Received-SPF: pass (google.com: domain of bounce+30b528.39b08c6-tjphuhs=gmail.com@mg-d1.substack.com designates 159.112.244.3 as permitted sender) client-ip=159.112.244.3;
Mime-Version: 1.0
Content-Type: multipart/alternative;
 boundary="048ba600e0d28f4072f72c169bbbcce27b88fc717e75d4ea4ee65db36374"
Subject: =?UTF-8?q?Tesofensine:_What=E2=80=99s_Worth_Knowing_About_The_Mechanism,_?=
 =?UTF-8?q?The_Side_Effects,_And_The_GLP-1_Washout_Question?=
From: Derek from Research Radar <derekpruski@substack.com>
To: tjphuhs@gmail.com
Message-Id: <20260511174019.3.5c1bc3d8e7093668@mg-d1.substack.com>
Date: Mon, 11 May 2026 17:40:19 +0000
Feedback-Id: post-197245835:cat-post:pub-3365367:substack
Sender: Derek from Research Radar <derekpruski@substack.com>
References: <post-197245835@substack.com>
In-Reply-To: <post-197245835@substack.com>
Reply-To: Derek from Research Radar
 <reply+39fnuz&4iwoe6&&7a8d2cf4821d6c654d175ac464941002c2c148db9c9d124dcd852b2ba746a3d0@mg1.substack.com>

--048ba600e0d28f4072f72c169bbbcce27b88fc717e75d4ea4ee65db36374
Content-Type: text/plain; charset="utf-8"
Content-Transfer-Encoding: quoted-printable

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 an=
d is not approved for human consumption in the United States. Nothing in th=
is post is a recommendation for personal use. If you are considering any of=
 this for non-research purposes, that=E2=80=99s a conversation for a qualif=
ied clinician =E2=80=94 not a Substack post.
The Landscape
Tesofensine has been showing up more often as a possible =E2=80=9Cbridge=E2=
=80=9D compound between GLP-1 cycles. The logic seems simple: your GLP-1 cy=
cle ends, you go into a washout (the off period), and tesofensine fills the=
 gap to keep appetite under control. It=E2=80=99s oral (a pill, no subQ adm=
inistration), and the trial weight loss numbers are real =E2=80=94 10-13% b=
ody weight loss over 24 weeks at higher doses, which is competitive with wh=
at GLP-1s do.
The compound is real. The data is real. And there=E2=80=99s a legitimate pl=
ace for it in the research conversation. But there=E2=80=99s one big thing =
worth knowing before going further:
Tesofensine is not a peptide. It=E2=80=99s a different kind of drug =E2=80=
=94 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 differ=
ent. The drug interactions are different. The timing is different. The peop=
le who tolerate it well versus poorly are different. None of this makes tes=
ofensine bad. It just means the mental model most peptide users have doesn=
=E2=80=99t really apply here, and the goal of this post is to lay out what=
=E2=80=99s worth being aware of so you can evaluate it honestly.
In plain terms, this post covers: what tesofensine actually is, what side e=
ffects showed up in the trials, why it acts a lot like an SSRI, what the GL=
P-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 de=
veloped in Denmark to treat Parkinson=E2=80=99s and Alzheimer=E2=80=99s dis=
ease. It didn=E2=80=99t work for either condition. But trial participants k=
ept losing weight as a side effect, so the company switched direction and s=
tarted developing it for obesity instead. The original company went bankrup=
t. Another company (Saniona) picked it up. Phase 3 trials have been done in=
 Mexico, but it=E2=80=99s 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 =E2=80=94 mood, sleep, appetite
Norepinephrine =E2=80=94 alertness, focus, energy, heart rate
Dopamine =E2=80=94 motivation, reward, pleasure, focus
After your brain cells use these chemicals, they normally get reabsorbed an=
d recycled. Tesofensine blocks that reabsorption process. As a result, all =
three chemicals stay in the brain longer and at higher levels. More seroton=
in, more norepinephrine, more dopamine, all at once.
The technical term for this is a =E2=80=9Ctriple monoamine reuptake inhibit=
or.=E2=80=9D Don=E2=80=99t worry about memorizing the name =E2=80=94 the im=
portant part is what it puts tesofensine in the same family as:
SSRIs (Prozac, Zoloft, Lexapro) =E2=86=92 block serotonin only
SNRIs (Effexor, Cymbalta) =E2=86=92 block serotonin and norepinephrine
NDRIs (Wellbutrin) =E2=86=92 block norepinephrine and dopamine
Sibutramine (Meridia, pulled off the market in 2010) =E2=86=92 blocked sero=
tonin and norepinephrine, used for weight loss
Tesofensine =E2=86=92 blocks all three
If you=E2=80=99ve ever known someone on an antidepressant =E2=80=94 or been=
 on one yourself =E2=80=94 that=E2=80=99s the closest comparison for how te=
sofensine works in the brain.
The sibutramine comparison is worth knowing too. Sibutramine was a weight l=
oss drug in the same general family. It got pulled from the market worldwid=
e in 2010 after a large trial (called SCOUT) showed it increased heart atta=
cks and strokes. Tesofensine has a similar heart-rate signal, which is part=
 of why getting it approved has been slow despite the impressive weight los=
s numbers.
One more practical detail: tesofensine stays in your system for a long time=
=2E
Half-life of tesofensine itself: about 9 days
Half-life of its active byproduct (NS2360): about 16 days
=E2=80=9CHalf-life=E2=80=9D means the time it takes for half the drug to cl=
ear from your body. A 9-day half-life is very long. For comparison, most pe=
ptides have half-lives measured in hours, and even semaglutide (a long-acti=
ng GLP-1) is about 7 days.
What this means in practice: it takes 6-7 weeks of daily dosing to reach fu=
ll effect. And once you stop, it takes another 4-6 weeks to fully clear. Yo=
u can=E2=80=99t just =E2=80=9Ctry it for a few days.=E2=80=9D By the time y=
ou have a clear read on whether it=E2=80=99s working for you, you=E2=80=99r=
e already deep into a multi-week commitment.
What The Trials Show For Side Effects
The casual summary you=E2=80=99ll see online is =E2=80=9Cwell-tolerated, mo=
stly dry mouth and nausea.=E2=80=9D That=E2=80=99s not the full picture. He=
re=E2=80=99s 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 effe=
cts depend on dose =E2=80=94 higher dose, more impact.
To put numbers in perspective: a resting heart rate of 65 going up to 75 mi=
ght not sound dramatic, but it=E2=80=99s measurable and it=E2=80=99s contin=
uous. If you=E2=80=99re already on the higher end for heart rate, or have a=
ny heart history, this matters.
Sleep problems.
Insomnia (trouble sleeping) was the second most common side effect, hitting=
 25-40% of trial participants. This isn=E2=80=99t =E2=80=9Cmild difficulty =
falling asleep.=E2=80=9D For a meaningful chunk of users, it=E2=80=99s bad =
enough to limit the dose or cause them to quit.
Why does it happen? Norepinephrine and dopamine are alertness chemicals. Wh=
en they=E2=80=99re elevated all the time, your brain doesn=E2=80=99t drop i=
nto deep sleep as easily. Taking the dose in the morning helps a little, bu=
t with a 9-day half-life, the compound is in your system 24/7 no matter whe=
n you take it.
Mood and mental health effects.
This is the section that gets glossed over most often, and it=E2=80=99s 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 showe=
d about 6% of people on the 0.5mg and 1mg doses developed depressed mood, i=
ncluding one case of major depression on the highest dose. The 1mg group al=
so showed measurable increases in anger and hostility on standardized mood =
tests.
Worth pausing on that 12-18% number. That=E2=80=99s roughly one in seven tr=
ial participants. And these were screened populations =E2=80=94 meaning the=
 trials excluded people with prior depression, anxiety disorders, or other =
mental health history. For people who already have a psychiatric history, t=
he rate is almost certainly higher, but we don=E2=80=99t have great data on=
 it because those people weren=E2=80=99t allowed in the trials.
The mechanism is straightforward. The same chemicals tesofensine elevates (=
especially serotonin and dopamine) are the chemicals involved in mood regul=
ation. For some people, having them elevated helps mood. For others, the sy=
stem gets dysregulated and mood drops. There=E2=80=99s no reliable way to p=
redict ahead of time which category you=E2=80=99ll fall into.
Other side effects.
The more typical ones: dry mouth, nausea, dizziness, abdominal pain, consti=
pation, headache. These usually improve over time and aren=E2=80=99t dose-l=
imiting for most people. The heart effects, sleep problems, and mood effect=
s 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 ant=
idepressant), some of this is going to sound familiar. That=E2=80=99s not a=
 coincidence =E2=80=94 tesofensine shares several behaviors with that class=
 of drugs. Worth knowing because the mental model from peptides doesn=E2=80=
=99t really fit here.
It takes weeks to fully kick in.
SSRIs don=E2=80=99t work right away =E2=80=94 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=E2=80=99t the=
 full picture yet.
The first few weeks can feel worse before they feel better.
SSRIs have a well-known =E2=80=9Cactivation phase=E2=80=9D early in treatme=
nt =E2=80=94 anxiety, agitation, sleep problems, sometimes worsening mood b=
efore 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=E2=80=99t drop instantly. They wa=
sh out over weeks. This is actually gentler than stopping an SSRI cold turk=
ey, but it has a downside: if you notice mood changes in the weeks after st=
opping, it=E2=80=99s hard to tell whether they=E2=80=99re from coming off t=
esofensine, from your brain readjusting, or from something else entirely.
Drug interactions are a real issue.
This is the one most people don=E2=80=99t realize until it=E2=80=99s too la=
te. Because tesofensine raises serotonin, combining it with other drugs tha=
t also raise serotonin can cause something called =E2=80=9Cserotonin syndro=
me=E2=80=9D =E2=80=94 a dangerous condition that can be fatal in severe cas=
es.
The list of things that don=E2=80=99t 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=E2=80=99s Wort (sold as a natural antidepressant)
And here=E2=80=99s the kicker: because tesofensine has a 9-day half-life, e=
ven after you stop taking it, this interaction risk continues for weeks. If=
 someone is currently on an antidepressant, this isn=E2=80=99t a =E2=80=9Ct=
alk to your doctor when you=E2=80=99re ready=E2=80=9D situation =E2=80=94 i=
t=E2=80=99s a =E2=80=9Cthis absolutely has to be sorted out before going an=
ywhere near tesofensine=E2=80=9D situation.
For people with no psychiatric medications and no mental health history, no=
ne of this is necessarily a dealbreaker. The point is just that this is wha=
t the compound actually is, and the framing matters when deciding whether a=
nd how to engage with it.
The GLP-1 Washout Question
This is the use case driving most of the current interest in tesofensine. I=
t=E2=80=99s worth its own section because the neurochemistry here is more c=
omplicated than the surface framing suggests.
The basic idea most people have: =E2=80=9CI came off semaglutide/tirzepatid=
e, I don=E2=80=99t want to gain weight back, I=E2=80=99ll run tesofensine t=
hrough my washout to keep appetite suppressed.=E2=80=9D
Sounds reasonable. Here=E2=80=99s what=E2=80=99s worth knowing.
GLP-1s aren=E2=80=99t just gut drugs.
For a long time, the understanding of GLP-1s (semaglutide, tirzepatide, etc=
=2E) was that they work in the gut =E2=
=80=94 slowing digestion, increasing fu=
llness, etc. That=E2=80=99s part of it. But research over the last few year=
s has shown they also have significant effects in the brain. GLP-1 receptor=
s 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 =E2=80=9Cfood noise=E2=
=80=9D =E2=80=94 they=E2=80=99re not just making your stomach feel full, th=
ey=E2=80=99re changing how your brain processes reward signals.
Coming off a GLP-1 doesn=E2=80=99t 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=E2=80=99t reset that quickly. Your do=
pamine system has been operating under altered conditions for months. It ne=
eds 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=E2=80=99t feel as rewardi=
ng)
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 =E2=80=94 a drug that floods the brain with =
extra serotonin, norepinephrine, and dopamine =E2=80=94 into that recalibra=
tion window. A few specific things happen that are worth being aware of:
You can=E2=80=99t tell what=E2=80=99s causing what. If your mood drops duri=
ng this overlap, is it the GLP-1 washout? The tesofensine? Both? An underly=
ing issue that was masked by the GLP-1? You=E2=80=99ve lost the ability to =
figure out what=E2=80=99s actually happening.
You=E2=80=99re stacking two brain-chemistry interventions back to back. Com=
ing off a GLP-1 is a neurochemical event. Starting tesofensine is a neuroch=
emical 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=E2=80=99t exist yet.
The washout doesn=E2=80=99t really happen. The whole point of a GLP-1 washo=
ut is to let your body return to baseline so you can see what=E2=80=99s act=
ually going on. Running a different appetite suppressant through the window=
 means you never see baseline. You=E2=80=99re 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 invo=
lves more variables than =E2=80=9Coral pill, easy, fills the gap=E2=80=9D =
=E2=80=94 and being aware of those variables is the input that lets you mak=
e the call with eyes open.
Personal Factors That Change The Picture
Because tesofensine works on brain chemistry, individual factors matter mor=
e than they typically do for peptides. The following categories are worth b=
eing aware of when thinking about whether tesofensine is a reasonable choic=
e for a given research situation.
History of depression.
The 12-18% mood-related side effect rate in trials happened in people who h=
ad been screened for prior depression. For someone with a history of depres=
sion =E2=80=94 especially major depressive episodes =E2=80=94 the data simp=
ly doesn=E2=80=99t tell us what their response would be, because those peop=
le weren=E2=80=99t allowed in the trials. The mechanism (chronic elevation =
of mood chemicals, then potential dysregulation) can go in different direct=
ions depending on the person.
History of bipolar disorder or hypomania.
Drugs in this class can sometimes trigger manic or hypomanic episodes in pe=
ople with bipolar spectrum conditions. SSRIs can do this too, and it=E2=80=
=99s a well-documented risk. Tesofensine=E2=80=99s long half-life means tha=
t if a manic episode does get triggered, the drug is still in the system fo=
r weeks.
Anxiety disorders, panic disorder, or strong mood reactivity.
Tesofensine=E2=80=99s strongest action is on norepinephrine =E2=80=94 the a=
lertness/stress chemical. Elevated norepinephrine feels a bit like chronic =
low-grade stimulant exposure. For someone with anxiety disorders or panic d=
isorder, 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 rea=
l and dose-dependent. Anyone starting with existing cardiovascular concerns=
 is starting from a less favorable baseline. The sibutramine market withdra=
wal 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 r=
eactivate those patterns. This isn=E2=80=99t specific to tesofensine, but t=
he strength of the appetite effect makes it more relevant than for milder i=
nterventions.
The reason these factors matter more for tesofensine than for most peptides=
 comes back to mechanism. Peptide side effects tend to be physical (injecti=
on site reactions, nausea, etc.) and resolve quickly. Brain-chemistry drugs=
 can cause mood and heart effects that take weeks to resolve and can have d=
ownstream consequences beyond the dosing window itself. Awareness of these =
factors is what makes informed evaluation possible =E2=80=94 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=E2=80=99re Real)
The trial data on weight loss is genuinely strong. This isn=E2=80=99t a com=
pound that doesn=E2=80=99t work =E2=80=94 that=E2=80=99s not the issue. The=
 numbers are worth knowing for context.
TIPO-1 (Phase 2b, published in The Lancet, 2008). 203 obese patients, 24 we=
eks 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 aft=
er a 3-month washout, then ran on 0.5mg with optional bump to 1.0mg. Averag=
e total weight loss of 13-14 kg over 48 weeks of treatment.
Phase 3 Viking trial (Saniona, conducted in Mexico). Significant weight los=
s 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 =E2=80=94 comparable to or close to semagluti=
de in some metrics, though direct head-to-head comparisons are limited.
What the trials don=E2=80=99t tell us as clearly: how many people dropped o=
ut specifically because of mood-related side effects, what happens to mood =
and cardiovascular markers over multi-year exposure, and how the compound p=
erforms in populations with psychiatric or cardiovascular history (since th=
ose populations get excluded). The full long-term picture is still developi=
ng.
So: the compound works for weight loss. The honest question isn=E2=80=99t w=
hether it produces results. The honest question is whether the mechanism cl=
ass, the side effect profile, and the timing relative to other things in yo=
ur protocol make it the right choice for a given research situation.
How To Think About This
Different situations call for different evaluations. Here=E2=80=99s how the=
 considerations roughly break down.
If you have no psychiatric history, no current medications that interact, a=
nd no heart concerns: the trial data supports a reasonable evaluation. Base=
line screening (PHQ-9 and GAD-7 for mood, ECG and blood pressure check) and=
 regular monitoring during the protocol is the framework the literature sug=
gests.
If you=E2=80=99re coming off a GLP-1 and considering tesofensine as a bridg=
e: the overlap of GLP-1 brain effects washing out and tesofensine effects c=
oming 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 choic=
e on real information.
If you have a history of depression, anxiety, bipolar tendencies, or any me=
ntal health condition involving mood: this is the situation where the trial=
 data has the biggest gap, since those populations were excluded. The mecha=
nism class is one that needs careful evaluation with a qualified clinician =
=E2=80=94 not a community-driven decision.
If you=E2=80=99re on an SSRI, SNRI, or any other serotonergic medication: t=
he drug interaction issue is the main constraint. This has to be sorted out=
 properly before tesofensine is even a real option.
If you=E2=80=99re choosing tesofensine just because it=E2=80=99s oral and n=
ot subQ: worth pausing on this one specifically. The mechanism class =E2=80=
=94 not the delivery method =E2=80=94 is the more important variable. Choos=
ing tesofensine because you don=E2=80=99t 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/dfeb11c0-3f=
71-40c6-bf84-874b68f05af5?j=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGM=
y3p768BWtuZifRB-Zs ] =E2=80=94 the TIPO-1 trial paper, foundational efficac=
y and side effect data.
Saniona Phase 3 Viking trial results =E2=80=94 most recent efficacy picture=
=2E
Neuropsychopharmacology paper [ https://substack.com/redirect/dcee2e26-d882=
-4210-bb87-3d4a8f237015?j=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3=
p768BWtuZifRB-Zs ] on tesofensine=E2=80=99s =CE=B11 adrenergic and D1 dopam=
ine receptor mechanisms =E2=80=94 for the underlying pharmacology.
Neuropsychiatric adverse effects of centrally acting antiobesity drugs (PMC=
6493804) [ https://substack.com/redirect/c9f99319-0d9a-47f0-8fda-abcb365277=
30?j=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ] =
=E2=80=94 context on tesofensine=E2=80=99s mood signal within the broader c=
lass.
The sibutramine SCOUT trial =E2=80=94 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 =E2=80=94 helps explain what=E2=80=99s happening durin=
g washouts.
