Subject: Tesofensine: What’s Worth Knowing About The Mechanism, The Side Effects, And The GLP-1 Washout Question
From: Derek from Research Radar <[email-masked]>
To: [email-masked]
Date: Mon, 11 May 2026 17:40:19 +0000
List-Id: <derekpruski.substack.com>

View this post on the web at https://derekpruski.substack.com/p/tesofensine-whats-worth-knowing-about

Read this first: Everything below is for research and educational purposes only. Nothing here is medical advice. Tesofensine is a research compound and is not approved for human consumption in the United States. Nothing in this post is a recommendation for personal use. If you are considering any of this for non-research purposes, that’s a conversation for a qualified clinician — not a Substack post.
The Landscape
Tesofensine has been showing up more often as a possible “bridge” compound between GLP-1 cycles. The logic seems simple: your GLP-1 cycle ends, you go into a washout (the off period), and tesofensine fills the gap to keep appetite under control. It’s oral (a pill, no subQ administration), and the trial weight loss numbers are real — 10-13% body weight loss over 24 weeks at higher doses, which is competitive with what GLP-1s do.
The compound is real. The data is real. And there’s a legitimate place for it in the research conversation. But there’s one big thing worth knowing before going further:
Tesofensine is not a peptide. It’s a different kind of drug — one that works much more like an antidepressant than like anything else commonly discussed in this community.
That single fact changes how to think about it. The side effects are different. The drug interactions are different. The timing is different. The people who tolerate it well versus poorly are different. None of this makes tesofensine bad. It just means the mental model most peptide users have doesn’t really apply here, and the goal of this post is to lay out what’s worth being aware of so you can evaluate it honestly.
In plain terms, this post covers: what tesofensine actually is, what side effects showed up in the trials, why it acts a lot like an SSRI, what the GLP-1 washout question really involves, and which factors about a person make tolerability different.
What Tesofensine Actually Is (In Plain Language)
A quick history first. Tesofensine (research name NS2330) was originally developed in Denmark to treat Parkinson’s and Alzheimer’s disease. It didn’t work for either condition. But trial participants kept losing weight as a side effect, so the company switched direction and started developing it for obesity instead. The original company went bankrupt. Another company (Saniona) picked it up. Phase 3 trials have been done in Mexico, but it’s still not FDA-approved in the US.
Now the mechanism, in simple terms.
Your brain uses chemicals called neurotransmitters to send signals between brain cells. Three of the most important ones are:
Serotonin — mood, sleep, appetite
Norepinephrine — alertness, focus, energy, heart rate
Dopamine — motivation, reward, pleasure, focus
After your brain cells use these chemicals, they normally get reabsorbed and recycled. Tesofensine blocks that reabsorption process. As a result, all three chemicals stay in the brain longer and at higher levels. More serotonin, more norepinephrine, more dopamine, all at once.
The technical term for this is a “triple monoamine reuptake inhibitor.” Don’t worry about memorizing the name — the important part is what it puts tesofensine in the same family as:
SSRIs (Prozac, Zoloft, Lexapro) → block serotonin only
SNRIs (Effexor, Cymbalta) → block serotonin and norepinephrine
NDRIs (Wellbutrin) → block norepinephrine and dopamine
Sibutramine (Meridia, pulled off the market in 2010) → blocked serotonin and norepinephrine, used for weight loss
Tesofensine → blocks all three
If you’ve ever known someone on an antidepressant — or been on one yourself — that’s the closest comparison for how tesofensine works in the brain.
The sibutramine comparison is worth knowing too. Sibutramine was a weight loss drug in the same general family. It got pulled from the market worldwide in 2010 after a large trial (called SCOUT) showed it increased heart attacks and strokes. Tesofensine has a similar heart-rate signal, which is part of why getting it approved has been slow despite the impressive weight loss numbers.
One more practical detail: tesofensine stays in your system for a long time.
