, but you’ll feel a smoother ride if you do daily or every other day injections.

The Benefits of Microdosing

Microdosing offers a number of advantages for people who are sensitive to peptides in this class.

The first and most obvious is less nausea and gastrointestinal distress.

Almost everyone who uses a GLP-1 or GIP peptide knows the feeling of that first 48-hour wave of nausea after an injection.

Smaller injections keep the concentration rise slower and smoother which prevents that wave from hitting all at once.

The second benefit is steadier appetite control.

When people use the full weekly dose they often feel no hunger for the first three days and then become ravenous toward the end of the week.

This feast and famine pattern can make it harder to eat consistently and can lead to energy crashes.

Microdosing prevents this by keeping appetite and satiety signals consistent across the week.

The third is more stable energy and mood.

Large peaks can make some people feel wired or anxious for a day or two, and then lethargic when the level drops.

Smaller injections create more stable neurotransmitter signaling and more predictable energy.

Finally, microdosing allows you to titrate slowly and find your personal sweet spot.

You can move up gradually without overwhelming your system.

This can make the difference between staying consistent and quitting because of side effects.

When Once Weekly Dosing Works Best

There are still plenty of cases where once weekly dosing is ideal.

If you tolerate the medication well and have little to no side effects, the simplicity of one injection each week can be a great advantage.

It may also be the best option for people who travel frequently or do not want to manage multiple doses.

In the clinical world, once weekly dosing provides consistent data collection and easier supervision, which is why it was used in trials.

Once the drug is eventually approved, most people will be prescribed the weekly form simply because it is easy and encourages adherence.

For someone with stable blood sugar and a healthy metabolism, a once-weekly schedule can work very well.

When Microdosing Makes the Most Sense

Microdosing shines when you are having trouble tolerating the medication or when you are just starting out.

If you experience nausea, reflux, headaches, fatigue, or hot flashes after your weekly injection, that is your body telling you the peak concentration is too high.

Breaking your dose up every other day or even daily can transform your experience for the better.

It is also helpful when beginning your journey because the body needs time to adjust to the delayed gastric emptying and glucose signaling that these peptides cause.

By microdosing, you give your system a gradual adaptation curve instead of a steep one.

People who live highly active lives or have variable schedules may also do better with microdosing.

A more consistent internal rhythm supports training, sleep, and cognitive focus.

Why There Are No Studies Yet

Because retatrutide is not FDA approved yet, there are no published studies directly comparing once weekly dosing to microdosing.

All of the data we have comes from pharmacokinetic modeling and from the structure of similar peptides like tirzepatide and semaglutide.

The once weekly dosing schedule was chosen for simplicity and compliance, not because it was proven superior to smaller and more frequent injections.

Most people dislike injecting themselves, so the manufacturers aimed for the least frequent schedule that would still maintain effectiveness.

As time goes on and retatrutide becomes more widely used, I expect we will see formal comparisons between different dosing frequencies.

For now, we use logic, experience, and patient feedback to determine what feels best and gives the most consistent results.

If I have one superpower, it’s definitely NOT my intelligence.

It's simply that I have one of the largest sample sizes of peptide field reports and receive more feedback from peptide users than anyone in the world.

And time and time again, I see microdosing work better in practice for most people.

Why I Always Prefer the Lowest Effective Dose

My approach is to always use the lowest effective dose that delivers the desired outcome.

I have seen too many people jump to high doses immediately and end up with terrible side effects such as rapid heart rate, nausea, vomiting, and hot flahses.

When that happens, they either stop the peptide altogether or spend weeks trying to recover.

Some people with advanced metabolic dysfunction truly do need higher doses, but that level should only come after the body has adapted and tolerance is built.

The safest and smartest way to get there is by starting with every other day injections, letting your system adjust, and then determining what your total weekly exposure to the drug needs to be.

Long term, the goal of GLP-1s should be to let the compound quietly repair the underlying dysfunction while you focus on eating correctly, training regularly, and managing your recovery.

Start low, go slow, and build up intelligently.

That is the path that always works long term.

Final Thoughts

Whether you microdose or inject once per week, retatrutide is simply a tool.

The art lies in how you use it and how well you listen to your body.

Personally, I believe microdosing is the most intelligent entry point for almost everyone.

It is the smoothest way to learn how your body responds and to avoid the discomfort that can come from hitting the gas too hard and too soon.

Ultimately, the best approach is the one that keeps you consistent, compliant, and progressing.

By microdosing, you are simply taking a more strategic path that is more closely aligned with your natural biology.

Best,

Hunter Williams