Final Thoughts
Tesofensine is an effective weight loss compound. The trial numbers prove t=
hat. It=E2=80=99s also a triple monoamine reuptake inhibitor =E2=80=94 a dr=
ug class much closer to antidepressants than to peptides =E2=80=94 with a 9=
-day half-life, a 12-18% rate of mood-related side effects in trial populat=
ions, 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 whet=
her and how to engage with the compound.
The peptide-community mental model =E2=80=94 =E2=80=9Cwell-tolerated, mild =
side effects, just titrate up slowly=E2=80=9D =E2=80=94 doesn=E2=80=99t ful=
ly apply here. The failure modes are different. The drug interactions are d=
ifferent. The personal factors that affect tolerability are different. None=
 of this rules out tesofensine. It just means the way you think about it sh=
ould match what the compound actually is, not just how it=E2=80=99s package=
d.
The GLP-1 washout question is its own conversation. Some protocols bridge w=
ith tesofensine and it works. Others let washouts run clean and use other a=
pproaches. Both are real choices that researchers make based on their goals=
=2E The point of this post isn=E2=80=99t=
 to push one way or the other =E2=80=
=94 it=E2=80=99s to surface the neurochemistry context so the choice gets m=
ade with awareness of what=E2=80=99s actually happening underneath.
The compound exists. The trial data exists. The side effects exist. The dru=
g interactions exist. The neurochemistry of GLP-1 washouts exists. The pers=
onal factors that change tolerability exist. Being aware of all of it is th=
e input that makes informed evaluation possible =E2=80=94 and that=E2=80=99=
s the goal of putting this information together in one place.
This is for research and educational purposes only. Tesofensine is a resear=
ch 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 =E2=80=94 and particularly if there=
=E2=80=99s any psychiatric or cardiovascular history involved =E2=80=94 tha=
t=E2=80=99s a conversation for a qualified medical professional.
Drop questions below =E2=80=94 happy to go deeper on the mechanism class, t=
he GLP-1 washout neurochemistry, the trial data, or any other angle.

Unsubscribe https://substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9kZXJla3BydXN=
raS5zdWJzdGFjay5jb20vYWN0aW9uL2Rpc2FibGVfZW1haWw_dG9rZW49ZXlKMWMyVnlYMmxrSW=
pveU56TTJNakl6T1Rnc0luQnZjM1JmYVdRaU9qRTVOekkwTlRnek5Td2lhV0YwSWpveE56YzROV=
El4TWpJM0xDSmxlSEFpT2pFNE1UQXdOVGN5TWpjc0ltbHpjeUk2SW5CMVlpMHpNelkxTXpZM0lp=
d2ljM1ZpSWpvaVpHbHpZV0pzWlY5bGJXRnBiQ0o5LmhKSkVhWTdqVm5aeWZzdXkxZHV6eEZnUFg=
3bGZwdEpRQ1BYMzN4SWV2MzQiLCJwIjoxOTcyNDU4MzUsInMiOjMzNjUzNjcsImYiOnRydWUsIn=
UiOjI3MzYyMjM5OCwiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjIwOTQwOTcyMjcsImlzcyI6InB1Y=
i0wIiwic3ViIjoibGluay1yZWRpcmVjdCJ9.MdzoSFNyf-Bpnf6sgHeajlMl1XAXxmLtDHy2q9P=
Gwug?
--048ba600e0d28f4072f72c169bbbcce27b88fc717e75d4ea4ee65db36374
Content-Type: text/html; charset="utf-8"
Content-Transfer-Encoding: quoted-printable

<html lang=3D"en" dir=3D"ltr" style=3D"scrollbar-width: thin;scrollbar-colo=
r: rgb(219,219,219)rgb(255,255,255);"><head><meta charset=3D"utf-8"><title>=
Tesofensine: What&#8217;s Worth Knowing About The Mechanism, The Side Effec=
ts, And The GLP-1 Washout Question</title><style>
@media (max-width: 1024px) {
  .typography .pullquote-align-left,
  .typography.editor .pullquote-align-left,
  .typography .pullquote-align-right,
  .typography.editor .pullquote-align-right,
  .typography .pullquote-align-wide,
  .typography.editor .pullquote-align-wide,
  .typography .pullquote-align-center,
  .typography.editor .pullquote-align-center {
    float: none;
    margin: 0 auto;
    width: 100%;
    max-width: 100%;
  }
}
@media all and (-ms-high-contrast: none), (-ms-high-contrast: active) {
  .typography .markup table.image-wrapper img,
  .typography.editor .markup table.image-wrapper img,
  .typography .markup table.kindle-wrapper img,
  .typography.editor .markup table.kindle-wrapper img {
    max-width: 550px;
  }
}
@media (min-width: 1024px) {
  .typography:not(:has(#toc)) .captioned-image-container figure:has(> a.ima=
ge2-offset-left),
  .typography.editor:not(:has(#toc)) .captioned-image-container figure:has(=
> a.image2-offset-left) {
    margin-left: var(--image-offset-margin);
  }
  .typography:not(:has(#toc)) .captioned-image-container figure:has(> a.ima=
ge2-offset-right),
  .typography.editor:not(:has(#toc)) .captioned-image-container figure:has(=
> a.image2-offset-right) {
    margin-right: var(--image-offset-margin);
  }
}
@media (min-width: 1300px) {
  .typography .captioned-image-container figure:has(> a.image2-offset-left)=
,
  .typography.editor .captioned-image-container figure:has(> a.image2-offse=
t-left) {
    margin-left: var(--image-offset-margin);
  }
  .typography .captioned-image-container figure:has(> a.image2-offset-right=
),
  .typography.editor .captioned-image-container figure:has(> a.image2-offse=
t-right) {
    margin-right: var(--image-offset-margin);
  }
}
@media (max-width: 1024px) {
  .typography,
  .typography.editor {
    /* Disable offset on mobile/tablet */
  }
  .typography .captioned-image-container figure:has(> a.image2-align-left),
  .typography.editor .captioned-image-container figure:has(> a.image2-align=
-left),
  .typography .captioned-image-container figure:has(> a.image2-align-right)=
,
  .typography.editor .captioned-image-container figure:has(> a.image2-align=
-right) {
    float: none;
    margin: 1em auto;
    max-width: 100%;
    width: auto;
    padding: 0;
  }
  .typography .captioned-image-container figure:has(> a.image2-align-left.t=
hefp),
  .typography.editor .captioned-image-container figure:has(> a.image2-align=
-left.thefp),
  .typography .captioned-image-container figure:has(> a.image2-align-right.=
thefp),
  .typography.editor .captioned-image-container figure:has(> a.image2-align=
-right.thefp) {
    margin: 1em auto;
  }
  .typography .captioned-image-container figure:has(> a.image2-offset-left)=
,
  .typography.editor .captioned-image-container figure:has(> a.image2-offse=
t-left),
  .typography .captioned-image-container figure:has(> a.image2-offset-right=
),
  .typography.editor .captioned-image-container figure:has(> a.image2-offse=
t-right) {
    margin: 1em auto;
  }
  .typography .captioned-image-container figure:has(> a.image2-align-left) =
=2Eimage2-inset,
  .typography.editor .captioned-image-container figure:has(> a.image2-align=
-left) .image2-inset,
  .typography .captioned-image-container figure:has(> a.image2-align-right)=
 .image2-inset,
  .typography.editor .captioned-image-container figure:has(> a.image2-align=
-right) .image2-inset {
    display: block;
    justify-content: initial;
  }
}
@media (max-width: 768px) {
  .typography .markup div.sponsorship-campaign-embed,
  .typography.editor .markup div.sponsorship-campaign-embed {
    margin-top: 24px;
    margin-bottom: 24px;
  }
  .typography .markup div.sponsorship-campaign-embed:first-child,
  .typography.editor .markup div.sponsorship-campaign-embed:first-child {
    margin-top: 0px;
  }
}
@media screen and (max-width: 650px) {
  .typography .markup div.youtube-overlay,
  .typography.editor .markup div.youtube-overlay,
  .typography .markup div.vimeo-overlay,
  .typography.editor .markup div.vimeo-overlay {
    display: none !important;
  }
}
@media screen and (max-width: 370px) {
  .typography .markup div.tiktok-wrap,
  .typography.editor .markup div.tiktok-wrap {
    width: calc(95vw - 32px);
    height: calc((95vw - 32px - 2px) / 0.485714);
  }
}
@media screen and (max-width: 650px) {
  .typography .markup div.embedded-publication-wrap .embedded-publication.s=
how-subscribe,
  .typography.editor .markup div.embedded-publication-wrap .embedded-public=
ation.show-subscribe {
    padding: 24px;
  }
}
@media screen and (max-width: 650px) {
  .typography .markup div.subscription-widget-wrap .subscription-widget.sho=
w-subscribe,
  .typography.editor .markup div.subscription-widget-wrap .subscription-wid=
get.show-subscribe,
  .typography .markup div.subscription-widget-wrap-editor .subscription-wid=
get.show-subscribe,
  .typography.editor .markup div.subscription-widget-wrap-editor .subscript=
ion-widget.show-subscribe,
  .typography .markup div.captioned-button-wrap .subscription-widget.show-s=
ubscribe,
  .typography.editor .markup div.captioned-button-wrap .subscription-widget=
=2Eshow-subscribe {
    padding: 0px 24px;
  }
}
@media screen and (max-width: 650px) {
  .typography .markup div.subscription-widget-wrap .subscription-widget.sho=
w-subscribe .subscription-widget-subscribe .button,
  .typography.editor .markup div.subscription-widget-wrap .subscription-wid=
get.show-subscribe .subscription-widget-subscribe .button,
  .typography .markup div.subscription-widget-wrap-editor .subscription-wid=
get.show-subscribe .subscription-widget-subscribe .button,
  .typography.editor .markup div.subscription-widget-wrap-editor .subscript=
ion-widget.show-subscribe .subscription-widget-subscribe .button,
  .typography .markup div.captioned-button-wrap .subscription-widget.show-s=
ubscribe .subscription-widget-subscribe .button,
  .typography.editor .markup div.captioned-button-wrap .subscription-widget=
=2Eshow-subscribe .subscription-widget-subscribe .button {
    padding: 10px 12px;
    min-width: 110px;
  }
}
@media (max-width: 650px) {
  .typography .markup .twitter-embed,
  .typography.editor .markup .twitter-embed,
  .typography .markup .tweet,
  .typography.editor .markup .tweet {
    padding: 12px;
  }
}
@media (max-width: 650px) {
  .typography .markup .twitter-embed .tweet-text,
  .typography.editor .markup .twitter-embed .tweet-text,
  .typography .markup .tweet .tweet-text,
  .typography.editor .markup .tweet .tweet-text {
    font-size: 14px;
    line-height: 20px;
  }
}
@media (max-width: 650px) {
  .typography .markup .twitter-embed .tweet-photos-container.two,
  .typography.editor .markup .twitter-embed .tweet-photos-container.two,
  .typography .markup .tweet .tweet-photos-container.two,
  .typography.editor .markup .tweet .tweet-photos-container.two,
  .typography .markup .twitter-embed .tweet-photos-container.three,
  .typography.editor .markup .twitter-embed .tweet-photos-container.three,
  .typography .markup .tweet .tweet-photos-container.three,
  .typography.editor .markup .tweet .tweet-photos-container.three,
  .typography .markup .twitter-embed .tweet-photos-container.four,
  .typography.editor .markup .twitter-embed .tweet-photos-container.four,
  .typography .markup .tweet .tweet-photos-container.four,
  .typography.editor .markup .tweet .tweet-photos-container.four {
    height: 200px;
  }
}
@media (max-width: 650px) {
  .typography .markup .twitter-embed a.expanded-link .expanded-link-img,
  .typography.editor .markup .twitter-embed a.expanded-link .expanded-link-=
img,
  .typography .markup .tweet a.expanded-link .expanded-link-img,
  .typography.editor .markup .tweet a.expanded-link .expanded-link-img {
    max-height: 180px;
  }
}
@media (max-width: 650px) {
  .typography .markup .twitter-embed a.expanded-link .expanded-link-descrip=
tion,
  .typography.editor .markup .twitter-embed a.expanded-link .expanded-link-=
description,
  .typography .markup .tweet a.expanded-link .expanded-link-description,
  .typography.editor .markup .tweet a.expanded-link .expanded-link-descript=
ion {
    display: none;
  }
}
@media screen and (max-width: 650px) {
  .typography .markup .apple-podcast-container,
  .typography.editor .markup .apple-podcast-container {
    width: unset;
  }
}
@media (max-width: 420px) {
  .typography .markup .install-substack-app-embed img.install-substack-app-=
embed-img,
  .typography.editor .markup .install-substack-app-embed img.install-substa=
ck-app-embed-img {
    margin: 0 auto 16px auto;
  }
}
@media (max-width: 420px) {
  .typography .markup .install-substack-app-embed .install-substack-app-emb=
ed-text,
  .typography.editor .markup .install-substack-app-embed .install-substack-=
app-embed-text {
    margin: 0 0 12px 0;
    max-width: 100%;
    width: auto;
    text-align: center;
  }
}
@media (max-width: 420px) {
  .typography .markup .install-substack-app-embed .install-substack-app-emb=
ed-link,
  .typography.editor .markup .install-substack-app-embed .install-substack-=
app-embed-link {
    display: flex;
    justify-content: center;
  }
}
@media screen and (min-width: 481px) {
  .share-button-container {
    height: 38px;
  }
}
@media screen and (min-width: 481px) {
  .share-button-container a.comment {
    height: 38px;
    line-height: 38px;
    padding-right: 10px;
  }
}
@media screen and (max-width: 480px) {
  .share-button-container .separator {
    display: block;
    margin: 0;
    height: 8px;
    border-left: none;
  }
}
@media screen and (max-width: 480px) {
  .share-button-container a.share.first img {
    padding-left: 0;
  }
}
@media screen and (min-width: 481px) {
  .share-button-container a.mobile {
    display: none !important;
  }
}
@media screen and (min-width: 541px) {
  .settings-add-pub-modal-wrapper .container .add-recommending-pub-modal-co=
ntainer {
    padding: 36px;
    height: 680px;
  }
}
@media screen and (min-width: 541px) {
  .settings-add-pub-modal-wrapper .container .add-recommending-pub-modal-co=
ntainer .footer {
    position: absolute;
    bottom: 36px;
    margin: 0px;
  }
}
@media screen and (max-width: 650px) {
  .header-anchor-parent {
    display: none;
  }
}
@media screen and (max-width: 768px) {
  .post {
    padding: 16px 0 0 0;
  }
}
@media screen and (max-width: 650px) {
  .post .post-header .post-label {
    margin-top: 8px;
  }
}
@media screen and (max-width: 650px) {
  .post .post-header .meta-author-wrap.alternative-meta .meta-right-column =
=2Epost-meta {
    margin-top: 6px;
  }
}
@media screen and (max-width: 650px) {
  .post .footer-facepile-container {
    height: 64px;
    padding: 0 16px;
    display: flex;
    align-items: center;
    justify-content: flex-start;
    width: 100%;
  }
}
@media screen and (max-width: 650px) {
  .post .post-footer.use-separators {
    justify-content: center;
  }
}
@media screen and (max-width: 650px) {
  .post .post-footer.next-prev {
    height: 64px;
    justify-content: space-between;
    box-sizing: border-box;
  }
}
@media screen and (max-width: 650px) {
  .post-contributor-footer .post-contributor-bio-table {
    display: block;
  }
  .post-contributor-footer .post-contributor-bio-table-row {
    display: flex;
    flex-direction: row;
  }
  .post-contributor-footer .post-contributor-bio-userhead-cell,
  .post-contributor-footer .post-contributor-bio-body-cell {
    display: block;
  }
  .post-contributor-footer .post-contributor-bio-body-cell {
    flex-grow: 1;
  }
  .post-contributor-footer .post-contributor-bio-body-table {
    display: block;
  }
  .post-contributor-footer .post-contributor-bio-body-table-row {
    display: block;
  }
  .post-contributor-footer .post-contributor-bio-copy-cell,
  .post-contributor-footer .post-contributor-bio-controls-cell {
    display: block;
  }
  .post-contributor-footer .post-contributor-bio-copy-cell {
    margin: 0 0 16px 0;
  }
  .post-contributor-footer .post-contributor-bio-controls-cell {
    width: auto;
  }
  .post-contributor-footer .post-contributor-bio-controls {
    margin: auto;
  }
  .post-contributor-footer .post-contributor-bio-controls .button.primary {
    width: 100%;
  }
  .post-contributor-footer .post-contributor-bio-text {
    font-size: 14px;
  }
}
@media screen and (min-width: 768px) {
  .post-silhouette {
    padding: 32px 0;
  }
}
@media screen and (max-width: 650px) {
  .post-silhouette .post-silhouette-title {
    margin-top: 10.44225025px;
    height: 120px;
  }
}
@media screen and (max-width: 650px) {
  .post-silhouette .post-silhouette-meta {
    width: 75%;
  }
}
@media screen and (max-width: 650px) {
  .post-silhouette .post-silhouette-meta.with-byline-image {
    margin: 20px 0;
  }
}
@media screen and (max-width: 650px) {
  .use-theme-bg .post-meta.alternative-meta .post-meta-item,
  .post-meta.alternative-meta .post-meta-item {
    padding-right: 16px;
  }
}
@media screen and (max-width: 370px) {
  .use-theme-bg .post-meta.alternative-meta .post-meta-item,
  .post-meta.alternative-meta .post-meta-item {
    font-size: 14px;
  }
}
@media screen and (max-width: 650px) {
  .use-theme-bg .post-meta.alternative-meta .post-meta-item.guest-author-pu=
blication,
  .post-meta.alternative-meta .post-meta-item.guest-author-publication {
    display: none;
  }
}
@media screen and (max-width: 370px) {
  .post-meta .post-meta-item .post-meta-button {
    height: 36px !important;
    /* important to override in-line height style on emails */
  }
  .post-meta .post-meta-item .post-meta-button .meta-button-label {
    display: none;
  }
  .post-meta .post-meta-item .post-meta-button > svg {
    margin-right: 0;
  }
}
@media screen and (max-width: 370px) {
  .post-meta .post-meta-item {
    font-size: 12px;
  }
}
@media screen and (max-width: 650px) {
  .post .floating-subscribe-button {
    bottom: 20px;
    right: 20px;
  }
}
@media (max-width: 1024px) {
  body .pullquote-align-left,
  body .pullquote-align-right,
  body .pullquote-align-wide,
  body .pullquote-align-center {
    float: none;
    margin: 0 auto;
    width: 100%;
