smbleh
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Tesofensine was an experimental weight loss compound that was being investigated before the takeover of GLP-1s and mogged every previous compound to slums but was discontinued due to adverse effects
It's also oral so perfect for you tards too afraid to pick up the needle
MOA
Oral weight loss drug works via inhibiting neuronal reuptake of dopamine, noradrenaline, and serotoninAlso seems to have upregulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of the dopamine transporter (https://pubmed.ncbi.nlm.nih.gov/24239329/)
Oral weight loss drug works via inhibiting neuronal reuptake of dopamine, noradrenaline, and serotoninAlso seems to have upregulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of the dopamine transporter (https://pubmed.ncbi.nlm.nih.gov/24239329/)
Clinical Data
After 24 weeks, tesofensine 0.25 and 0.5 mg/day had no significant effect on systolic and diastolic blood pressures compared with placebo, but heart rate increased by 7.4/minute
The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea, and insomnia (anecdotally my sleep was completely destroyed using this tbh , with its stim like effects + 9 day half life I could not stay asleep but lemborexant and clonidine did fix it for me)
After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60).
Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84)
So it seems there's not much benefit in pushing above 0.5mg in terms of appetite suppression with disproportionately more sides
Though tesofensine appetite suppression effects seem to attenuate after 24 weeks though this is unclear whether it is due to actual tachyphylaxis or due to the reduced weight state of the participants but it seems you can just cycle it to prevent this
https://pubmed.ncbi.nlm.nih.gov/21720440/ TLDR - The appetite suppression begun to fall gradually after week 12 then after the drug was withdrawn and deployed again after some time participants started reporting appetite suppression and satiety again
Its comparable to something like semaglutide that had reductions reach roughly 15% to 17.3% at 68 weeks (2.8x the time frame)
With the biggest difference being those taking GLP-1s often get a huge weight rebound putting much of it back on after coming off however tesofensine may have far less weight rebound
It was found in a rat study that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss and it's now being looked into again after years due to this with the study about this being as recent as 2024
(https://pubmed.ncbi.nlm.nih.gov/38656972/) (https://pubmed.ncbi.nlm.nih.gov/20385125/) - Sustained weight loss in rats observed again
Though I couldn't find any follow up data regarding if the human participants kept the weight off after though
There is also some rat data suggesting that tesofensine likely also increases energy expenditure and its weight loss may be a combined synergistic effect of appetite suppression and increased energy expenditure (https://pubmed.ncbi.nlm.nih.gov/20385125/)
After 24 weeks, tesofensine 0.25 and 0.5 mg/day had no significant effect on systolic and diastolic blood pressures compared with placebo, but heart rate increased by 7.4/minute
The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea, and insomnia (anecdotally my sleep was completely destroyed using this tbh , with its stim like effects + 9 day half life I could not stay asleep but lemborexant and clonidine did fix it for me)
After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60).
Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84)
So it seems there's not much benefit in pushing above 0.5mg in terms of appetite suppression with disproportionately more sides
Though tesofensine appetite suppression effects seem to attenuate after 24 weeks though this is unclear whether it is due to actual tachyphylaxis or due to the reduced weight state of the participants but it seems you can just cycle it to prevent this
https://pubmed.ncbi.nlm.nih.gov/21720440/ TLDR - The appetite suppression begun to fall gradually after week 12 then after the drug was withdrawn and deployed again after some time participants started reporting appetite suppression and satiety again
Its comparable to something like semaglutide that had reductions reach roughly 15% to 17.3% at 68 weeks (2.8x the time frame)
With the biggest difference being those taking GLP-1s often get a huge weight rebound putting much of it back on after coming off however tesofensine may have far less weight rebound
It was found in a rat study that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss and it's now being looked into again after years due to this with the study about this being as recent as 2024
(https://pubmed.ncbi.nlm.nih.gov/38656972/) (https://pubmed.ncbi.nlm.nih.gov/20385125/) - Sustained weight loss in rats observed again
Though I couldn't find any follow up data regarding if the human participants kept the weight off after though
There is also some rat data suggesting that tesofensine likely also increases energy expenditure and its weight loss may be a combined synergistic effect of appetite suppression and increased energy expenditure (https://pubmed.ncbi.nlm.nih.gov/20385125/)
Pharmokinetics
Tesofensine has a very fucking long half life of 9 days and its active metabolite , M1 , has an even longer half life of 16 days , so it reaches a steady state concentration after about 4 - 6 weeks of daily dosing so I think it is appropriate to frontload this and have