Half-life of tesofensine itself: about 9 days
Half-life of its active byproduct (NS2360): about 16 days
“Half-life” means the time it takes for half the drug to clear from your body. A 9-day half-life is very long. For comparison, most peptides have half-lives measured in hours, and even semaglutide (a long-acting GLP-1) is about 7 days.
What this means in practice: it takes 6-7 weeks of daily dosing to reach full effect. And once you stop, it takes another 4-6 weeks to fully clear. You can’t just “try it for a few days.” By the time you have a clear read on whether it’s working for you, you’re already deep into a multi-week commitment.
What The Trials Show For Side Effects
The casual summary you’ll see online is “well-tolerated, mostly dry mouth and nausea.” That’s not the full picture. Here’s what the actual trial data shows.
Heart-related effects.
Most people on tesofensine see their resting heart rate go up by 7-10 beats per minute. Roughly 40-50% of trial participants experienced this. About 8% developed sustained high blood pressure that needed treatment. These effects depend on dose — higher dose, more impact.
To put numbers in perspective: a resting heart rate of 65 going up to 75 might not sound dramatic, but it’s measurable and it’s continuous. If you’re already on the higher end for heart rate, or have any heart history, this matters.
Sleep problems.
Insomnia (trouble sleeping) was the second most common side effect, hitting 25-40% of trial participants. This isn’t “mild difficulty falling asleep.” For a meaningful chunk of users, it’s bad enough to limit the dose or cause them to quit.
Why does it happen? Norepinephrine and dopamine are alertness chemicals. When they’re elevated all the time, your brain doesn’t drop into deep sleep as easily. Taking the dose in the morning helps a little, but with a 9-day half-life, the compound is in your system 24/7 no matter when you take it.
Mood and mental health effects.
This is the section that gets glossed over most often, and it’s the one most worth understanding.
Across the trials, 12-18% of participants experienced anxiety, mood changes, irritability, or depressive episodes. The TIPO-1 trial specifically showed about 6% of people on the 0.5mg and 1mg doses developed depressed mood, including one case of major depression on the highest dose. The 1mg group also showed measurable increases in anger and hostility on standardized mood tests.
Worth pausing on that 12-18% number. That’s roughly one in seven trial participants. And these were screened populations — meaning the trials excluded people with prior depression, anxiety disorders, or other mental health history. For people who already have a psychiatric history, the rate is almost certainly higher, but we don’t have great data on it because those people weren’t allowed in the trials.
The mechanism is straightforward. The same chemicals tesofensine elevates (especially serotonin and dopamine) are the chemicals involved in mood regulation. For some people, having them elevated helps mood. For others, the system gets dysregulated and mood drops. There’s no reliable way to predict ahead of time which category you’ll fall into.
Other side effects.
The more typical ones: dry mouth, nausea, dizziness, abdominal pain, constipation, headache. These usually improve over time and aren’t dose-limiting for most people. The heart effects, sleep problems, and mood effects are the ones that tend not to improve and that cause people to quit.
Why Tesofensine Behaves Like An SSRI
If you or someone you know has been on an SSRI (the most common type of antidepressant), some of this is going to sound familiar. That’s not a coincidence — tesofensine shares several behaviors with that class of drugs. Worth knowing because the mental model from peptides doesn’t really fit here.
It takes weeks to fully kick in.
SSRIs don’t work right away — they typically take 4-6 weeks to reach full effect. Tesofensine is similar, but for a different reason: the long half-life means levels keep building up for about 6-7 weeks before they stabilize. Whatever you feel in the first few weeks isn’t the full picture yet.
The first few weeks can feel worse before they feel better.
SSRIs have a well-known “activation phase” early in treatment — anxiety, agitation, sleep problems, sometimes worsening mood before things improve. Tesofensine shows a similar pattern. The early weeks are when most of the side effects show up as the brain adjusts to elevated chemicals.
Stopping is a slow process.
When you stop tesofensine, the levels don’t drop instantly. They wash out over weeks. This is actually gentler than stopping an SSRI cold turkey, but it has a downside: if you notice mood changes in the weeks after stopping, it’s hard to tell whether they’re from coming off tesofensine, from your brain readjusting, or from something else entirely.