    max-width: 100%;
  }
}
@media all and (-ms-high-contrast: none), (-ms-high-contrast: active) {
  body .markup table.image-wrapper img,
  body .markup table.kindle-wrapper img {
    max-width: 550px;
  }
}
@media (min-width: 1024px) {
  body:not(:has(#toc)) .captioned-image-container figure:has(> a.image2-off=
set-left) {
    margin-left: var(--image-offset-margin);
  }
  body:not(:has(#toc)) .captioned-image-container figure:has(> a.image2-off=
set-right) {
    margin-right: var(--image-offset-margin);
  }
}
@media (min-width: 1300px) {
  body .captioned-image-container figure:has(> a.image2-offset-left) {
    margin-left: var(--image-offset-margin);
  }
  body .captioned-image-container figure:has(> a.image2-offset-right) {
    margin-right: var(--image-offset-margin);
  }
}
@media (max-width: 1024px) {
  body {
    /* Disable offset on mobile/tablet */
  }
  body .captioned-image-container figure:has(> a.image2-align-left),
  body .captioned-image-container figure:has(> a.image2-align-right) {
    float: none;
    margin: 1em auto;
    max-width: 100%;
    width: auto;
    padding: 0;
  }
  body .captioned-image-container figure:has(> a.image2-align-left.thefp),
  body .captioned-image-container figure:has(> a.image2-align-right.thefp) =
{
    margin: 1em auto;
  }
  body .captioned-image-container figure:has(> a.image2-offset-left),
  body .captioned-image-container figure:has(> a.image2-offset-right) {
    margin: 1em auto;
  }
  body .captioned-image-container figure:has(> a.image2-align-left) .image2=
-inset,
  body .captioned-image-container figure:has(> a.image2-align-right) .image=
2-inset {
    display: block;
    justify-content: initial;
  }
}
@media (max-width: 768px) {
  body .markup div.sponsorship-campaign-embed {
    margin-top: 24px;
    margin-bottom: 24px;
  }
  body .markup div.sponsorship-campaign-embed:first-child {
    margin-top: 0px;
  }
}
@media screen and (max-width: 650px) {
  body .markup div.youtube-overlay,
  body .markup div.vimeo-overlay {
    display: none !important;
  }
}
@media screen and (max-width: 370px) {
  body .markup div.tiktok-wrap {
    width: calc(95vw - 32px);
    height: calc((95vw - 32px - 2px) / 0.485714);
  }
}
@media screen and (max-width: 650px) {
  body .markup div.embedded-publication-wrap .embedded-publication.show-sub=
scribe {
    padding: 24px;
  }
}
@media screen and (max-width: 650px) {
  body .markup div.subscription-widget-wrap .subscription-widget.show-subsc=
ribe,
  body .markup div.subscription-widget-wrap-editor .subscription-widget.sho=
w-subscribe,
  body .markup div.captioned-button-wrap .subscription-widget.show-subscrib=
e {
    padding: 0px 24px;
  }
}
@media screen and (max-width: 650px) {
  body .markup div.subscription-widget-wrap .subscription-widget.show-subsc=
ribe .subscription-widget-subscribe .button,
  body .markup div.subscription-widget-wrap-editor .subscription-widget.sho=
w-subscribe .subscription-widget-subscribe .button,
  body .markup div.captioned-button-wrap .subscription-widget.show-subscrib=
e .subscription-widget-subscribe .button {
    padding: 10px 12px;
    min-width: 110px;
  }
}
@media (max-width: 650px) {
  body .markup .twitter-embed,
  body .markup .tweet {
    padding: 12px;
  }
}
@media (max-width: 650px) {
  body .markup .twitter-embed .tweet-text,
  body .markup .tweet .tweet-text {
    font-size: 14px;
    line-height: 20px;
  }
}
@media (max-width: 650px) {
  body .markup .twitter-embed .tweet-photos-container.two,
  body .markup .tweet .tweet-photos-container.two,
  body .markup .twitter-embed .tweet-photos-container.three,
  body .markup .tweet .tweet-photos-container.three,
  body .markup .twitter-embed .tweet-photos-container.four,
  body .markup .tweet .tweet-photos-container.four {
    height: 200px;
  }
}
@media (max-width: 650px) {
  body .markup .twitter-embed a.expanded-link .expanded-link-img,
  body .markup .tweet a.expanded-link .expanded-link-img {
    max-height: 180px;
  }
}
@media (max-width: 650px) {
  body .markup .twitter-embed a.expanded-link .expanded-link-description,
  body .markup .tweet a.expanded-link .expanded-link-description {
    display: none;
  }
}
@media screen and (max-width: 650px) {
  body .markup .apple-podcast-container {
    width: unset;
  }
}
@media (max-width: 420px) {
  body .markup .install-substack-app-embed img.install-substack-app-embed-i=
mg {
    margin: 0 auto 16px auto;
  }
}
@media (max-width: 420px) {
  body .markup .install-substack-app-embed .install-substack-app-embed-text=
 {
    margin: 0 0 12px 0;
    max-width: 100%;
    width: auto;
    text-align: center;
  }
}
@media (max-width: 420px) {
  body .markup .install-substack-app-embed .install-substack-app-embed-link=
 {
    display: flex;
    justify-content: center;
  }
}
@media screen and (min-width: 500px) {
  body .header a.logo {
    width: 42px;
    height: 42px;
    border-radius: 12px;
  }
}
@media screen and (max-width: 420px) {
  body .subscription-receipt table:first-of-type .subscription-amount .subs=
cription-discount {
    width: 72px !important;
  }
}
@media screen and (min-width: 481px) {
  body .share-button-container {
    height: auto;
  }
}
@media screen and (max-width: 480px) {
  body .share-button-container .separator {
    display: block !important;
    margin: 0 !important;
    height: 8px !important;
    border-left: none !important;
  }
}
@media screen and (max-width: 650px) {
  .digest .item .post-meta-item.audience {
    display: none;
  }
}
@media screen and (min-width: 500px) {
  .digest-publication .logo img {
    width: 42px;
    height: 42px;
    border-radius: 8px;
  }
}
@media screen and (max-width: 650px) {
  .comments-page .container .comment-list .collapsed-reply {
    margin-left: calc(10 + 32px - 24px);
  }
}
@media screen and (max-width: 650px) {
  .comment > .comment-list {
    padding-left: 24px;
  }
}
@media screen and (max-width: 650px) {
  .finish-magic-login-modal .modal-content .container {
    padding: 24px 0;
  }
}
@media (max-width: 650px) {
  .reader2-text-b3 {
    line-height: 24px;
  }
}
@media screen and (max-width: 650px) {
  .reader2-text-h4 {
    line-height: 24px;
  }
}
@media screen and (min-width: 541px) {
  .user-profile-modal {
    padding-left: 12px;
    padding-right: 12px;
  }
}
@media screen and (max-width: 650px) {
  .subscribe-widget form.form .sideBySideWrap button.rightButton {
    padding: 10px 12px;
  }
}
@media screen and (min-width: 541px) {
  .pub-icon:hover .logo-hover,
  .feed-item-icon:hover .logo-hover {
    display: block;
  }
}
@media screen and (max-width: 650px) {
  .post-ufi.single-full-width-button .post-ufi-button-wrapper {
    width: 100%;
    padding: 16px;
  }
  .post-ufi.single-full-width-button .post-ufi-button-wrapper:empty {
    display: none;
  }
  .post-ufi.single-full-width-button .post-ufi-button {
    width: 100%;
    justify-content: center;
  }
}
@media screen and (max-width: 768px) {
  .file-embed-wrapper {
    padding: 0;
  }
}
@media screen and (max-width: 768px) {
  .file-embed-wrapper-editor {
    padding: 0;
  }
}
@media screen and (max-width: 768px) {
  .file-embed-wrapper-editor:active {
    padding: 0;
  }
}
@media only screen and (max-width: 650px) {
  .file-embed-button.wide,
  .file-embed-error-button.wide {
    display: none;
  }
}
@media only screen and (min-width: 630px) {
  .file-embed-button.narrow,
  .file-embed-error-button.narrow {
    display: none;
  }
}
@media screen and (min-width: 541px) {
  .audio-player-wrapper .audio-player {
    min-width: 500px;
  }
}
@media screen and (max-width: 650px) {
  .audio-player-wrapper .audio-player .audio-player-progress {
    border-left-width: 16px;
    border-right-width: 16px;
  }
}
@media screen and (max-width: 650px) {
  .audio-player-wrapper .audio-player .audio-player-progress .audio-player-=
progress-bar .audio-player-progress-bar-popup {
    top: -54px;
  }
}
@media screen and (max-width: 650px) {
  .audio-player-wrapper-fancy .audio-player .audio-player-progress {
    border-left-width: 16px;
    border-right-width: 16px;
  }
}
@media screen and (max-width: 650px) {
  .audio-player-wrapper-fancy .audio-player .audio-player-progress .audio-p=
layer-progress-bar .audio-player-progress-bar-popup {
    top: -54px;
  }
}
@media (min-width: 250px) {
  .audio-player-wrapper-fancy .audio-player {
    padding: 32px;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group {
    display: flex;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group .button:last-of-type=
 {
    display: block;
  }
}
@media (min-width: 300px) {
  .audio-player-wrapper-fancy .audio-player .btn-group {
    display: block;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group .button:first-of-typ=
e {
    display: block;
  }
}
@media (min-width: 350px) {
  .audio-player-wrapper-fancy .audio-player .audio-player-substack-logo {
    display: block;
  }
  .audio-player-wrapper-fancy .audio-player .audio-player-title {
    margin-top: 16px;
  }
  .audio-player-wrapper-fancy .audio-player .audio-player-hero-image-contai=
ner {
    padding-top: 15%;
    width: 15%;
    display: block;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group .button:first-of-typ=
e {
    display: block;
  }
  .audio-player-wrapper-fancy .audio-player .audio-player-substack-logo {
    display: block;
  }
}
@media (min-width: 350px) {
  .audio-player-wrapper-fancy .audio-player .audio-player-hero-image-contai=
ner {
    padding-top: 25%;
    width: 25%;
    display: block;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group {
    display: flex;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group .button:first-of-typ=
e {
    display: block;
  }
}
@media (min-width: 400px) {
  .audio-player-wrapper-fancy .audio-player .audio-player-hero-image-contai=
ner {
    padding-top: 40%;
    width: 40%;
  }
}
@media (max-width: 400px) {
  .audio-player-wrapper-fancy .audio-player .btn-group {
    margin-top: 12px;
  }
  .audio-player-wrapper-fancy .audio-player .btn-group .button {
    font-size: 13px;
    padding: 6px 12px;
    height: auto;
    margin-top: 10px;
  }
}
@media (min-width: 600px) {
  .audio-player-wrapper-fancy .audio-player .audio-player-hero-image-contai=
ner {
    padding-top: 55%;
    width: 55%;
  }
}
@media (max-width: 650px) {
  .poll-editor-modal {
    min-width: calc(100% - 20px);
  }
}
@media (max-width: 750px) {
  .poll-embed .poll-anchor-target .poll-anchor-copy-button {
    left: 8px;
    top: 45px;
  }
}
@media not all and (min-resolution: 0.001dpcm) {
  @supports (-webkit-appearance: none) {
    p a:not(.primary.button),
    .post p:not(.button-wrapper) a:not(.primary.button),
    .footnote a.footnote-anchor:not(.primary.button),
    .thread-head .markup p:not(.button-wrapper) a:not(.primary.button) {
      color: #ff6719;
      text-decoration: none;
    }
    p a:not(.primary.button):hover,
    .post p:not(.button-wrapper) a:not(.primary.button):hover,
    .footnote a.footnote-anchor:not(.primary.button):hover,
    .thread-head .markup p:not(.button-wrapper) a:not(.primary.button):hove=
r {
      text-decoration: underline;
    }
  }
}</style></head><body class=3D"email-body" style=3D"font-kerning: auto;--im=
age-offset-margin: -120px;"><img src=3D"https://eotrx.substackcdn.com/o/262=
0e1910afabda2/p.gif?token=3DeyJtIjoiPDIwMjYwNTExMTc0MDE5LjMuNWMxYmMzZDhlNzA=
5MzY2OEBtZy1kMS5zdWJzdGFjay5jb20-IiwidSI6MjczNjIyMzk4LCJyIjoidGpwaHVoc0BnbW=
FpbC5jb20iLCJkIjoibWctZDEuc3Vic3RhY2suY29tIiwicCI6MTk3MjQ1ODM1LCJ0IjoibmV3c=
2xldHRlciIsImEiOiJldmVyeW9uZSIsInMiOjMzNjUzNjcsImMiOiJwb3N0IiwiZiI6dHJ1ZSwi=
cG9zaXRpb24iOiJ0b3AiLCJpYXQiOjE3Nzg1MjEyMjcsImV4cCI6MTc4MTExMzIyNywiaXNzIjo=
icHViLTAiLCJzdWIiOiJlbyJ9.HC0-vkVat3PwKZo1zZJpqKMRlEhVBuBIN-7gcn_SKZM" alt=
=3D"" width=3D"1" height=3D"1" border=3D"0" style=3D"height:1px !important;=
width:1px !important;border-width:0 !important;margin-top:0 !important;marg=
in-bottom:0 !important;margin-right:0 !important;margin-left:0 !important;p=
adding-top:0 !important;padding-bottom:0 !important;padding-right:0 !import=
ant;padding-left:0 !important;"/><div class=3D"preview" style=3D"display:no=
ne;font-size:1px;color:#333333;line-height:1px;max-height:0px;max-width:0px=
;opacity:0;overflow:hidden;">Read this first: Everything below is for resea=
rch and educational purposes only.</div><div class=3D"preview" style=3D"dis=
play:none;font-size:1px;color:#333333;line-height:1px;max-height:0px;max-wi=
dth:0px;opacity:0;overflow:hidden;">&#847; &nbsp; &#8199; &#173;&#847; &nbs=
p; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#=
847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199;=
 &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp=
; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#8=
47; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; =
&#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp;=
 &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#84=
7; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &=
#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; =
&#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847=
; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#=
173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &=
#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847;=
 &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; =
73;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#=
8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; =
&nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#17=
3;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8=
199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &=
nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173=
;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#81=
99; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &n=
bsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;=
&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#819=
9; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nb=
sp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&=
#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199=
; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbs=
p; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#=
847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199;=
 &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp=
; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#8=
47; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; =
&#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp;=
 &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#84=
7; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &=
#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; =
&#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847=
; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#=
173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &=
#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847;=
 &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; =
73;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#=
8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; =
&nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#17=
3;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8=
199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &=
nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173=
;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#81=
99; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &n=
bsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;=
&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#819=
9; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nb=
sp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&=
#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199=
; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbs=
p; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#=
847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199;=
 &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp=
; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#8=
47; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; =
&#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp;=
 &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#84=
7; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &=
#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; =
&#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847=
; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#=
173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &=
#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847;=
 &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; =
73;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#=
8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; =
&nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#17=
3;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8199; &#173;&#847; &nbsp; &#8=
199; &#173;</div><table class=3D"email-body-container" role=3D"presentation=
" width=3D"100%" border=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><t=
r><td></td><td class=3D"content" width=3D"550"></td><td></td></tr><tr><td><=
/td><td class=3D"content" width=3D"550" align=3D"left"><div style=3D"font-s=
ize: 16px;line-height: 26px;max-width: 550px;width: 100%;margin: 0 auto;ove=
rflow-wrap: break-word;"><table role=3D"presentation" width=3D"100%" border=
=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td align=3D"right" s=
tyle=3D"height:20px;"><table role=3D"presentation" width=3D"auto" border=3D=
"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td style=3D"vertical-al=
ign:middle;"><span class=3D"pencraft pc-reset reset-IxiVJZ tw-font-body tw-=
text-ssm tw-text-substack-secondary" style=3D"font-family: SF Pro Text, -ap=
ple-system, system-ui, BlinkMacSystemFont, Inter, Segoe UI, Roboto, Helveti=
ca, Arial, sans-serif, Apple Color Emoji, Segoe UI Emoji, Segoe UI Symbol;f=
ont-size: 13px;color: unset;list-style: none;text-decoration: unset;margin:=
 0;"><div class=3D"pencraft pc-reset align-right-VJbKw5 size-12-mmZ61m rese=
t-IxiVJZ" style=3D"list-style: none;color: unset;text-align: right;font-siz=
e: 12px;line-height: 16px;text-decoration: unset;margin: 0;"><span class=3D=
"pencraft pc-reset reset-IxiVJZ" translated=3D"" style=3D"list-style: none;=
color: unset;text-decoration: unset;margin: 0;">Forwarded this email? <a cl=
ass=3D"pencraft pc-reset decoration-underline-ClTkYc reset-IxiVJZ" href=3D"=
https://substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9kZXJla3BydXNraS5zdWJzdGF=
jay5jb20vc3Vic2NyaWJlP3V0bV9zb3VyY2U9ZW1haWwmdXRtX2NhbXBhaWduPWVtYWlsLXN1Yn=
NjcmliZSZyPTRpd29lNiZuZXh0PWh0dHBzJTNBJTJGJTJGZGVyZWtwcnVza2kuc3Vic3RhY2suY=
29tJTJGcCUyRnRlc29mZW5zaW5lLXdoYXRzLXdvcnRoLWtub3dpbmctYWJvdXQiLCJwIjoxOTcy=
NDU4MzUsInMiOjMzNjUzNjcsImYiOnRydWUsInUiOjI3MzYyMjM5OCwiaWF0IjoxNzc4NTIxMjI=
3LCJleHAiOjIwOTQwOTcyMjcsImlzcyI6InB1Yi0wIiwic3ViIjoibGluay1yZWRpcmVjdCJ9.t=
m9Td6_3ptYQh6MPNkhIDUy69YcZVMCxi0I0MsFX1ww?" style=3D"list-style: none;colo=
r: unset;text-decoration: unset;margin: 0;-webkit-text-decoration-line: und=
erline;text-decoration-line: underline;">Subscribe here</a> for more</span>=
</div></span></td></tr></tbody></table></td></tr></tbody></table><div class=
=3D"post typography" dir=3D"auto" style=3D"--image-offset-margin: -120px;pa=
dding: 32px 0 0 0;font-size: 16px;line-height: 26px;"><div class=3D"post-he=
ader" role=3D"region" aria-label=3D"Post header" style=3D"font-size: 16px;l=
ine-height: 26px;"><h1 class=3D"post-title published title-X77sOw" dir=3D"a=
uto" style=3D"direction: auto;text-align: start;unicode-bidi: isolate;color=
: rgb(54,55,55);font-family: 'SF Pro Display',-apple-system-headline,system=
-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans=
-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';font-weight: =
bold;-webkit-font-smoothing: antialiased;-moz-osx-font-smoothing: antialias=
ed;-webkit-appearance: optimizelegibility;-moz-appearance: optimizelegibili=
ty;appearance: optimizelegibility;margin: 0;line-height: 36px;font-size: 32=
px;"><a href=3D"https://substack.com/app-link/post?publication_id=3D3365367=
&post_id=3D197245835&utm_source=3Dpost-email-title&utm_campaign=3Demail-pos=
t-title&isFreemail=3Dtrue&r=3D4iwoe6&token=3DeyJ1c2VyX2lkIjoyNzM2MjIzOTgsIn=
Bvc3RfaWQiOjE5NzI0NTgzNSwiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjE3ODExMTMyMjcsImlzc=
yI6InB1Yi0zMzY1MzY3Iiwic3ViIjoicG9zdC1yZWFjdGlvbiJ9.6MUoHdXDtDGIH6iQEdSw_sE=
sCqOKpzDhIZKkD4HoUWI" style=3D"color: rgb(54,55,55);text-decoration: none;"=
>Tesofensine: What&#8217;s Worth Knowing About The Mechanism, The Side Effe=
cts, And The GLP-1 Washout Question</a></h1><table class=3D"post-meta" role=
=3D"presentation" width=3D"100%" border=3D"0" cellspacing=3D"0" cellpadding=
=3D"0" style=3D"margin: 1em 0;height: 20px;align-items: center;"><tbody><tr=
><td><table role=3D"presentation" width=3D"auto" border=3D"0" cellspacing=
=3D"0" cellpadding=3D"0"><tbody><tr><td><table role=3D"presentation" width=
=3D"auto" border=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td s=
tyle=3D"vertical-align:middle;"><div class=3D"pencraft pc-reset color-prima=
ry-zABazT line-height-20-t4M0El font-meta-MWBumP size-11-NuY2Zx weight-medi=
um-fw81nC transform-uppercase-yKDgcq reset-IxiVJZ meta-EgzBVA custom-css-em=
ail-post-author" style=3D"list-style: none;font-size: 11px;line-height: 20p=
x;text-decoration: unset;color: rgb(54,55,55);margin: 0;font-family: 'SF Co=
mpact',-apple-system,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',=
Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Seg=
oe UI Symbol';font-weight: 500;text-transform: uppercase;letter-spacing: .2=
px;"><a class=3D"pencraft pc-reset color-primary-zABazT line-height-20-t4M0=
El font-meta-MWBumP size-11-NuY2Zx weight-medium-fw81nC transform-uppercase=
-yKDgcq reset-IxiVJZ meta-EgzBVA" style=3D"list-style: none;color: rgb(54,5=
5,55);margin: 0;font-size: 11px;line-height: 20px;font-family: 'SF Compact'=
,-apple-system,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto=
,Helvetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI =
Symbol';font-weight: 500;text-transform: uppercase;letter-spacing: .2px;tex=
t-decoration: none" href=3D"https://substack.com/@dereksresearchradar">Dere=
k</a></div></td></tr></tbody></table></td></tr><tr><td><table role=3D"prese=
ntation" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpadding=3D"0"><t=
body><tr><td style=3D"vertical-align:middle;"><div class=3D"pencraft pc-res=
et color-secondary-ls1g8s line-height-20-t4M0El font-meta-MWBumP size-11-Nu=
Y2Zx weight-medium-fw81nC transform-uppercase-yKDgcq reset-IxiVJZ meta-EgzB=
VA" style=3D"list-style: none;font-size: 11px;line-height: 20px;text-decora=
tion: unset;color: rgb(119,119,119);margin: 0;font-family: 'SF Compact',-ap=
ple-system,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Hel=
vetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symb=
ol';font-weight: 500;text-transform: uppercase;letter-spacing: .2px;"><time=
 datetime=3D"2026-05-11T17:40:18.870Z">May 11</time></div></td></tr></tbody=
></table></td></tr></tbody></table></td><td align=3D"right"><table role=3D"=
presentation" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpadding=3D"=
0"><tbody><tr><td style=3D"vertical-align:middle;"><a href=3D"https://subst=
ack.com/@dereksresearchradar"><img class=3D"custom-css-email-avatar avatar-=
QIQ5yR" src=3D"https://substackcdn.com/image/fetch/$s_!27SK!,f_auto,q_auto:=
good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.co=
m%2Fpublic%2Fimages%2Ff07a8bac-9f53-43a0-af70-e96356c0f3f3_500x500.png" sty=
le=3D"box-sizing: border-box;max-width: 550px;border: none;vertical-align: =
middle;width: 40px;height: 40px;min-width: 40px;min-height: 40px;object-fit=
: cover;margin: 0px;display: inline;border-radius: 50%" width=3D"40" height=
=3D"40"></a></td></tr></tbody></table></td></tr></tbody></table><table clas=
s=3D"email-ufi-2-top" role=3D"presentation" width=3D"100%" border=3D"0" cel=
lspacing=3D"0" cellpadding=3D"0" style=3D"border-top: 1px solid rgb(0,0,0,.=
1);border-bottom: 1px solid rgb(0,0,0,.1);min-width: 100%;"><tbody><tr heig=
ht=3D"16"><td height=3D"16" style=3D"font-size:0px;line-height:0;">&nbsp;</=
td></tr><tr><td><table role=3D"presentation" width=3D"100%" border=3D"0" ce=
llspacing=3D"0" cellpadding=3D"0"><tbody><tr><td><table role=3D"presentatio=
n" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><=
tr><td style=3D"vertical-align:middle;"><table role=3D"presentation" width=
=3D"38" border=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td ali=
gn=3D"center"><a class=3D"email-icon-button" href=3D"https://substack.com/a=
pp-link/post?publication_id=3D3365367&post_id=3D197245835&utm_source=3Dsubs=
tack&isFreemail=3Dtrue&submitLike=3Dtrue&token=3DeyJ1c2VyX2lkIjoyNzM2MjIzOT=
gsInBvc3RfaWQiOjE5NzI0NTgzNSwicmVhY3Rpb24iOiLinaQiLCJpYXQiOjE3Nzg1MjEyMjcsI=
mV4cCI6MTc4MTExMzIyNywiaXNzIjoicHViLTMzNjUzNjciLCJzdWIiOiJyZWFjdGlvbiJ9.KF0=
LQKgyHH5jC1YUPSHCjU6ypop_xOPAvFj40RwmYx4&utm_medium=3Demail&utm_campaign=3D=
email-reaction&r=3D4iwoe6" style=3D"font-family: system-ui,-apple-system,Bl=
inkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color =
Emoji','Segoe UI Emoji','Segoe UI Symbol';display: inline-block;font-weight=
: 500;border: 1px solid rgb(0,0,0,.1);border-radius: 9999px;text-transform:=
 uppercase;font-size: 12px;line-height: 1;padding: 9px 0;text-decoration: n=
one;color: rgb(119,119,119);min-width: 38px;box-sizing: border-box;width: 3=
8px"><img class=3D"icon" src=3D"https://substackcdn.com/image/fetch/$s_!PeV=
s!,w_36,c_scale,f_png,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubsta=
ck.com%2Ficon%2FLucideHeart%3Fv%3D4%26height%3D36%26fill%3Dnone%26stroke%3D=
%2523808080%26strokeWidth%3D2" width=3D"18" height=3D"18" style=3D"border: =
none;vertical-align: middle;max-width: 18px" alt=3D""></a></td></tr></tbody=
></table></td><td width=3D"8" style=3D"min-width:8px;"></td><td style=3D"ve=
rtical-align:middle;"><table role=3D"presentation" width=3D"38" border=3D"0=
" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td align=3D"center"><a cl=
ass=3D"email-icon-button" href=3D"https://substack.com/app-link/post?public=
ation_id=3D3365367&post_id=3D197245835&utm_source=3Dsubstack&utm_medium=3De=
mail&isFreemail=3Dtrue&comments=3Dtrue&token=3DeyJ1c2VyX2lkIjoyNzM2MjIzOTgs=
InBvc3RfaWQiOjE5NzI0NTgzNSwiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjE3ODExMTMyMjcsIml=
zcyI6InB1Yi0zMzY1MzY3Iiwic3ViIjoicG9zdC1yZWFjdGlvbiJ9.6MUoHdXDtDGIH6iQEdSw_=
sEsCqOKpzDhIZKkD4HoUWI&r=3D4iwoe6&utm_campaign=3Demail-half-magic-comments&=
action=3Dpost-comment&utm_source=3Dsubstack&utm_medium=3Demail" style=3D"fo=
nt-family: system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Hel=
vetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symb=
ol';display: inline-block;font-weight: 500;border: 1px solid rgb(0,0,0,.1);=
border-radius: 9999px;text-transform: uppercase;font-size: 12px;line-height=
: 1;padding: 9px 0;text-decoration: none;color: rgb(119,119,119);min-width:=
 38px;box-sizing: border-box;width: 38px"><img class=3D"icon" src=3D"https:=
//substackcdn.com/image/fetch/$s_!x1tS!,w_36,c_scale,f_png,q_auto:good,fl_p=
rogressive:steep/https%3A%2F%2Fsubstack.com%2Ficon%2FLucideComments%3Fv%3D4=
%26height%3D36%26fill%3Dnone%26stroke%3D%2523808080%26strokeWidth%3D2" widt=
h=3D"18" height=3D"18" style=3D"border: none;vertical-align: middle;max-wid=
th: 18px" alt=3D""></a></td></tr></tbody></table></td><td width=3D"8" style=
=3D"min-width:8px;"></td><td style=3D"vertical-align:middle;"><table role=
=3D"presentation" width=3D"38" border=3D"0" cellspacing=3D"0" cellpadding=
=3D"0"><tbody><tr><td align=3D"center"><a class=3D"email-icon-button" href=
=3D"https://substack.com/app-link/post?publication_id=3D3365367&post_id=3D1=
97245835&utm_source=3Dsubstack&utm_medium=3Demail&utm_content=3Dshare&utm_c=
ampaign=3Demail-share&action=3Dshare&triggerShare=3Dtrue&isFreemail=3Dtrue&=
r=3D4iwoe6&token=3DeyJ1c2VyX2lkIjoyNzM2MjIzOTgsInBvc3RfaWQiOjE5NzI0NTgzNSwi=
aWF0IjoxNzc4NTIxMjI3LCJleHAiOjE3ODExMTMyMjcsImlzcyI6InB1Yi0zMzY1MzY3Iiwic3V=
iIjoicG9zdC1yZWFjdGlvbiJ9.6MUoHdXDtDGIH6iQEdSw_sEsCqOKpzDhIZKkD4HoUWI" styl=
e=3D"font-family: system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Rob=
oto,Helvetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe =
UI Symbol';display: inline-block;font-weight: 500;border: 1px solid rgb(0,0=
,0,.1);border-radius: 9999px;text-transform: uppercase;font-size: 12px;line=
-height: 1;padding: 9px 0;text-decoration: none;color: rgb(119,119,119);min=
-width: 38px;box-sizing: border-box;width: 38px"><img class=3D"icon" src=3D=
"https://substackcdn.com/image/fetch/$s_!_L14!,w_36,c_scale,f_png,q_auto:go=
od,fl_progressive:steep/https%3A%2F%2Fsubstack.com%2Ficon%2FLucideShare2%3F=
v%3D4%26height%3D36%26fill%3Dnone%26stroke%3D%2523808080%26strokeWidth%3D2"=
 width=3D"18" height=3D"18" style=3D"border: none;vertical-align: middle;ma=
x-width: 18px" alt=3D""></a></td></tr></tbody></table></td><td width=3D"8" =
style=3D"min-width:8px;"></td><td style=3D"vertical-align:middle;"><table r=
ole=3D"presentation" width=3D"38" border=3D"0" cellspacing=3D"0" cellpaddin=
g=3D"0"><tbody><tr><td align=3D"center"><a class=3D"email-icon-button" href=
=3D"https://substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9vcGVuLnN1YnN0YWNrLmN=
vbS9wdWIvZGVyZWtwcnVza2kvcC90ZXNvZmVuc2luZS13aGF0cy13b3J0aC1rbm93aW5nLWFib3=
V0P3V0bV9zb3VyY2U9c3Vic3RhY2smdXRtX21lZGl1bT1lbWFpbCZ1dG1fY2FtcGFpZ249ZW1ha=
WwtcmVzdGFjay1jb21tZW50JmFjdGlvbj1yZXN0YWNrLWNvbW1lbnQmcj00aXdvZTYmdG9rZW49=
ZXlKMWMyVnlYMmxrSWpveU56TTJNakl6T1Rnc0luQnZjM1JmYVdRaU9qRTVOekkwTlRnek5Td2l=
hV0YwSWpveE56YzROVEl4TWpJM0xDSmxlSEFpT2pFM09ERXhNVE15TWpjc0ltbHpjeUk2SW5CMV=
lpMHpNelkxTXpZM0lpd2ljM1ZpSWpvaWNHOXpkQzF5WldGamRHbHZiaUo5LjZNVW9IZFhEdERHS=
Ug2aVFFZFN3X3NFc0NxT0twekRoSVpLa0Q0SG9VV0kiLCJwIjoxOTcyNDU4MzUsInMiOjMzNjUz=
NjcsImYiOnRydWUsInUiOjI3MzYyMjM5OCwiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjIwOTQwOTc=
yMjcsImlzcyI6InB1Yi0wIiwic3ViIjoibGluay1yZWRpcmVjdCJ9.I0tztTF-b482fwr2Zuci1=
cVcQSyNVKsh-glCeeaEDak?&utm_source=3Dsubstack&utm_medium=3Demail" style=3D"=
font-family: system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,H=
elvetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Sy=
mbol';display: inline-block;font-weight: 500;border: 1px solid rgb(0,0,0,.1=
);border-radius: 9999px;text-transform: uppercase;font-size: 12px;line-heig=
ht: 1;padding: 9px 0;text-decoration: none;color: rgb(119,119,119);min-widt=
h: 38px;box-sizing: border-box;width: 38px"><img class=3D"icon" src=3D"http=
s://substackcdn.com/image/fetch/$s_!ubXF!,w_36,c_scale,f_png,q_auto:good,fl=
_progressive:steep/https%3A%2F%2Fsubstack.com%2Ficon%2Fnotes__NoteRestackIc=
on%3Fv%3D4%26height%3D36%26fill%3Dnone%26stroke%3D%2523808080%26strokeWidth=
%3D2%26strokeLinecap%3Dround%26strokeLinejoin%3Dround" width=3D"18" height=
=3D"18" alt=3D"" style=3D"max-width: 550px;border: none !important;vertical=
-align: middle;"></a></td></tr></tbody></table></td></tr></tbody></table></=
td><td align=3D"right"><table role=3D"presentation" width=3D"auto" border=
=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td style=3D"vertical=
-align:middle;"><table role=3D"presentation" width=3D"auto" border=3D"0" ce=
llspacing=3D"0" cellpadding=3D"0"><tbody><tr><td align=3D"center"><a class=
=3D"email-button-outline" href=3D"https://open.substack.com/pub/derekpruski=
/p/tesofensine-whats-worth-knowing-about?utm_source=3Demail&redirect=3Dapp-=
store&utm_campaign=3Demail-read-in-app" style=3D"font-family: system-ui,-ap=
ple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,=
'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';display: inline-bloc=
k;font-weight: 500;border: 1px solid rgb(0,0,0,.1);border-radius: 9999px;te=
xt-transform: uppercase;font-size: 12px;line-height: 12px;padding: 9px 14px=
;text-decoration: none;color: rgb(119,119,119);"><div class=3D"email-button=
-spacer" style=3D"font-size: 16px;line-height: 26px;display: inline-block;v=
ertical-align: middle;max-width: 0;min-height: 18px;"></div><span class=3D"=
email-button-text" style=3D"vertical-align: middle;margin-right: 4px">READ =
IN APP</span><img class=3D"icon text-icon" src=3D"https://substackcdn.com/i=
mage/fetch/$s_!ET-_!,w_36,c_scale,f_png,q_auto:good,fl_progressive:steep/ht=
tps%3A%2F%2Fsubstack.com%2Ficon%2FLucideArrowUpRight%3Fv%3D4%26height%3D36%=
26fill%3Dnone%26stroke%3D%2523808080%26strokeWidth%3D2" width=3D"18" height=
=3D"18" style=3D"min-width: 18px;min-height: 18px;border: none;vertical-ali=
gn: middle;margin-right: 0;margin-left: 0;max-width: 18px" alt=3D""></a></t=
d></tr></tbody></table></td></tr></tbody></table></td></tr></tbody></table>=
</td></tr><tr height=3D"16"><td height=3D"16" style=3D"font-size:0px;line-h=
eight:0;">&nbsp;</td></tr></tbody></table></div></div><div class=3D"post ty=
pography" dir=3D"auto" style=3D"--image-offset-margin: -120px;padding: 32px=
 0 0 0;font-size: 16px;line-height: 26px;"><div class=3D"body markup" dir=
=3D"auto" style=3D"text-align: initial;font-size: 16px;line-height: 26px;wi=
dth: 100%;word-break: break-word;margin-bottom: 16px;"><p style=3D"margin: =
0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;margin-to=
p: 0;"><em>Read this first: Everything below is for research and educationa=
l purposes only. Nothing here is medical advice. Tesofensine is a research =
compound and is not approved for human consumption in the United States. No=
thing in this post is a recommendation for personal use. If you are conside=
ring any of this for non-research purposes, that&#8217;s a conversation for=
 a qualified clinician &#8212; not a Substack post.</em></p><div style=3D"f=
ont-size: 16px;line-height: 26px;"><hr style=3D"margin: 32px 0;padding: 0;h=
eight: 1px;background: rgb(0,0,0,.1);border: none;"></div><h2 class=3D"head=
er-anchor-post" style=3D"position: relative;font-family: 'SF Pro Display',-=
apple-system-headline,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI'=
,Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Se=
goe UI Symbol';font-weight: bold;-webkit-font-smoothing: antialiased;-moz-o=
sx-font-smoothing: antialiased;-webkit-appearance: optimizelegibility;-moz-=
appearance: optimizelegibility;appearance: optimizelegibility;margin: 1em 0=
 0.625em 0;color: rgb(54,55,55);line-height: 1.16em;font-size: calc(1.625em=
 * 1);">The Landscape</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,5=
5);line-height: 26px;font-size: 16px;">Tesofensine has been showing up more=
 often as a possible &#8220;bridge&#8221; compound between GLP-1 cycles. Th=