Drug interactions are a real issue.
This is the one most people don’t realize until it’s too late. Because tesofensine raises serotonin, combining it with other drugs that also raise serotonin can cause something called “serotonin syndrome” — a dangerous condition that can be fatal in severe cases.
The list of things that don’t mix safely with tesofensine includes:
Any SSRI (Prozac, Zoloft, Lexapro, etc.)
Any SNRI (Effexor, Cymbalta)
MAOIs (older antidepressants)
Tricyclic antidepressants
Triptans (migraine medications like sumatriptan/Imitrex)
Tramadol (pain medication)
Meperidine (Demerol)
Lithium
MDMA or similar recreational substances
St. John’s Wort (sold as a natural antidepressant)
And here’s the kicker: because tesofensine has a 9-day half-life, even after you stop taking it, this interaction risk continues for weeks. If someone is currently on an antidepressant, this isn’t a “talk to your doctor when you’re ready” situation — it’s a “this absolutely has to be sorted out before going anywhere near tesofensine” situation.
For people with no psychiatric medications and no mental health history, none of this is necessarily a dealbreaker. The point is just that this is what the compound actually is, and the framing matters when deciding whether and how to engage with it.
The GLP-1 Washout Question
This is the use case driving most of the current interest in tesofensine. It’s worth its own section because the neurochemistry here is more complicated than the surface framing suggests.
The basic idea most people have: “I came off semaglutide/tirzepatide, I don’t want to gain weight back, I’ll run tesofensine through my washout to keep appetite suppressed.”
Sounds reasonable. Here’s what’s worth knowing.
GLP-1s aren’t just gut drugs.
For a long time, the understanding of GLP-1s (semaglutide, tirzepatide, etc.) was that they work in the gut — slowing digestion, increasing fullness, etc. That’s part of it. But research over the last few years has shown they also have significant effects in the brain. GLP-1 receptors are present in brain regions that control:
Reward and motivation (the dopamine system)
Mood
Cravings and food noise
Some addictive behavior patterns
This is part of why GLP-1s can dramatically reduce “food noise” — they’re not just making your stomach feel full, they’re changing how your brain processes reward signals.
Coming off a GLP-1 doesn’t happen instantly.
When you stop a GLP-1, the gut effects fade in days to weeks (depending on which one). But the brain effects don’t reset that quickly. Your dopamine system has been operating under altered conditions for months. It needs time to recalibrate.
During that recalibration window, some people experience:
Lower motivation
Mild low mood or depressive feelings
Anhedonia (things that used to feel rewarding don’t feel as rewarding)
Food noise coming back strong
Cravings for things that had felt easy to skip during the cycle
None of this means a GLP-1 caused depression. It means the brain is finding a new baseline after months of altered signaling.
Where tesofensine complicates this.
Now imagine adding tesofensine — a drug that floods the brain with extra serotonin, norepinephrine, and dopamine — into that recalibration window. A few specific things happen that are worth being aware of:
You can’t tell what’s causing what. If your mood drops during this overlap, is it the GLP-1 washout? The tesofensine? Both? An underlying issue that was masked by the GLP-1? You’ve lost the ability to figure out what’s actually happening.
You’re stacking two brain-chemistry interventions back to back. Coming off a GLP-1 is a neurochemical event. Starting tesofensine is a neurochemical event. Running them in close sequence means the brain is processing both at once, without recovery time. The long-term data on what this looks like over multiple cycles doesn’t exist yet.
The washout doesn’t really happen. The whole point of a GLP-1 washout is to let your body return to baseline so you can see what’s actually going on. Running a different appetite suppressant through the window means you never see baseline. You’re just swapping one suppressing drug for another.
None of this means tesofensine during washout is automatically a bad call. Some protocols do this and it works fine. The point is that the choice involves more variables than “oral pill, easy, fills the gap” — and being aware of those variables is the input that lets you make the call with eyes open.
Personal Factors That Change The Picture
Because tesofensine works on brain chemistry, individual factors matter more than they typically do for peptides. The following categories are worth being aware of when thinking about whether tesofensine is a reasonable choice for a given research situation.