e 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&=
#8217;s oral (a pill, no subQ administration), and the trial weight loss nu=
mbers are real &#8212; 10-13% body weight loss over 24 weeks at higher dose=
s, which is competitive with what GLP-1s do.</p><div class=3D"video-player-=
with-background is-static video-player-wrapper" role=3D"region" aria-label=
=3D"Video player" style=3D"flex-grow: 1;font-size: 16px;line-height: 26px;m=
argin-top: 0.5em;"><a class=3D"video-player video-player-with-background" h=
ref=3D"https://substack.com/redirect/5decd7c5-7736-4185-8de3-ce27914e106d?j=
=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs" style=
=3D"position: relative;display: block;width: 100%;cursor: pointer;backgroun=
d-color: rgb(0,0,0);height: auto;border-radius: 8px;padding-bottom: 0"><img=
 class=3D"video-player-preview" width=3D"550" src=3D"https://substackcdn.co=
m/image/fetch/$s_!7V7J!,w_1100,h_1100,c_pad,f_auto,q_auto:good,fl_progressi=
ve:steep/l_play_button_usfui2,w_144,e_colorize:0/https%3A%2F%2Fsubstack-vid=
eo.s3.amazonaws.com%2Fvideo_upload%2Fpost%2F197245835%2Fda5ce048-6530-49ce-=
8d58-f5b84b15fc23%2Ftranscoded-00640.png" data-component-name=3D"VideoPlaye=
r-PreviewImg" data-testid=3D"video-player-static-preview-image" style=3D"bo=
rder: none !important;vertical-align: middle;display: block;-ms-interpolati=
on-mode: bicubic;max-width: 100%;height: auto;margin: 0 auto;width: 100%;ma=
x-height: 100%;background: black;cursor: pointer;position: relative;border-=
radius: 8px;"></a></div><div class=3D"subscribe-widget is-signed-up" data-c=
omponent-name=3D"SubscribeWidget" style=3D"margin: 0 0 1em;direction: ltr;f=
ont-size: 16px;line-height: 26px;"><div class=3D"pencraft pc-reset button-w=
rapper" style=3D"text-decoration: unset;list-style: none;font-size: 16px;li=
ne-height: 26px;text-align: center;cursor: pointer;border-radius: 4px;"><a =
class=3D"button subscribe-btn primary" href=3D"https://substack.com/redirec=
t/2/eyJlIjoiaHR0cHM6Ly9kZXJla3BydXNraS5zdWJzdGFjay5jb20vc3Vic2NyaWJlP3V0bV9=
zb3VyY2U9cG9zdCZ1dG1fY2FtcGFpZ249ZW1haWwtY2hlY2tvdXQmbmV4dD1odHRwcyUzQSUyRi=
UyRmRlcmVrcHJ1c2tpLnN1YnN0YWNrLmNvbSUyRnAlMkZ0ZXNvZmVuc2luZS13aGF0cy13b3J0a=
C1rbm93aW5nLWFib3V0JnI9NGl3b2U2JnRva2VuPWV5SjFjMlZ5WDJsa0lqb3lOek0yTWpJek9U=
Z3NJbWxoZENJNk1UYzNPRFV5TVRJeU55d2laWGh3SWpveE56Z3hNVEV6TWpJM0xDSnBjM01pT2l=
Kd2RXSXRNek0yTlRNMk55SXNJbk4xWWlJNkltTm9aV05yYjNWMEluMC5CcEo3aGM2Q0dHTkFRdD=
loTFdhb0VlWEpfOFlhLUh5VmNGMGIwZkRKdmMwIiwicCI6MTk3MjQ1ODM1LCJzIjozMzY1MzY3L=
CJmIjp0cnVlLCJ1IjoyNzM2MjIzOTgsImlhdCI6MTc3ODUyMTIyNywiZXhwIjoyMDk0MDk3MjI3=
LCJpc3MiOiJwdWItMCIsInN1YiI6ImxpbmstcmVkaXJlY3QifQ.z3aGfjcu6S2H2aGp4dXvWmWi=
YXeJ4Ha1jV-kdyQfsmo?&utm_medium=3Demail&utm_source=3Dsubscribe-widget&utm_c=
ontent=3D197245835" style=3D"font-family: system-ui,-apple-system,BlinkMacS=
ystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji',=
'Segoe UI Emoji','Segoe UI Symbol';display: inline-block;box-sizing: border=
-box;cursor: pointer;border: none;border-radius: 8px;font-size: 14px;line-h=
eight: 20px;font-weight: 600;text-align: center;opacity: 1;outline: none;wh=
ite-space: nowrap;text-decoration: none !important;margin: 0 auto;backgroun=
d-color: #FF6719;color: #ffffff !important;padding: 12px 20px;height: auto;=
"><span style=3D"color: #ffffff;text-decoration: none;">Upgrade to paid</sp=
an></a></div></div><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line=
-height: 26px;font-size: 16px;">The compound is real. The data is real. And=
 there&#8217;s a legitimate place for it in the research conversation. But =
there&#8217;s one big thing worth knowing before going further:</p><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;"><strong>Tesofensine is not a peptide. It&#8217;s a different kind of d=
rug &#8212; one that works much more like an antidepressant than like anyth=
ing else commonly discussed in this community.</strong></p><p style=3D"marg=
in: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">Tha=
t single fact changes how to think about it. The side effects are different=
=2E The drug interactions are different=
=2E The timing is different. The people=20=
who tolerate it well versus poorly are different. None of this makes tesofe=
nsine bad. It just means the mental model most peptide users have doesn&#82=
17;t really apply here, and the goal of this post is to lay out what&#8217;=
s worth being aware of so you can evaluate it honestly.</p><p style=3D"marg=
in: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">In =
plain terms, this post covers: what tesofensine actually is, what side effe=
cts 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 to=
lerability different.</p><div style=3D"font-size: 16px;line-height: 26px;">=
<hr style=3D"margin: 32px 0;padding: 0;height: 1px;background: rgb(0,0,0,.1=
);border: none;"></div><h2 class=3D"header-anchor-post" style=3D"position: =
relative;font-family: 'SF Pro Display',-apple-system-headline,system-ui,-ap=
ple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,=
'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';font-weight: bold;-w=
ebkit-font-smoothing: antialiased;-moz-osx-font-smoothing: antialiased;-web=
kit-appearance: optimizelegibility;-moz-appearance: optimizelegibility;appe=
arance: optimizelegibility;margin: 1em 0 0.625em 0;color: rgb(54,55,55);lin=
e-height: 1.16em;font-size: calc(1.625em * 1);">What Tesofensine Actually I=
s (In Plain Language)</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,5=
5);line-height: 26px;font-size: 16px;">A quick history first. Tesofensine (=
research name NS2330) was originally developed in Denmark to treat Parkinso=
n&#8217;s and Alzheimer&#8217;s disease. It didn&#8217;t work for either co=
ndition. 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&#8217;s still not FDA-appr=
oved in the US.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line=
-height: 26px;font-size: 16px;">Now the mechanism, in simple terms.</p><p s=
tyle=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size=
: 16px;"><span>Your brain uses chemicals called </span><strong>neurotransmi=
tters</strong><span> to send signals between brain cells. Three of the most=
 important ones are:</span></p><ul style=3D"margin-top: 0;padding: 0;"><li =
style=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=3D"colo=
r: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizing: border-box;=
padding-left: 4px;font-size: 16px;margin: 0;"><strong>Serotonin</strong><sp=
an> &#8212; mood, sleep, appetite</span></p></li><li style=3D"margin: 8px 0=
 0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-=
height: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font=
-size: 16px;margin: 0;"><strong>Norepinephrine</strong><span> &#8212; alert=
ness, focus, energy, heart rate</span></p></li><li style=3D"margin: 8px 0 0=
 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-he=
ight: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-s=
ize: 16px;margin: 0;"><strong>Dopamine</strong><span> &#8212; motivation, r=
eward, pleasure, focus</span></p></li></ul><div class=3D"captioned-image-co=
ntainer-static" style=3D"font-size: 16px;line-height: 26px;margin: 32px aut=
o;"><figure style=3D"width: 100%;margin: 0 auto;"><table class=3D"image-wra=
pper" width=3D"100%" border=3D"0" cellspacing=3D"0" cellpadding=3D"0" data-=
component-name=3D"Image2ToDOMStatic" style=3D"mso-padding-alt: 1em 0 1.6em;=
"><tbody><tr><td style=3D"text-align: center;"></td><td class=3D"content" a=
lign=3D"left" width=3D"662" style=3D"text-align: center;"><a class=3D"image=
-link" target=3D"_blank" href=3D"https://substack.com/redirect/09dfb84c-d2e=
0-42ea-a4b4-0b22f520e755?j=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy=
3p768BWtuZifRB-Zs" style=3D"position: relative;flex-direction: column;align=
-items: center;padding: 0;width: auto;height: auto;border: none;text-decora=
tion: none;display: block;margin: 0;"><img class=3D"wide-image" data-attrs=
=3D"{&quot;src&quot;:&quot;https://substack-post-media.s3.amazonaws.com/pub=
lic/images/7305daa9-da17-4b9c-9938-8626bce4994e_1254x1254.png&quot;,&quot;s=
rcNoWatermark&quot;:null,&quot;fullscreen&quot;:null,&quot;imageSize&quot;:=
null,&quot;height&quot;:1254,&quot;width&quot;:1254,&quot;resizeWidth&quot;=
:662,&quot;bytes&quot;:1645158,&quot;alt&quot;:null,&quot;title&quot;:null,=
&quot;type&quot;:&quot;image/png&quot;,&quot;href&quot;:null,&quot;belowThe=
Fold&quot;:true,&quot;topImage&quot;:false,&quot;internalRedirect&quot;:&qu=
ot;https://derekpruski.substack.com/i/197245835?img=3Dhttps%3A%2F%2Fsubstac=
k-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F7305daa9-da17-4b9c-9938-8=
626bce4994e_1254x1254.png&quot;,&quot;isProcessing&quot;:false,&quot;align&=
quot;:null,&quot;offset&quot;:false}" alt=3D"" width=3D"550" height=3D"550"=
 src=3D"https://substackcdn.com/image/fetch/$s_!SBzM!,w_1100,c_limit,f_auto=
,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amaz=
onaws.com%2Fpublic%2Fimages%2F7305daa9-da17-4b9c-9938-8626bce4994e_1254x125=
4.png" style=3D"border: none !important;vertical-align: middle;display: blo=
ck;-ms-interpolation-mode: bicubic;height: auto;margin-bottom: 0;width: aut=
o !important;max-width: 100% !important;margin: 0 auto;"></a></td><td style=
=3D"text-align: center;"></td></tr></tbody></table></figure></div><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;">After your brain cells use these chemicals, they normally get reabsorb=
ed and recycled. Tesofensine blocks that reabsorption process. As a result,=
 all three chemicals stay in the brain longer and at higher levels. More se=
rotonin, more norepinephrine, more dopamine, all at once.</p><p style=3D"ma=
rgin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">T=
he technical term for this is a &#8220;triple monoamine reuptake inhibitor.=
&#8221; Don&#8217;t worry about memorizing the name &#8212; the important p=
art is what it puts tesofensine in the same family as:</p><ul style=3D"marg=
in-top: 0;padding: 0;"><li style=3D"margin: 8px 0 0 32px;mso-special-format=
: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom=
: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;"><s=
trong>SSRIs</strong><span> (Prozac, Zoloft, Lexapro) &#8594; block serotoni=
n only</span></p></li><li style=3D"margin: 8px 0 0 32px;mso-special-format:=
 bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom:=
 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;"><st=
rong>SNRIs</strong><span> (Effexor, Cymbalta) &#8594; block serotonin and n=
orepinephrine</span></p></li><li style=3D"margin: 8px 0 0 32px;mso-special-=
format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-=
bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: =
0;"><strong>NDRIs</strong><span> (Wellbutrin) &#8594; block norepinephrine =
and dopamine</span></p></li><li style=3D"margin: 8px 0 0 32px;mso-special-f=
ormat: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-b=
ottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0=
;"><strong>Sibutramine</strong><span> (Meridia, pulled off the market in 20=
10) &#8594; blocked serotonin and norepinephrine, used for weight loss</spa=
n></p></li><li style=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><=
p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizi=
ng: border-box;padding-left: 4px;font-size: 16px;margin: 0;"><strong>Tesofe=
nsine</strong><span> &#8594; blocks all three</span></p></li></ul><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;">If you&#8217;ve ever known someone on an antidepressant &#8212; or bee=
n on one yourself &#8212; that&#8217;s the closest comparison for how tesof=
ensine works in the brain.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,=
55,55);line-height: 26px;font-size: 16px;">The sibutramine comparison is wo=
rth knowing too. Sibutramine was a weight loss drug in the same general fam=
ily. It got pulled from the market worldwide in 2010 after a large trial (c=
alled 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.</p><p style=3D"margin=
: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><span=
>One more practical detail: </span><strong>tesofensine stays in your system=
 for a long time.</strong></p><ul style=3D"margin-top: 0;padding: 0;"><li s=
tyle=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=3D"color=
: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizing: border-box;p=
adding-left: 4px;font-size: 16px;margin: 0;">Half-life of tesofensine itsel=
f: about 9 days</p></li><li style=3D"margin: 8px 0 0 32px;mso-special-forma=
t: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-botto=
m: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;">H=
alf-life of its active byproduct (NS2360): about 16 days</p></li></ul><p st=
yle=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size:=
 16px;">&#8220;Half-life&#8221; means the time it takes for half the drug t=
o clear from your body. A 9-day half-life is very long. For comparison, mos=
t peptides have half-lives measured in hours, and even semaglutide (a long-=
acting GLP-1) is about 7 days.</p><p style=3D"margin: 0 0 20px 0;color: rgb=
(54,55,55);line-height: 26px;font-size: 16px;">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&#8217;t just &#8220;tr=
y it for a few days.&#8221; By the time you have a clear read on whether it=
&#8217;s working for you, you&#8217;re already deep into a multi-week commi=
tment.</p><div style=3D"font-size: 16px;line-height: 26px;"><hr style=3D"ma=
rgin: 32px 0;padding: 0;height: 1px;background: rgb(0,0,0,.1);border: none;=
"></div><h2 class=3D"header-anchor-post" style=3D"position: relative;font-f=
amily: 'SF Pro Display',-apple-system-headline,system-ui,-apple-system,Blin=
kMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color Em=
oji','Segoe UI Emoji','Segoe UI Symbol';font-weight: bold;-webkit-font-smoo=
thing: antialiased;-moz-osx-font-smoothing: antialiased;-webkit-appearance:=
 optimizelegibility;-moz-appearance: optimizelegibility;appearance: optimiz=
elegibility;margin: 1em 0 0.625em 0;color: rgb(54,55,55);line-height: 1.16e=
m;font-size: calc(1.625em * 1);">What The Trials Show For Side Effects</h2>=
<p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-=
size: 16px;">The casual summary you&#8217;ll see online is &#8220;well-tole=
rated, mostly dry mouth and nausea.&#8221; That&#8217;s not the full pictur=
e. Here&#8217;s what the actual trial data shows.</p><p style=3D"margin: 0 =
0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>H=
eart-related effects.</strong></p><p style=3D"margin: 0 0 20px 0;color: rgb=
(54,55,55);line-height: 26px;font-size: 16px;">Most people on tesofensine s=
ee 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 b=
lood pressure that needed treatment. These effects depend on dose &#8212; h=
igher dose, more impact.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55=
,55);line-height: 26px;font-size: 16px;">To put numbers in perspective: a r=
esting heart rate of 65 going up to 75 might not sound dramatic, but it&#82=
17;s measurable and it&#8217;s continuous. If you&#8217;re already on the h=
igher end for heart rate, or have any heart history, this matters.</p><p st=
yle=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size:=
 16px;"><strong>Sleep problems.</strong></p><p style=3D"margin: 0 0 20px 0;=
color: rgb(54,55,55);line-height: 26px;font-size: 16px;">Insomnia (trouble =
sleeping) was the second most common side effect, hitting 25-40% of trial p=
articipants. This isn&#8217;t &#8220;mild difficulty falling asleep.&#8221;=
 For a meaningful chunk of users, it&#8217;s bad enough to limit the dose o=
r cause them to quit.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55=
);line-height: 26px;font-size: 16px;">Why does it happen? Norepinephrine an=
d dopamine are alertness chemicals. When they&#8217;re elevated all the tim=
e, your brain doesn&#8217;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.</p><p style=3D"margin: 0 0=
 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>Mo=
od and mental health effects.</strong></p><p style=3D"margin: 0 0 20px 0;co=
lor: rgb(54,55,55);line-height: 26px;font-size: 16px;">This is the section =
that gets glossed over most often, and it&#8217;s the one most worth unders=
tanding.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height=
: 26px;font-size: 16px;">Across the trials, 12-18% of participants experien=
ced anxiety, mood changes, irritability, or depressive episodes. The TIPO-1=
 trial specifically showed about 6% of people on the 0.5mg and 1mg doses de=
veloped depressed mood, including one case of major depression on the highe=
st dose. The 1mg group also showed measurable increases in anger and hostil=
ity on standardized mood tests.</p><p style=3D"margin: 0 0 20px 0;color: rg=
b(54,55,55);line-height: 26px;font-size: 16px;">Worth pausing on that 12-18=
% number. That&#8217;s roughly one in seven trial participants. And these w=
ere screened populations &#8212; meaning the trials excluded people with pr=
ior depression, anxiety disorders, or other mental health history. For peop=
le who already have a psychiatric history, the rate is almost certainly hig=
her, but we don&#8217;t have great data on it because those people weren&#8=
217;t allowed in the trials.</p><p style=3D"margin: 0 0 20px 0;color: rgb(5=
4,55,55);line-height: 26px;font-size: 16px;">The mechanism is straightforwa=
rd. The same chemicals tesofensine elevates (especially serotonin and dopam=
ine) are the chemicals involved in mood regulation. For some people, having=
 them elevated helps mood. For others, the system gets dysregulated and moo=
d drops. There&#8217;s no reliable way to predict ahead of time which categ=
ory you&#8217;ll fall into.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54=
,55,55);line-height: 26px;font-size: 16px;"><strong>Other side effects.</st=
rong></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 2=
6px;font-size: 16px;">The more typical ones: dry mouth, nausea, dizziness, =
abdominal pain, constipation, headache. These usually improve over time and=
 aren&#8217;t dose-limiting for most people. The heart effects, sleep probl=
ems, and mood effects are the ones that tend not to improve and that cause =
people to quit.</p><div style=3D"font-size: 16px;line-height: 26px;"><hr st=
yle=3D"margin: 32px 0;padding: 0;height: 1px;background: rgb(0,0,0,.1);bord=
er: none;"></div><h2 class=3D"header-anchor-post" style=3D"position: relati=
ve;font-family: 'SF Pro Display',-apple-system-headline,system-ui,-apple-sy=
stem,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple=
 Color Emoji','Segoe UI Emoji','Segoe UI Symbol';font-weight: bold;-webkit-=
font-smoothing: antialiased;-moz-osx-font-smoothing: antialiased;-webkit-ap=
pearance: optimizelegibility;-moz-appearance: optimizelegibility;appearance=
: optimizelegibility;margin: 1em 0 0.625em 0;color: rgb(54,55,55);line-heig=
ht: 1.16em;font-size: calc(1.625em * 1);">Why Tesofensine Behaves Like An S=
SRI</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26=
px;font-size: 16px;">If you or someone you know has been on an SSRI (the mo=
st common type of antidepressant), some of this is going to sound familiar.=
 That&#8217;s not a coincidence &#8212; tesofensine shares several behavior=
s with that class of drugs. Worth knowing because the mental model from pep=
tides doesn&#8217;t really fit here.</p><p style=3D"margin: 0 0 20px 0;colo=
r: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>It takes weeks=
 to fully kick in.</strong></p><p style=3D"margin: 0 0 20px 0;color: rgb(54=
,55,55);line-height: 26px;font-size: 16px;">SSRIs don&#8217;t work right aw=
ay &#8212; they typically take 4-6 weeks to reach full effect. Tesofensine =
is similar, but for a different reason: the long half-life means levels kee=
p building up for about 6-7 weeks before they stabilize. Whatever you feel =
in the first few weeks isn&#8217;t the full picture yet.</p><p style=3D"mar=
gin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><s=
trong>The first few weeks can feel worse before they feel better.</strong><=
/p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;fo=
nt-size: 16px;">SSRIs have a well-known &#8220;activation phase&#8221; earl=
y in treatment &#8212; anxiety, agitation, sleep problems, sometimes worsen=
ing mood before things improve. Tesofensine shows a similar pattern. The ea=
rly weeks are when most of the side effects show up as the brain adjusts to=
 elevated chemicals.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55)=
;line-height: 26px;font-size: 16px;"><strong>Stopping is a slow process.</s=
trong></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: =
26px;font-size: 16px;">When you stop tesofensine, the levels don&#8217;t dr=
op instantly. They wash out over weeks. This is actually gentler than stopp=
ing an SSRI cold turkey, but it has a downside: if you notice mood changes =
in the weeks after stopping, it&#8217;s hard to tell whether they&#8217;re =
from coming off tesofensine, from your brain readjusting, or from something=
 else entirely.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line=
-height: 26px;font-size: 16px;"><strong>Drug interactions are a real issue.=
</strong></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-heigh=
t: 26px;font-size: 16px;">This is the one most people don&#8217;t realize u=
ntil it&#8217;s too late. Because tesofensine raises serotonin, combining i=
t with other drugs that also raise serotonin can cause something called &#8=
220;serotonin syndrome&#8221; &#8212; a dangerous condition that can be fat=
al in severe cases.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);=
line-height: 26px;font-size: 16px;">The list of things that don&#8217;t mix=
 safely with tesofensine includes:</p><ul style=3D"margin-top: 0;padding: 0=
;"><li style=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=
=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizing: bor=
der-box;padding-left: 4px;font-size: 16px;margin: 0;">Any SSRI (Prozac, Zol=
oft, Lexapro, etc.)</p></li><li style=3D"margin: 8px 0 0 32px;mso-special-f=
ormat: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-b=
ottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0=
;">Any SNRI (Effexor, Cymbalta)</p></li><li style=3D"margin: 8px 0 0 32px;m=
so-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 2=
6px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16=
px;margin: 0;">MAOIs (older antidepressants)</p></li><li style=3D"margin: 8=
px 0 0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);l=
ine-height: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;=
font-size: 16px;margin: 0;">Tricyclic antidepressants</p></li><li style=3D"=
margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54=
,55,55);line-height: 26px;margin-bottom: 0;box-sizing: border-box;padding-l=
eft: 4px;font-size: 16px;margin: 0;">Triptans (migraine medications like su=
matriptan/Imitrex)</p></li><li style=3D"margin: 8px 0 0 32px;mso-special-fo=
rmat: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bo=
ttom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;=
">Tramadol (pain medication)</p></li><li style=3D"margin: 8px 0 0 32px;mso-=
special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px=
;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;=
margin: 0;">Meperidine (Demerol)</p></li><li style=3D"margin: 8px 0 0 32px;=
mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: =
26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 1=
6px;margin: 0;">Lithium</p></li><li style=3D"margin: 8px 0 0 32px;mso-speci=
al-format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;marg=
in-bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margi=
n: 0;">MDMA or similar recreational substances</p></li><li style=3D"margin:=
 8px 0 0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55)=
;line-height: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4p=
x;font-size: 16px;margin: 0;">St. John&#8217;s Wort (sold as a natural anti=
depressant)</p></li></ul><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55=
);line-height: 26px;font-size: 16px;">And here&#8217;s the kicker: because =
tesofensine has a 9-day half-life, even after you stop taking it, this inte=
raction risk continues for weeks. If someone is currently on an antidepress=
ant, this isn&#8217;t a &#8220;talk to your doctor when you&#8217;re ready&=
#8221; situation &#8212; it&#8217;s a &#8220;this absolutely has to be sort=
ed out before going anywhere near tesofensine&#8221; situation.</p><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;">For people with no psychiatric medications and no mental health histor=
y, none of this is necessarily a dealbreaker. The point is just that this i=
s what the compound actually is, and the framing matters when deciding whet=
her and how to engage with it.</p><div style=3D"font-size: 16px;line-height=
: 26px;"><hr style=3D"margin: 32px 0;padding: 0;height: 1px;background: rgb=
(0,0,0,.1);border: none;"></div><h2 class=3D"header-anchor-post" style=3D"p=
osition: relative;font-family: 'SF Pro Display',-apple-system-headline,syst=
em-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sa=
ns-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';font-weight=
: bold;-webkit-font-smoothing: antialiased;-moz-osx-font-smoothing: antiali=
ased;-webkit-appearance: optimizelegibility;-moz-appearance: optimizelegibi=
lity;appearance: optimizelegibility;margin: 1em 0 0.625em 0;color: rgb(54,5=
5,55);line-height: 1.16em;font-size: calc(1.625em * 1);">The GLP-1 Washout =
Question</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-heigh=
t: 26px;font-size: 16px;">This is the use case driving most of the current =
interest in tesofensine. It&#8217;s worth its own section because the neuro=
chemistry here is more complicated than the surface framing suggests.</p><p=
 style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-si=
ze: 16px;"><span>The basic idea most people have: </span><em>&#8220;I came =
off semaglutide/tirzepatide, I don&#8217;t want to gain weight back, I&#821=
7;ll run tesofensine through my washout to keep appetite suppressed.&#8221;=
</em></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 2=
6px;font-size: 16px;">Sounds reasonable. Here&#8217;s what&#8217;s worth kn=
owing.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: =
26px;font-size: 16px;"><strong>GLP-1s aren&#8217;t just gut drugs.</strong>=
</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;f=
ont-size: 16px;">For a long time, the understanding of GLP-1s (semaglutide,=
 tirzepatide, etc.) was that they work in the gut &#8212; slowing digestion=
, increasing fullness, etc. That&#8217;s part of it. But research over the =
last few years has shown they also have significant effects in the brain. G=
LP-1 receptors are present in brain regions that control:</p><ul style=3D"m=
argin-top: 0;padding: 0;"><li style=3D"margin: 8px 0 0 32px;mso-special-for=
mat: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bot=
tom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;"=
>Reward and motivation (the dopamine system)</p></li><li style=3D"margin: 8=
px 0 0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);l=
ine-height: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;=
font-size: 16px;margin: 0;">Mood</p></li><li style=3D"margin: 8px 0 0 32px;=
mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: =
26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 1=
6px;margin: 0;">Cravings and food noise</p></li><li style=3D"margin: 8px 0 =
0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line-h=
eight: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-=
size: 16px;margin: 0;">Some addictive behavior patterns</p></li></ul><p sty=
le=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: =
16px;">This is part of why GLP-1s can dramatically reduce &#8220;food noise=
&#8221; &#8212; they&#8217;re not just making your stomach feel full, they&=
#8217;re changing how your brain processes reward signals.</p><p style=3D"m=
argin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">=
<strong>Coming off a GLP-1 doesn&#8217;t happen instantly.</strong></p><p s=
tyle=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size=
: 16px;">When you stop a GLP-1, the gut effects fade in days to weeks (depe=
nding on which one). But the brain effects don&#8217;t reset that quickly. =
Your dopamine system has been operating under altered conditions for months=
=2E It needs time to recalibrate.</p><=
p style=3D"margin: 0 0 20px 0;color: rg=
b(54,55,55);line-height: 26px;font-size: 16px;">During that recalibration w=
indow, some people experience:</p><ul style=3D"margin-top: 0;padding: 0;"><=
li style=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=3D"c=
olor: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizing: border-b=
ox;padding-left: 4px;font-size: 16px;margin: 0;">Lower motivation</p></li><=
li style=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=3D"c=
olor: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizing: border-b=
ox;padding-left: 4px;font-size: 16px;margin: 0;">Mild low mood or depressiv=
e feelings</p></li><li style=3D"margin: 8px 0 0 32px;mso-special-format: bu=
llet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom: 0;=
box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;">Anhedo=
nia (things that used to feel rewarding don&#8217;t feel as rewarding)</p><=
/li><li style=3D"margin: 8px 0 0 32px;mso-special-format: bullet;"><p style=
=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom: 0;box-sizing: bor=
der-box;padding-left: 4px;font-size: 16px;margin: 0;">Food noise coming bac=
k strong</p></li><li style=3D"margin: 8px 0 0 32px;mso-special-format: bull=
et;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom: 0;bo=
x-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;">Cravings=
 for things that had felt easy to skip during the cycle</p></li></ul><p sty=
le=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: =
16px;">None of this means a GLP-1 caused depression. It means the brain is =
finding a new baseline after months of altered signaling.</p><p style=3D"ma=
rgin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><=
strong>Where tesofensine complicates this.</strong></p><p style=3D"margin: =
0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">Now ima=
gine adding tesofensine &#8212; a drug that floods the brain with extra ser=
otonin, norepinephrine, and dopamine &#8212; into that recalibration window=
=2E A few specific things happen that=20=
are worth being aware of:</p><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;"><em>You can&#8217;t tell what&#8217;s causing what.</em><span> 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&#8217;ve lost t=
he ability to figure out what&#8217;s actually happening.</span></p><p styl=
e=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 1=
6px;"><em>You&#8217;re stacking two brain-chemistry interventions back to b=
ack.</em><span> Coming off a GLP-1 is a neurochemical event. Starting tesof=
ensine is a neurochemical event. Running them in close sequence means the b=
rain is processing both at once, without recovery time. The long-term data =
on what this looks like over multiple cycles doesn&#8217;t exist yet.</span=
></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;=
font-size: 16px;"><em>The washout doesn&#8217;t really happen.</em><span> T=
he whole point of a GLP-1 washout is to let your body return to baseline so=
 you can see what&#8217;s actually going on. Running a different appetite s=
uppressant through the window means you never see baseline. You&#8217;re ju=
st swapping one suppressing drug for another.</span></p><p style=3D"margin:=
 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">None o=
f this means tesofensine during washout is automatically a bad call. Some p=
rotocols do this and it works fine. The point is that the choice involves m=
ore variables than &#8220;oral pill, easy, fills the gap&#8221; &#8212; and=
 being aware of those variables is the input that lets you make the call wi=
th eyes open.</p><div style=3D"font-size: 16px;line-height: 26px;"><hr styl=
e=3D"margin: 32px 0;padding: 0;height: 1px;background: rgb(0,0,0,.1);border=
: none;"></div><h2 class=3D"header-anchor-post" style=3D"position: relative=
;font-family: 'SF Pro Display',-apple-system-headline,system-ui,-apple-syst=
em,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple C=
olor Emoji','Segoe UI Emoji','Segoe UI Symbol';font-weight: bold;-webkit-fo=
nt-smoothing: antialiased;-moz-osx-font-smoothing: antialiased;-webkit-appe=
arance: optimizelegibility;-moz-appearance: optimizelegibility;appearance: =
optimizelegibility;margin: 1em 0 0.625em 0;color: rgb(54,55,55);line-height=
: 1.16em;font-size: calc(1.625em * 1);">Personal Factors That Change The Pi=
cture</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: =
26px;font-size: 16px;">Because tesofensine works on brain chemistry, indivi=
dual factors matter more than they typically do for peptides. The following=
 categories are worth being aware of when thinking about whether tesofensin=
e is a reasonable choice for a given research situation.</p><p style=3D"mar=
gin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><s=
trong>History of depression.</strong></p><p style=3D"margin: 0 0 20px 0;col=
or: rgb(54,55,55);line-height: 26px;font-size: 16px;">The 12-18% mood-relat=
ed side effect rate in trials happened in people who had been screened for =
prior depression. For someone with a history of depression &#8212; especial=
ly major depressive episodes &#8212; the data simply doesn&#8217;t tell us =
what their response would be, because those people weren&#8217;t allowed in=
 the trials. The mechanism (chronic elevation of mood chemicals, then poten=
tial dysregulation) can go in different directions depending on the person.=
</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;f=
ont-size: 16px;"><strong>History of bipolar disorder or hypomania.</strong>=
</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;f=
ont-size: 16px;">Drugs in this class can sometimes trigger manic or hypoman=
ic episodes in people with bipolar spectrum conditions. SSRIs can do this t=
oo, and it&#8217;s a well-documented risk. Tesofensine&#8217;s long half-li=
fe means that if a manic episode does get triggered, the drug is still in t=
he system for weeks.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55)=
;line-height: 26px;font-size: 16px;"><strong>Anxiety disorders, panic disor=