History of depression.
The 12-18% mood-related side effect rate in trials happened in people who had been screened for prior depression. For someone with a history of depression — especially major depressive episodes — the data simply doesn’t tell us what their response would be, because those people weren’t allowed in the trials. The mechanism (chronic elevation of mood chemicals, then potential dysregulation) can go in different directions depending on the person.
History of bipolar disorder or hypomania.
Drugs in this class can sometimes trigger manic or hypomanic episodes in people with bipolar spectrum conditions. SSRIs can do this too, and it’s a well-documented risk. Tesofensine’s long half-life means that if a manic episode does get triggered, the drug is still in the system for weeks.
Anxiety disorders, panic disorder, or strong mood reactivity.
Tesofensine’s strongest action is on norepinephrine — the alertness/stress chemical. Elevated norepinephrine feels a bit like chronic low-grade stimulant exposure. For someone with anxiety disorders or panic disorder, this can amplify existing symptoms rather than help.
Currently on antidepressant or related medication.
This is the drug interaction issue from the previous section. SSRIs, SNRIs, and the other serotonergic medications listed earlier can cause serotonin syndrome when combined with tesofensine. The 9-day half-life means the risk window extends well beyond the dosing period.
Heart issues or high blood pressure.
The 7-10 bpm heart rate increase and 8% sustained hypertension rate are real and dose-dependent. Anyone starting with existing cardiovascular concerns is starting from a less favorable baseline. The sibutramine market withdrawal is the most relevant historical precedent.
Active stimulant use (recreational or prescription).
Combining a triple monoamine reuptake inhibitor with stimulants stacks both the heart effects and the mental health effects.
History of eating disorders.
Strong appetite suppressants in people with disordered eating history can reactivate those patterns. This isn’t specific to tesofensine, but the strength of the appetite effect makes it more relevant than for milder interventions.
The reason these factors matter more for tesofensine than for most peptides comes back to mechanism. Peptide side effects tend to be physical (injection site reactions, nausea, etc.) and resolve quickly. Brain-chemistry drugs can cause mood and heart effects that take weeks to resolve and can have downstream consequences beyond the dosing window itself. Awareness of these factors is what makes informed evaluation possible — and for people in any of the categories above, the right path is direct conversation with a qualified clinician rather than self-directed protocol design.
The Weight Loss Numbers (Because They’re Real)
The trial data on weight loss is genuinely strong. This isn’t a compound that doesn’t work — that’s not the issue. The numbers are worth knowing for context.
TIPO-1 (Phase 2b, published in The Lancet, 2008). 203 obese patients, 24 weeks of treatment. Weight loss by dose:
0.25mg/day: 6.7 kg average loss
0.5mg/day: 11.3 kg average loss
1.0mg/day: 12.8 kg average loss
For comparison, sibutramine in similar trials produced about half of those numbers.
TIPO-4 (48-week extension). 140 patients who completed TIPO-1 came back after a 3-month washout, then ran on 0.5mg with optional bump to 1.0mg. Average total weight loss of 13-14 kg over 48 weeks of treatment.
Phase 3 Viking trial (Saniona, conducted in Mexico). Significant weight loss at both tested doses. About 10% body weight loss over 24 weeks on average, with more than half of participants losing over 10%.
These are competitive numbers — comparable to or close to semaglutide in some metrics, though direct head-to-head comparisons are limited.
What the trials don’t tell us as clearly: how many people dropped out specifically because of mood-related side effects, what happens to mood and cardiovascular markers over multi-year exposure, and how the compound performs in populations with psychiatric or cardiovascular history (since those populations get excluded). The full long-term picture is still developing.
So: the compound works for weight loss. The honest question isn’t whether it produces results. The honest question is whether the mechanism class, the side effect profile, and the timing relative to other things in your protocol make it the right choice for a given research situation.
How To Think About This
Different situations call for different evaluations. Here’s how the considerations roughly break down.