der, or strong mood reactivity.</strong></p><p style=3D"margin: 0 0 20px 0;=
color: rgb(54,55,55);line-height: 26px;font-size: 16px;">Tesofensine&#8217;=
s strongest action is on norepinephrine &#8212; the alertness/stress chemic=
al. Elevated norepinephrine feels a bit like chronic low-grade stimulant ex=
posure. For someone with anxiety disorders or panic disorder, this can ampl=
ify existing symptoms rather than help.</p><p style=3D"margin: 0 0 20px 0;c=
olor: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>Currently o=
n antidepressant or related medication.</strong></p><p style=3D"margin: 0 0=
 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">This is th=
e drug interaction issue from the previous section. SSRIs, SNRIs, and the o=
ther serotonergic medications listed earlier can cause serotonin syndrome w=
hen combined with tesofensine. The 9-day half-life means the risk window ex=
tends well beyond the dosing period.</p><p style=3D"margin: 0 0 20px 0;colo=
r: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>Heart issues o=
r high blood pressure.</strong></p><p style=3D"margin: 0 0 20px 0;color: rg=
b(54,55,55);line-height: 26px;font-size: 16px;">The 7-10 bpm heart rate inc=
rease and 8% sustained hypertension rate are real and dose-dependent. Anyon=
e starting with existing cardiovascular concerns is starting from a less fa=
vorable baseline. The sibutramine market withdrawal is the most relevant hi=
storical precedent.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);=
line-height: 26px;font-size: 16px;"><strong>Active stimulant use (recreatio=
nal or prescription).</strong></p><p style=3D"margin: 0 0 20px 0;color: rgb=
(54,55,55);line-height: 26px;font-size: 16px;">Combining a triple monoamine=
 reuptake inhibitor with stimulants stacks both the heart effects and the m=
ental health effects.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55=
);line-height: 26px;font-size: 16px;"><strong>History of eating disorders.<=
/strong></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height=
: 26px;font-size: 16px;">Strong appetite suppressants in people with disord=
ered eating history can reactivate those patterns. This isn&#8217;t specifi=
c to tesofensine, but the strength of the appetite effect makes it more rel=
evant than for milder interventions.</p><p style=3D"margin: 0 0 20px 0;colo=
r: rgb(54,55,55);line-height: 26px;font-size: 16px;">The reason these facto=
rs matter more for tesofensine than for most peptides comes back to mechani=
sm. Peptide side effects tend to be physical (injection site reactions, nau=
sea, etc.) and resolve quickly. Brain-chemistry drugs can cause mood and he=
art 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 &#8212; and for people in any of the categorie=
s above, the right path is direct conversation with a qualified clinician r=
ather than self-directed protocol design.</p><div style=3D"font-size: 16px;=
line-height: 26px;"><hr style=3D"margin: 32px 0;padding: 0;height: 1px;back=
ground: rgb(0,0,0,.1);border: none;"></div><h2 class=3D"header-anchor-post"=
 style=3D"position: relative;font-family: 'SF Pro Display',-apple-system-he=
adline,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helveti=
ca,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';=
font-weight: bold;-webkit-font-smoothing: antialiased;-moz-osx-font-smoothi=
ng: antialiased;-webkit-appearance: optimizelegibility;-moz-appearance: opt=
imizelegibility;appearance: optimizelegibility;margin: 1em 0 0.625em 0;colo=
r: rgb(54,55,55);line-height: 1.16em;font-size: calc(1.625em * 1);">The Wei=
ght Loss Numbers (Because They&#8217;re Real)</h2><p style=3D"margin: 0 0 2=
0px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">The trial da=
ta on weight loss is genuinely strong. This isn&#8217;t a compound that doe=
sn&#8217;t work &#8212; that&#8217;s not the issue. The numbers are worth k=
nowing for context.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);=
line-height: 26px;font-size: 16px;"><strong>TIPO-1</strong><span> (Phase 2b=
, published in </span><em>The Lancet</em><span>, 2008). 203 obese patients,=
 24 weeks of treatment. Weight loss by dose:</span></p><ul style=3D"margin-=
top: 0;padding: 0;"><li style=3D"margin: 8px 0 0 32px;mso-special-format: b=
ullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;margin-bottom: 0=
;box-sizing: border-box;padding-left: 4px;font-size: 16px;margin: 0;">0.25m=
g/day: 6.7 kg average loss</p></li><li style=3D"margin: 8px 0 0 32px;mso-sp=
ecial-format: bullet;"><p style=3D"color: rgb(54,55,55);line-height: 26px;m=
argin-bottom: 0;box-sizing: border-box;padding-left: 4px;font-size: 16px;ma=
rgin: 0;">0.5mg/day: 11.3 kg average loss</p></li><li style=3D"margin: 8px =
0 0 32px;mso-special-format: bullet;"><p style=3D"color: rgb(54,55,55);line=
-height: 26px;margin-bottom: 0;box-sizing: border-box;padding-left: 4px;fon=
t-size: 16px;margin: 0;">1.0mg/day: 12.8 kg average loss</p></li></ul><p st=
yle=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size:=
 16px;">For comparison, sibutramine in similar trials produced about half o=
f those numbers.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);lin=
e-height: 26px;font-size: 16px;"><strong>TIPO-4</strong><span> (48-week ext=
ension). 140 patients who completed TIPO-1 came back after a 3-month washou=
t, then ran on 0.5mg with optional bump to 1.0mg. Average total weight loss=
 of 13-14 kg over 48 weeks of treatment.</span></p><p style=3D"margin: 0 0 =
20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>Pha=
se 3 Viking trial</strong><span> (Saniona, conducted in Mexico). Significan=
t weight loss at both tested doses. About 10% body weight loss over 24 week=
s on average, with more than half of participants losing over 10%.</span></=
p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;fon=
t-size: 16px;">These are competitive numbers &#8212; comparable to or close=
 to semaglutide in some metrics, though direct head-to-head comparisons are=
 limited.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-heigh=
t: 26px;font-size: 16px;">What the trials don&#8217;t tell us as clearly: h=
ow many people dropped out specifically because of mood-related side effect=
s, what happens to mood and cardiovascular markers over multi-year exposure=
, and how the compound performs in populations with psychiatric or cardiova=
scular history (since those populations get excluded). The full long-term p=
icture is still developing.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54=
,55,55);line-height: 26px;font-size: 16px;">So: the compound works for weig=
ht loss. The honest question isn&#8217;t whether it produces results. The h=
onest question is whether the mechanism class, the side effect profile, and=
 the timing relative to other things in your protocol make it the right cho=
ice for a given research situation.</p><div style=3D"font-size: 16px;line-h=
eight: 26px;"><hr style=3D"margin: 32px 0;padding: 0;height: 1px;background=
: rgb(0,0,0,.1);border: none;"></div><h2 class=3D"header-anchor-post" style=
=3D"position: relative;font-family: 'SF Pro Display',-apple-system-headline=
,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Ari=
al,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';font-w=
eight: bold;-webkit-font-smoothing: antialiased;-moz-osx-font-smoothing: an=
tialiased;-webkit-appearance: optimizelegibility;-moz-appearance: optimizel=
egibility;appearance: optimizelegibility;margin: 1em 0 0.625em 0;color: rgb=
(54,55,55);line-height: 1.16em;font-size: calc(1.625em * 1);">How To Think =
About This</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-hei=
ght: 26px;font-size: 16px;">Different situations call for different evaluat=
ions. Here&#8217;s how the considerations roughly break down.</p><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;"><strong>If you have no psychiatric history, no current medications tha=
t interact, and no heart concerns:</strong><span> the trial data supports a=
 reasonable evaluation. Baseline screening (PHQ-9 and GAD-7 for mood, ECG a=
nd blood pressure check) and regular monitoring during the protocol is the =
framework the literature suggests.</span></p><p style=3D"margin: 0 0 20px 0=
;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>If you&#8=
217;re coming off a GLP-1 and considering tesofensine as a bridge:</strong>=
<span> the overlap of GLP-1 brain effects washing out and tesofensine effec=
ts coming on is the specific consideration. Some protocols bridge through t=
his; others choose to let the washout run clean and use lower-impact approa=
ches (diet structure, fiber, training adjustments, etc.) during the off per=
iod. Knowing the neurochemistry overlap exists is what lets you make that c=
hoice on real information.</span></p><p style=3D"margin: 0 0 20px 0;color: =
rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>If you have a his=
tory of depression, anxiety, bipolar tendencies, or any mental health condi=
tion involving mood:</strong><span> this is the situation where the trial d=
ata has the biggest gap, since those populations were excluded. The mechani=
sm class is one that needs careful evaluation with a qualified clinician &#=
8212; not a community-driven decision.</span></p><p style=3D"margin: 0 0 20=
px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><strong>If yo=
u&#8217;re on an SSRI, SNRI, or any other serotonergic medication:</strong>=
<span> the drug interaction issue is the main constraint. This has to be so=
rted out properly before tesofensine is even a real option.</span></p><p st=
yle=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size:=
 16px;"><strong>If you&#8217;re choosing tesofensine just because it&#8217;=
s oral and not subQ:</strong><span> worth pausing on this one specifically.=
 The mechanism class &#8212; not the delivery method &#8212; is the more im=
portant variable. Choosing tesofensine because you don&#8217;t want to inje=
ct is choosing on the wrong factor. There are other compounds with simpler =
profiles if injection avoidance is the main goal.</span></p><div style=3D"f=
ont-size: 16px;line-height: 26px;"><hr style=3D"margin: 32px 0;padding: 0;h=
eight: 1px;background: rgb(0,0,0,.1);border: none;"></div><h2 class=3D"head=
er-anchor-post" style=3D"position: relative;font-family: 'SF Pro Display',-=
apple-system-headline,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI'=
,Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Se=
goe UI Symbol';font-weight: bold;-webkit-font-smoothing: antialiased;-moz-o=
sx-font-smoothing: antialiased;-webkit-appearance: optimizelegibility;-moz-=
appearance: optimizelegibility;appearance: optimizelegibility;margin: 1em 0=
 0.625em 0;color: rgb(54,55,55);line-height: 1.16em;font-size: calc(1.625em=
 * 1);">Things Worth Reading If You Want To Go Deeper</h2><p style=3D"margi=
n: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;"><a h=
ref=3D"https://substack.com/redirect/dfeb11c0-3f71-40c6-bf84-874b68f05af5?j=
=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs" style=
=3D"color: #ff6719;text-decoration: none;">Astrup et al. 2008 (The Lancet)<=
/a><span> &#8212; the TIPO-1 trial paper, foundational efficacy and side ef=
fect data.</span></p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);li=
ne-height: 26px;font-size: 16px;">Saniona Phase 3 Viking trial results &#82=
12; most recent efficacy picture.</p><p style=3D"margin: 0 0 20px 0;color: =
rgb(54,55,55);line-height: 26px;font-size: 16px;"><a href=3D"https://substa=
ck.com/redirect/dcee2e26-d882-4210-bb87-3d4a8f237015?j=3DeyJ1IjoiNGl3b2U2In=
0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs" style=3D"color: #ff6719;text=
-decoration: none;">Neuropsychopharmacology paper</a><span> on tesofensine&=
#8217;s &#945;1 adrenergic and D1 dopamine receptor mechanisms &#8212; for =
the underlying pharmacology.</span></p><p style=3D"margin: 0 0 20px 0;color=
: rgb(54,55,55);line-height: 26px;font-size: 16px;"><a href=3D"https://subs=
tack.com/redirect/c9f99319-0d9a-47f0-8fda-abcb36527730?j=3DeyJ1IjoiNGl3b2U2=
In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs" style=3D"color: #ff6719;te=
xt-decoration: none;">Neuropsychiatric adverse effects of centrally acting =
antiobesity drugs (PMC6493804)</a><span> &#8212; context on tesofensine&#82=
17;s mood signal within the broader class.</span></p><p style=3D"margin: 0 =
0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16px;">The sibut=
ramine SCOUT trial &#8212; for understanding why regulators are cautious ab=
out this drug class.</p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55)=
;line-height: 26px;font-size: 16px;">Growing literature on GLP-1 effects in=
 the brain, particularly on dopamine and reward circuitry &#8212; helps exp=
lain what&#8217;s happening during washouts.</p><div style=3D"font-size: 16=
px;line-height: 26px;"><hr style=3D"margin: 32px 0;padding: 0;height: 1px;b=
ackground: rgb(0,0,0,.1);border: none;"></div><h2 class=3D"header-anchor-po=
st" style=3D"position: relative;font-family: 'SF Pro Display',-apple-system=
-headline,system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helv=
etica,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbo=
l';font-weight: bold;-webkit-font-smoothing: antialiased;-moz-osx-font-smoo=
thing: antialiased;-webkit-appearance: optimizelegibility;-moz-appearance: =
optimizelegibility;appearance: optimizelegibility;margin: 1em 0 0.625em 0;c=
olor: rgb(54,55,55);line-height: 1.16em;font-size: calc(1.625em * 1);">Fina=
l Thoughts</h2><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-hei=
ght: 26px;font-size: 16px;">Tesofensine is an effective weight loss compoun=
d. The trial numbers prove that. It&#8217;s also a triple monoamine reuptak=
e inhibitor &#8212; a drug class much closer to antidepressants than to pep=
tides &#8212; with a 9-day half-life, a 12-18% rate of mood-related side ef=
fects in trial populations, and a significant list of drug interactions. Bo=
th of those things are true at the same time, and both are worth knowing ab=
out when deciding whether and how to engage with the compound.</p><p style=
=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-size: 16=
px;">The peptide-community mental model &#8212; &#8220;well-tolerated, mild=
 side effects, just titrate up slowly&#8221; &#8212; doesn&#8217;t fully ap=
ply here. The failure modes are different. The drug interactions are differ=
ent. The personal factors that affect tolerability are different. None of t=
his rules out tesofensine. It just means the way you think about it should =
match what the compound actually is, not just how it&#8217;s packaged.</p><=
p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-s=
ize: 16px;">The GLP-1 washout question is its own conversation. Some protoc=
ols 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&#8217;t to push one way or the oth=
er &#8212; it&#8217;s to surface the neurochemistry context so the choice g=
ets made with awareness of what&#8217;s actually happening underneath.</p><=
p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-s=
ize: 16px;">The compound exists. The trial data exists. The side effects ex=
ist. The drug interactions exist. The neurochemistry of GLP-1 washouts exis=
ts. The personal factors that change tolerability exist. Being aware of all=
 of it is the input that makes informed evaluation possible &#8212; and tha=
t&#8217;s the goal of putting this information together in one place.</p><p=
 style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;font-si=
ze: 16px;"><em>This is for research and educational purposes only. Tesofens=
ine is a research compound and is not approved for human consumption. Nothi=
ng in this post is medical advice or a recommendation for personal use. If =
the topic is of interest for any non-research reason &#8212; and particular=
ly if there&#8217;s any psychiatric or cardiovascular history involved &#82=
12; that&#8217;s a conversation for a qualified medical professional.</em><=
/p><p style=3D"margin: 0 0 20px 0;color: rgb(54,55,55);line-height: 26px;fo=
nt-size: 16px;">Drop questions below &#8212; happy to go deeper on the mech=
anism class, the GLP-1 washout neurochemistry, the trial data, or any other=
 angle.</p><div class=3D"subscribe-widget is-signed-up" data-component-name=
=3D"SubscribeWidget" style=3D"margin: 0 0 1em;direction: ltr;font-size: 16p=
x;line-height: 26px;margin-bottom: 0;"><div class=3D"pencraft pc-reset butt=
on-wrapper" style=3D"text-decoration: unset;list-style: none;font-size: 16p=
x;line-height: 26px;text-align: center;cursor: pointer;border-radius: 4px;"=
><a class=3D"button subscribe-btn primary" href=3D"https://substack.com/red=
irect/2/eyJlIjoiaHR0cHM6Ly9kZXJla3BydXNraS5zdWJzdGFjay5jb20vc3Vic2NyaWJlP3V=
0bV9zb3VyY2U9cG9zdCZ1dG1fY2FtcGFpZ249ZW1haWwtY2hlY2tvdXQmbmV4dD1odHRwcyUzQS=
UyRiUyRmRlcmVrcHJ1c2tpLnN1YnN0YWNrLmNvbSUyRnAlMkZ0ZXNvZmVuc2luZS13aGF0cy13b=
3J0aC1rbm93aW5nLWFib3V0JnI9NGl3b2U2JnRva2VuPWV5SjFjMlZ5WDJsa0lqb3lOek0yTWpJ=
ek9UZ3NJbWxoZENJNk1UYzNPRFV5TVRJeU55d2laWGh3SWpveE56Z3hNVEV6TWpJM0xDSnBjM01=
pT2lKd2RXSXRNek0yTlRNMk55SXNJbk4xWWlJNkltTm9aV05yYjNWMEluMC5CcEo3aGM2Q0dHTk=
FRdDloTFdhb0VlWEpfOFlhLUh5VmNGMGIwZkRKdmMwIiwicCI6MTk3MjQ1ODM1LCJzIjozMzY1M=
zY3LCJmIjp0cnVlLCJ1IjoyNzM2MjIzOTgsImlhdCI6MTc3ODUyMTIyNywiZXhwIjoyMDk0MDk3=
MjI3LCJpc3MiOiJwdWItMCIsInN1YiI6ImxpbmstcmVkaXJlY3QifQ.z3aGfjcu6S2H2aGp4dXv=
WmWiYXeJ4Ha1jV-kdyQfsmo?&utm_medium=3Demail&utm_source=3Dsubscribe-widget&u=
tm_content=3D197245835" style=3D"font-family: system-ui,-apple-system,Blink=
MacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color Emo=
ji','Segoe UI Emoji','Segoe UI Symbol';display: inline-block;box-sizing: bo=
rder-box;cursor: pointer;border: none;border-radius: 8px;font-size: 14px;li=
ne-height: 20px;font-weight: 600;text-align: center;opacity: 1;outline: non=
e;white-space: nowrap;text-decoration: none !important;margin: 0 auto;backg=
round-color: #FF6719;color: #ffffff !important;padding: 12px 20px;height: a=
uto;"><span style=3D"color: #ffffff;text-decoration: none;">Upgrade to paid=
</span></a></div></div></div></div><div class=3D"container-border" style=3D=
"margin: 32px 0 0;width: 100%;box-sizing: border-box;border-top: 1px solid =
#e6e6e6;font-size: 16px;line-height: 26px;"></div><div class=3D"post-cta ty=
pography markup" style=3D"--image-offset-margin: -120px;text-align: initial=
;word-break: break-word;margin-bottom: 32px;margin: 32px 0;font-size: 16px;=
line-height: 26px;"><p style=3D"color: rgb(54,55,55);margin: 0 auto 20px;te=
xt-align: center;width: 90%;line-height: 26px;font-size: 16px;margin-top: 0=
;"><span class=3D"pencraft pc-reset reset-IxiVJZ" translated=3D"" style=3D"=
list-style: none;color: unset;text-decoration: unset;margin: 0;">You're cur=
rently a free subscriber to <a href=3D"https://substack.com/redirect/7e184f=
5a-2979-406a-9d34-4e22105922f3?j=3DeyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0k=
rRXGMy3p768BWtuZifRB-Zs" style=3D"color: #ff6719;text-decoration: none;">Re=
search Radar</a>. For the full experience, <a href=3D"https://substack.com/=
redirect/2/eyJlIjoiaHR0cHM6Ly9kZXJla3BydXNraS5zdWJzdGFjay5jb20vc3Vic2NyaWJl=
P3V0bV9zb3VyY2U9cG9zdCZ1dG1fY2FtcGFpZ249ZW1haWwtY2hlY2tvdXQmbmV4dD1odHRwcyU=
zQSUyRiUyRmRlcmVrcHJ1c2tpLnN1YnN0YWNrLmNvbSUyRnAlMkZ0ZXNvZmVuc2luZS13aGF0cy=
13b3J0aC1rbm93aW5nLWFib3V0JnI9NGl3b2U2JnRva2VuPWV5SjFjMlZ5WDJsa0lqb3lOek0yT=
WpJek9UZ3NJbWxoZENJNk1UYzNPRFV5TVRJeU55d2laWGh3SWpveE56Z3hNVEV6TWpJM0xDSnBj=
M01pT2lKd2RXSXRNek0yTlRNMk55SXNJbk4xWWlJNkltTm9aV05yYjNWMEluMC5CcEo3aGM2Q0d=
HTkFRdDloTFdhb0VlWEpfOFlhLUh5VmNGMGIwZkRKdmMwIiwicCI6MTk3MjQ1ODM1LCJzIjozMz=
Y1MzY3LCJmIjp0cnVlLCJ1IjoyNzM2MjIzOTgsImlhdCI6MTc3ODUyMTIyNywiZXhwIjoyMDk0M=
Dk3MjI3LCJpc3MiOiJwdWItMCIsInN1YiI6ImxpbmstcmVkaXJlY3QifQ.z3aGfjcu6S2H2aGp4=
dXvWmWiYXeJ4Ha1jV-kdyQfsmo?&utm_source=3Dsubstack&utm_medium=3Demail&utm_co=
ntent=3Dpostcta" style=3D"color: #ff6719;text-decoration: none;">upgrade yo=
ur subscription.</a></span></p><p class=3D"cta-box" style=3D"color: rgb(54,=
55,55);margin: 0 auto 20px;width: 90%;line-height: 26px;font-size: 16px;mar=
gin-bottom: 0;text-align: center;margin-left: auto;margin-right: auto;"><a =
class=3D"button primary" role=3D"button" href=3D"https://substack.com/redir=
ect/2/eyJlIjoiaHR0cHM6Ly9kZXJla3BydXNraS5zdWJzdGFjay5jb20vc3Vic2NyaWJlP3V0b=
V9zb3VyY2U9cG9zdCZ1dG1fY2FtcGFpZ249ZW1haWwtY2hlY2tvdXQmbmV4dD1odHRwcyUzQSUy=
RiUyRmRlcmVrcHJ1c2tpLnN1YnN0YWNrLmNvbSUyRnAlMkZ0ZXNvZmVuc2luZS13aGF0cy13b3J=
0aC1rbm93aW5nLWFib3V0JnI9NGl3b2U2JnRva2VuPWV5SjFjMlZ5WDJsa0lqb3lOek0yTWpJek=
9UZ3NJbWxoZENJNk1UYzNPRFV5TVRJeU55d2laWGh3SWpveE56Z3hNVEV6TWpJM0xDSnBjM01pT=
2lKd2RXSXRNek0yTlRNMk55SXNJbk4xWWlJNkltTm9aV05yYjNWMEluMC5CcEo3aGM2Q0dHTkFR=
dDloTFdhb0VlWEpfOFlhLUh5VmNGMGIwZkRKdmMwIiwicCI6MTk3MjQ1ODM1LCJzIjozMzY1MzY=
3LCJmIjp0cnVlLCJ1IjoyNzM2MjIzOTgsImlhdCI6MTc3ODUyMTIyNywiZXhwIjoyMDk0MDk3Mj=
I3LCJpc3MiOiJwdWItMCIsInN1YiI6ImxpbmstcmVkaXJlY3QifQ.z3aGfjcu6S2H2aGp4dXvWm=
WiYXeJ4Ha1jV-kdyQfsmo?&utm_source=3Dsubstack&utm_medium=3Demail&utm_content=
=3Dpostcta" style=3D"font-family: system-ui,-apple-system,BlinkMacSystemFon=
t,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji','Segoe U=
I Emoji','Segoe UI Symbol';display: inline-block;box-sizing: border-box;cur=
sor: pointer;border: none;height: 40px;border-radius: 8px;font-size: 14px;l=
ine-height: 20px;font-weight: 600;text-align: center;padding: 10px 20px;mar=
gin: 0;opacity: 1;outline: none;white-space: nowrap;color: #ffffff !importa=
nt;text-decoration: none !important;background-color: #FF6719;">Upgrade to =
paid</a></p></div><table class=3D"email-ufi-2-bottom" role=3D"presentation"=
 width=3D"100%" border=3D"0" cellspacing=3D"0" cellpadding=3D"0" style=3D"b=
order-top: 1px solid rgb(0,0,0,.1);border-bottom: 1px solid rgb(0,0,0,.1);m=
in-width: 100%;"><tbody><tr height=3D"16"><td height=3D"16" style=3D"font-s=
ize:0px;line-height:0;">&nbsp;</td></tr><tr><td><table class=3D"email-ufi-2=
-row" role=3D"presentation" width=3D"100%" border=3D"0" cellspacing=3D"0" c=
ellpadding=3D"0" style=3D"border-bottom: 1px solid rgb(0,0,0,.1);"><tbody><=
tr><td width=3D"95%"><table class=3D"email-button-outline-wrapper-full-widt=
h" role=3D"presentation" width=3D"auto" border=3D"0" cellspacing=3D"0" cell=
padding=3D"0" style=3D"width: 95%;margin: 0 auto;"><tbody><tr><td align=3D"=
center"><a class=3D"email-button-outline full-width" href=3D"https://substa=
ck.com/app-link/post?publication_id=3D3365367&post_id=3D197245835&utm_sourc=
e=3Dsubstack&utm_medium=3Demail&utm_content=3Dshare&utm_campaign=3Demail-sh=
are&action=3Dshare&triggerShare=3Dtrue&isFreemail=3Dtrue&r=3D4iwoe6&token=
=3DeyJ1c2VyX2lkIjoyNzM2MjIzOTgsInBvc3RfaWQiOjE5NzI0NTgzNSwiaWF0IjoxNzc4NTIx=
MjI3LCJleHAiOjE3ODExMTMyMjcsImlzcyI6InB1Yi0zMzY1MzY3Iiwic3ViIjoicG9zdC1yZWF=
jdGlvbiJ9.6MUoHdXDtDGIH6iQEdSw_sEsCqOKpzDhIZKkD4HoUWI" style=3D"font-family=
: system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Ar=
ial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';displ=
ay: inline-block;font-weight: 500;border: 1px solid rgb(0,0,0,.1);border-ra=
dius: 9999px;text-transform: uppercase;font-size: 12px;line-height: 12px;pa=
dding: 9px 14px;text-decoration: none;color: rgb(119,119,119);width: 100%;p=
adding-left: 0;padding-right: 0;"><img class=3D"icon" src=3D"https://substa=
ckcdn.com/image/fetch/$s_!rmYa!,w_36,c_scale,f_png,q_auto:good,fl_progressi=
ve:steep/https%3A%2F%2Fsubstack.com%2Ficon%2FLucideShare%3Fv%3D4%26height%3=
D36%26fill%3Dnone%26stroke%3D%2523808080%26strokeWidth%3D2" width=3D"18" he=
ight=3D"18" style=3D"margin-right: 8px;min-width: 18px;min-height: 18px;bor=
der: none;vertical-align: middle;max-width: 18px" alt=3D""><span class=3D"e=
mail-button-text" style=3D"vertical-align: middle;">Share</span></a></td></=
tr></tbody></table></td></tr><tr height=3D"16"><td height=3D"16" style=3D"f=
ont-size:0px;line-height:0;">&nbsp;</td></tr></tbody></table></td></tr><tr =
height=3D"16"><td height=3D"16" style=3D"font-size:0px;line-height:0;">&nbs=
p;</td></tr><tr><td><table role=3D"presentation" width=3D"100%" border=3D"0=
" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr><td><table role=3D"present=
ation" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpadding=3D"0" styl=
e=3D"margin:0 auto;"><tbody><tr><td style=3D"vertical-align:middle;"><table=
 role=3D"presentation" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpa=
dding=3D"0"><tbody><tr><td align=3D"center"><a class=3D"email-button-outlin=
e" href=3D"https://substack.com/app-link/post?publication_id=3D3365367&post=
_id=3D197245835&utm_source=3Dsubstack&isFreemail=3Dtrue&submitLike=3Dtrue&t=
oken=3DeyJ1c2VyX2lkIjoyNzM2MjIzOTgsInBvc3RfaWQiOjE5NzI0NTgzNSwicmVhY3Rpb24i=
OiLinaQiLCJpYXQiOjE3Nzg1MjEyMjcsImV4cCI6MTc4MTExMzIyNywiaXNzIjoicHViLTMzNjU=
zNjciLCJzdWIiOiJyZWFjdGlvbiJ9.KF0LQKgyHH5jC1YUPSHCjU6ypop_xOPAvFj40RwmYx4&u=
tm_medium=3Demail&utm_campaign=3Demail-reaction&r=3D4iwoe6" style=3D"font-f=
amily: system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helveti=
ca,Arial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';=
display: inline-block;font-weight: 500;border: 1px solid rgb(0,0,0,.1);bord=
er-radius: 9999px;text-transform: uppercase;font-size: 12px;line-height: 12=
px;padding: 9px 14px;text-decoration: none;color: rgb(119,119,119);"><img c=
lass=3D"icon" src=3D"https://substackcdn.com/image/fetch/$s_!PeVs!,w_36,c_s=
cale,f_png,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack.com%2Fic=
on%2FLucideHeart%3Fv%3D4%26height%3D36%26fill%3Dnone%26stroke%3D%2523808080=
%26strokeWidth%3D2" width=3D"18" height=3D"18" style=3D"margin-right: 8px;m=
in-width: 18px;min-height: 18px;border: none;vertical-align: middle;max-wid=
th: 18px" alt=3D""><span class=3D"email-button-text" style=3D"vertical-alig=
n: middle;">Like</span></a></td></tr></tbody></table></td><td width=3D"8" s=
tyle=3D"min-width:8px;"></td><td style=3D"vertical-align:middle;"><table ro=
le=3D"presentation" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpaddi=
ng=3D"0"><tbody><tr><td align=3D"center"><a class=3D"email-button-outline" =
href=3D"https://substack.com/app-link/post?publication_id=3D3365367&post_id=
=3D197245835&utm_source=3Dsubstack&utm_medium=3Demail&isFreemail=3Dtrue&com=
ments=3Dtrue&token=3DeyJ1c2VyX2lkIjoyNzM2MjIzOTgsInBvc3RfaWQiOjE5NzI0NTgzNS=
wiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjE3ODExMTMyMjcsImlzcyI6InB1Yi0zMzY1MzY3Iiwic=
3ViIjoicG9zdC1yZWFjdGlvbiJ9.6MUoHdXDtDGIH6iQEdSw_sEsCqOKpzDhIZKkD4HoUWI&r=
=3D4iwoe6&utm_campaign=3Demail-half-magic-comments&action=3Dpost-comment&ut=
m_source=3Dsubstack&utm_medium=3Demail" style=3D"font-family: system-ui,-ap=
ple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,=
'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';display: inline-bloc=
k;font-weight: 500;border: 1px solid rgb(0,0,0,.1);border-radius: 9999px;te=
xt-transform: uppercase;font-size: 12px;line-height: 12px;padding: 9px 14px=
;text-decoration: none;color: rgb(119,119,119);"><img class=3D"icon" src=3D=
"https://substackcdn.com/image/fetch/$s_!x1tS!,w_36,c_scale,f_png,q_auto:go=
od,fl_progressive:steep/https%3A%2F%2Fsubstack.com%2Ficon%2FLucideComments%=
3Fv%3D4%26height%3D36%26fill%3Dnone%26stroke%3D%2523808080%26strokeWidth%3D=
2" width=3D"18" height=3D"18" style=3D"margin-right: 8px;min-width: 18px;mi=
n-height: 18px;border: none;vertical-align: middle;max-width: 18px" alt=3D"=
"><span class=3D"email-button-text" style=3D"vertical-align: middle;">Comme=
nt</span></a></td></tr></tbody></table></td><td width=3D"8" style=3D"min-wi=
dth:8px;"></td><td style=3D"vertical-align:middle;"><table role=3D"presenta=
tion" width=3D"auto" border=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbod=
y><tr><td align=3D"center"><a class=3D"email-button-outline" href=3D"https:=
//substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9vcGVuLnN1YnN0YWNrLmNvbS9wdWIvZ=
GVyZWtwcnVza2kvcC90ZXNvZmVuc2luZS13aGF0cy13b3J0aC1rbm93aW5nLWFib3V0P3V0bV9z=
b3VyY2U9c3Vic3RhY2smdXRtX21lZGl1bT1lbWFpbCZ1dG1fY2FtcGFpZ249ZW1haWwtcmVzdGF=
jay1jb21tZW50JmFjdGlvbj1yZXN0YWNrLWNvbW1lbnQmcj00aXdvZTYmdG9rZW49ZXlKMWMyVn=
lYMmxrSWpveU56TTJNakl6T1Rnc0luQnZjM1JmYVdRaU9qRTVOekkwTlRnek5Td2lhV0YwSWpve=
E56YzROVEl4TWpJM0xDSmxlSEFpT2pFM09ERXhNVE15TWpjc0ltbHpjeUk2SW5CMVlpMHpNelkx=
TXpZM0lpd2ljM1ZpSWpvaWNHOXpkQzF5WldGamRHbHZiaUo5LjZNVW9IZFhEdERHSUg2aVFFZFN=
3X3NFc0NxT0twekRoSVpLa0Q0SG9VV0kiLCJwIjoxOTcyNDU4MzUsInMiOjMzNjUzNjcsImYiOn=
RydWUsInUiOjI3MzYyMjM5OCwiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjIwOTQwOTcyMjcsImlzc=
yI6InB1Yi0wIiwic3ViIjoibGluay1yZWRpcmVjdCJ9.I0tztTF-b482fwr2Zuci1cVcQSyNVKs=
h-glCeeaEDak?&utm_source=3Dsubstack&utm_medium=3Demail" style=3D"font-famil=
y: system-ui,-apple-system,BlinkMacSystemFont,'Segoe UI',Roboto,Helvetica,A=
rial,sans-serif,'Apple Color Emoji','Segoe UI Emoji','Segoe UI Symbol';disp=
lay: inline-block;font-weight: 500;border: 1px solid rgb(0,0,0,.1);border-r=
adius: 9999px;text-transform: uppercase;font-size: 12px;line-height: 12px;p=
adding: 9px 14px;text-decoration: none;color: rgb(119,119,119);"><img class=
=3D"icon" src=3D"https://substackcdn.com/image/fetch/$s_!ubXF!,w_36,c_scale=
,f_png,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack.com%2Ficon%2=
Fnotes__NoteRestackIcon%3Fv%3D4%26height%3D36%26fill%3Dnone%26stroke%3D%252=
3808080%26strokeWidth%3D2%26strokeLinecap%3Dround%26strokeLinejoin%3Dround"=
 width=3D"18" height=3D"18" alt=3D"" style=3D"margin-right: 8px;min-width: =
18px;min-height: 18px;max-width: 550px;border: none !important;vertical-ali=
gn: middle;"><span class=3D"email-button-text" style=3D"vertical-align: mid=
dle;">Restack</span></a></td></tr></tbody></table></td></tr></tbody></table=
></td><td align=3D"right"><table role=3D"presentation" width=3D"auto" borde=
r=3D"0" cellspacing=3D"0" cellpadding=3D"0"><tbody><tr></tr></tbody></table=
></td></tr></tbody></table></td></tr><tr height=3D"16"><td height=3D"16" st=
yle=3D"font-size:0px;line-height:0;">&nbsp;</td></tr></tbody></table><div c=
lass=3D"footer footer-ZM59BM" style=3D"color: rgb(119,119,119);text-align: =
center;font-size: 16px;line-height: 26px;padding: 24px0;"><div style=3D"fon=
t-size: 16px;line-height: 26px;padding-bottom: 24px"><p class=3D"pencraft p=
c-reset color-secondary-ls1g8s size-12-mmZ61m reset-IxiVJZ small meta-B2bqa=
5" style=3D"list-style: none;font-family: system-ui,-apple-system,BlinkMacS=
ystemFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji',=
'Segoe UI Emoji','Segoe UI Symbol';padding-bottom: 0;font-size: 12px;line-h=
eight: 16px;margin: 0;color: rgb(119,119,119);text-decoration: unset;">&#16=
9; 2026 <span>Derek Pruski</span><br>548 Market Street PMB 72296, San Franc=
isco, CA 94104 <br><a href=3D"https://substack.com/redirect/2/eyJlIjoiaHR0c=
HM6Ly9kZXJla3BydXNraS5zdWJzdGFjay5jb20vYWN0aW9uL2Rpc2FibGVfZW1haWw_dG9rZW49=
ZXlKMWMyVnlYMmxrSWpveU56TTJNakl6T1Rnc0luQnZjM1JmYVdRaU9qRTVOekkwTlRnek5Td2l=
hV0YwSWpveE56YzROVEl4TWpJM0xDSmxlSEFpT2pFNE1UQXdOVGN5TWpjc0ltbHpjeUk2SW5CMV=
lpMHpNelkxTXpZM0lpd2ljM1ZpSWpvaVpHbHpZV0pzWlY5bGJXRnBiQ0o5LmhKSkVhWTdqVm5ae=
WZzdXkxZHV6eEZnUFg3bGZwdEpRQ1BYMzN4SWV2MzQiLCJwIjoxOTcyNDU4MzUsInMiOjMzNjUz=
NjcsImYiOnRydWUsInUiOjI3MzYyMjM5OCwiaWF0IjoxNzc4NTIxMjI3LCJleHAiOjIwOTQwOTc=
yMjcsImlzcyI6InB1Yi0wIiwic3ViIjoibGluay1yZWRpcmVjdCJ9.MdzoSFNyf-Bpnf6sgHeaj=
lMl1XAXxmLtDHy2q9PGwug?" style=3D"color: #ff6719;text-decoration: none;"><s=
pan style=3D"color: rgb(119,119,119);text-decoration: underline;">Unsubscri=
be</span></a></p></div><p class=3D"footerSection-EHR0jG small powered-by-su=
bstack" style=3D"padding: 0 24px;font-size: 12px;line-height: 20px;margin: =
0;color: rgb(119,119,119);font-family: system-ui,-apple-system,BlinkMacSyst=
emFont,'Segoe UI',Roboto,Helvetica,Arial,sans-serif,'Apple Color Emoji','Se=
goe UI Emoji','Segoe UI Symbol';padding-bottom: 0;margin-top: 0;"><a href=
=3D"https://substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9zdWJzdGFjay5jb20vc2l=
nbnVwP3V0bV9zb3VyY2U9c3Vic3RhY2smdXRtX21lZGl1bT1lbWFpbCZ1dG1fY29udGVudD1mb2=
90ZXImdXRtX2NhbXBhaWduPWF1dG9maWxsZWQtZm9vdGVyJmZyZWVTaWdudXBFbWFpbD10anBod=
WhzQGdtYWlsLmNvbSZyPTRpd29lNiIsInAiOjE5NzI0NTgzNSwicyI6MzM2NTM2NywiZiI6dHJ1=
ZSwidSI6MjczNjIyMzk4LCJpYXQiOjE3Nzg1MjEyMjcsImV4cCI6MjA5NDA5NzIyNywiaXNzIjo=
icHViLTAiLCJzdWIiOiJsaW5rLXJlZGlyZWN0In0.G75MfdomkynH5ZYyAAwG9goT7u_nCsDCQP=
FE6AZtUDs?" style=3D"color: #ff6719;text-decoration: none;display: inline-b=
lock;margin: 0 4px;"><img src=3D"https://substackcdn.com/image/fetch/$s_!Lk=
rL!,w_270,c_limit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsub=
stack.com%2Fimg%2Femail%2Fpublish-button%402x.png" srcset=3D"https://substa=
ckcdn.com/image/fetch/$s_!wgfj!,w_135,c_limit,f_auto,q_auto:good,fl_progres=
sive:steep/https%3A%2F%2Fsubstack.com%2Fimg%2Femail%2Fpublish-button.png, h=
ttps://substackcdn.com/image/fetch/$s_!LkrL!,w_270,c_limit,f_auto,q_auto:go=
od,fl_progressive:steep/https%3A%2F%2Fsubstack.com%2Fimg%2Femail%2Fpublish-=
button%402x.png 2x, https://substackcdn.com/image/fetch/$s_!KjtY!,w_405,c_l=
imit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack.com%2Fi=
mg%2Femail%2Fpublish-button%403x.png 3x" width=3D"135" alt=3D"Start writing=
" height=3D"40" style=3D"max-width: 550px;border: none !important;vertical-=
align: middle;"></a></p></div></div></td><td></td></tr></tbody></table><img=
 src=3D"https://eotrx.substackcdn.com/o/d9b881a4c7d978ba/p.gif?token=3DeyJt=
IjoiPDIwMjYwNTExMTc0MDE5LjMuNWMxYmMzZDhlNzA5MzY2OEBtZy1kMS5zdWJzdGFjay5jb20=
-IiwidSI6MjczNjIyMzk4LCJyIjoidGpwaHVoc0BnbWFpbC5jb20iLCJkIjoibWctZDEuc3Vic3=
RhY2suY29tIiwicCI6MTk3MjQ1ODM1LCJ0IjoibmV3c2xldHRlciIsImEiOiJldmVyeW9uZSIsI=
nMiOjMzNjUzNjcsImMiOiJwb3N0IiwiZiI6dHJ1ZSwicG9zaXRpb24iOiJib3R0b20iLCJpYXQi=
OjE3Nzg1MjEyMjcsImV4cCI6MTc4MTExMzIyNywiaXNzIjoicHViLTAiLCJzdWIiOiJlbyJ9.bm=
rRutt2uKnHZ9oAAgAOWC63MMcblrPtffZzwtyCGko" alt=3D"" width=3D"1" height=3D"1=
" border=3D"0" style=3D"height:1px !important;width:1px !important;border-w=
idth:0 !important;margin-top:0 !important;margin-bottom:0 !important;margin=
-right:0 !important;margin-left:0 !important;padding-top:0 !important;paddi=
ng-bottom:0 !important;padding-right:0 !important;padding-left:0 !important=
;"/><img width=3D"1" height=3D"1" alt=3D"" src=3D"https://email.mg-d1.subst=
ack.com/o/eJxM0EuO6yAQheHVhNm1eJjCHrAWi0fF4cYGC4q0vPuWkwx6ekr69amCI1xLPe1RG=
rFo1ez5FIChFcZMWgopDcPdpW1ZMWN1hHFx9Oc6Gs4eVoE0c3T6HkYBCCog3kEHgDGCkFKzZCWX=
wLUQwoxczIMadBA-qDih4bMCmG4j39d_UQyt-0YuPIdQdpbacq_4JliqHdklXVyPCXNAiy-sZ8n=
fOUUrZiNHPSn9Weg80Gb8aRsSYWVH90so-95zonPB7PyG8RvufkvBUSr5CikFWoFh1dL_49Ef7T=
by9WK8Wa37WHaXso1Y8XnU3p6J0eePvWG9EtIokFLNE3tZ-RsAAP__NbJ3gQ"></body></html=
>
--048ba600e0d28f4072f72c169bbbcce27b88fc717e75d4ea4ee65db36374--