If you have no psychiatric history, no current medications that interact, and no heart concerns: the trial data supports a reasonable evaluation. Baseline screening (PHQ-9 and GAD-7 for mood, ECG and blood pressure check) and regular monitoring during the protocol is the framework the literature suggests.
If you’re coming off a GLP-1 and considering tesofensine as a bridge: the overlap of GLP-1 brain effects washing out and tesofensine effects coming on is the specific consideration. Some protocols bridge through this; others choose to let the washout run clean and use lower-impact approaches (diet structure, fiber, training adjustments, etc.) during the off period. Knowing the neurochemistry overlap exists is what lets you make that choice on real information.
If you have a history of depression, anxiety, bipolar tendencies, or any mental health condition involving mood: this is the situation where the trial data has the biggest gap, since those populations were excluded. The mechanism class is one that needs careful evaluation with a qualified clinician — not a community-driven decision.
If you’re on an SSRI, SNRI, or any other serotonergic medication: the drug interaction issue is the main constraint. This has to be sorted out properly before tesofensine is even a real option.
If you’re choosing tesofensine just because it’s oral and not subQ: worth pausing on this one specifically. The mechanism class — not the delivery method — is the more important variable. Choosing tesofensine because you don’t want to inject is choosing on the wrong factor. There are other compounds with simpler profiles if injection avoidance is the main goal.
Things Worth Reading If You Want To Go Deeper
Astrup et al. 2008 (The Lancet) [ https://substack.com/redirect/dfeb11c0-3f71-40c6-bf84-874b68f05af5?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ] — the TIPO-1 trial paper, foundational efficacy and side effect data.
Saniona Phase 3 Viking trial results — most recent efficacy picture.
Neuropsychopharmacology paper [ https://substack.com/redirect/dcee2e26-d882-4210-bb87-3d4a8f237015?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ] on tesofensine’s α1 adrenergic and D1 dopamine receptor mechanisms — for the underlying pharmacology.
Neuropsychiatric adverse effects of centrally acting antiobesity drugs (PMC6493804) [ https://substack.com/redirect/c9f99319-0d9a-47f0-8fda-abcb36527730?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ] — context on tesofensine’s mood signal within the broader class.
The sibutramine SCOUT trial — for understanding why regulators are cautious about this drug class.
Growing literature on GLP-1 effects in the brain, particularly on dopamine and reward circuitry — helps explain what’s happening during washouts.
Final Thoughts
Tesofensine is an effective weight loss compound. The trial numbers prove that. It’s also a triple monoamine reuptake inhibitor — a drug class much closer to antidepressants than to peptides — with a 9-day half-life, a 12-18% rate of mood-related side effects in trial populations, and a significant list of drug interactions. Both of those things are true at the same time, and both are worth knowing about when deciding whether and how to engage with the compound.
The peptide-community mental model — “well-tolerated, mild side effects, just titrate up slowly” — doesn’t fully apply here. The failure modes are different. The drug interactions are different. The personal factors that affect tolerability are different. None of this rules out tesofensine. It just means the way you think about it should match what the compound actually is, not just how it’s packaged.
The GLP-1 washout question is its own conversation. Some protocols bridge with tesofensine and it works. Others let washouts run clean and use other approaches. Both are real choices that researchers make based on their goals. The point of this post isn’t to push one way or the other — it’s to surface the neurochemistry context so the choice gets made with awareness of what’s actually happening underneath.
The compound exists. The trial data exists. The side effects exist. The drug interactions exist. The neurochemistry of GLP-1 washouts exists. The personal factors that change tolerability exist. Being aware of all of it is the input that makes informed evaluation possible — and that’s the goal of putting this information together in one place.
This is for research and educational purposes only. Tesofensine is a research compound and is not approved for human consumption. Nothing in this post is medical advice or a recommendation for personal use. If the topic is of interest for any non-research reason — and particularly if there’s any psychiatric or cardiovascular history involved — that’s a conversation for a qualified medical professional.
Drop questions below — happy to go deeper on the mechanism class, the GLP-1 washout neurochemistry, the trial data, or any other angle.

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