Also strong CYP3A4 inhibitors can reduce clearance and prolong half life
Frontloading dose
To frontload straight to 0.5mg steady state concentration theoretically you should use a 7mg dose then 0.5mg going forward , dosing everyday at 0.5mg
Makes you alot more prone to sides ofc , and you most likely won't sleep for the foreseeable future but this did not really touch my blood pressure or HR anecdotally and doesn't seem to significantly in the data
+ it's chemical structure is almost identical to cocaine so you just know this shit mogs
Cocaine Chemical Structure
Tesofensine Chemical Structure
Tesofensine has a very fucking long half life of 9 days and its active metabolite , M1 , has an even longer half life of 16 days , so it reaches a steady state concentration after about 4 - 6 weeks of daily dosing so I think it is appropriate to frontload this and have
Also strong CYP3A4 inhibitors can reduce clearance and prolong half life
Frontloading dose
To frontload straight to 0.5mg steady state concentration theoretically you should use a 7mg dose then 0.5mg going forward , dosing everyday at 0.5mg
Makes you alot more prone to sides ofc , and you most likely won't sleep for the foreseeable future but this did not really touch my blood pressure or HR anecdotally and doesn't seem to significantly in the data
+ it's chemical structure is almost identical to cocaine so you just know this shit mogs
Cocaine Chemical Structure
Tesofensine Chemical Structure
Practical use case
I would personally use to cycle in conjunction with GLP-1s to nuke appetite year-round as GLP-1s also have attenuating appetite suppression when ran for too long but the GLP-1 receptors to resensitise after some time off
12 weeks on GLP-1s (+ Cagri if you want)
8 weeks off During these 8 weeks off using tesofensine for appetite , then 12 weeks back on GLP-1s , rinse and repeat
In terms of stim like effect it is atomoxetine tier so not amazing according to the data , but anecdotally It was solid for me and I for sure felt the mental effects even without reaching steady state concentration
Of course anecdotes generally don't hold up too much merit but I have read a lot of anecdotes about it and have seen many people report complete appetite death far more than GLP-1s even and I believe this could be due to it's MOA being mediated via pathways in the brain , any want for food due to boredom and such are just completely eliminated and can have a positive effect on your entire relationship with food if you struggle with this and some people having very extreme appetite suppression that they can't even eat anything
I can't give a reliable anecdote here as I never reached serum state concentration as I was already having nuked appetite by using d-meth basically everyday but this will have more 24 hour coverage whereas the appetite rebound from stims can be fucking brutal and cause some insane binges
I would personally use to cycle in conjunction with GLP-1s to nuke appetite year-round as GLP-1s also have attenuating appetite suppression when ran for too long but the GLP-1 receptors to resensitise after some time off
12 weeks on GLP-1s (+ Cagri if you want)
8 weeks off During these 8 weeks off using tesofensine for appetite , then 12 weeks back on GLP-1s , rinse and repeat
In terms of stim like effect it is atomoxetine tier so not amazing according to the data , but anecdotally It was solid for me and I for sure felt the mental effects even without reaching steady state concentration
Of course anecdotes generally don't hold up too much merit but I have read a lot of anecdotes about it and have seen many people report complete appetite death far more than GLP-1s even and I believe this could be due to it's MOA being mediated via pathways in the brain , any want for food due to boredom and such are just completely eliminated and can have a positive effect on your entire relationship with food if you struggle with this and some people having very extreme appetite suppression that they can't even eat anything
I can't give a reliable anecdote here as I never reached serum state concentration as I was already having nuked appetite by using d-meth basically everyday but this will have more 24 hour coverage whereas the appetite rebound from stims can be fucking brutal and cause some insane binges
Interaction with other compounds
Do not combined with SSRIS , MAOI or other SNRI as they both interact with serotonin and carries a theoretical risk of serotonin toxicity (though this shit is basically meme tier)
https://www.ovid.com/jnls/psychopha...s-and-clinical?redirectionsource=fulltextview
1 fatal case of serotonin toxicity reported in 1010 people combining drugs far more potent on 5-HT receptors , you will almost certainly be fine regardless but just an interaction to be aware of
Combining with stims (amphetamines/d-meth)
Again you will be fine here but you will probably have some issues with sleep and complete appetite wipeout and should monitor BP and HR
Do not combined with SSRIS , MAOI or other SNRI as they both interact with serotonin and carries a theoretical risk of serotonin toxicity (though this shit is basically meme tier)
https://www.ovid.com/jnls/psychopha...s-and-clinical?redirectionsource=fulltextview
1 fatal case of serotonin toxicity reported in 1010 people combining drugs far more potent on 5-HT receptors , you will almost certainly be fine regardless but just an interaction to be aware of
Combining with stims (amphetamines/d-meth)
Again you will be fine here but you will probably have some issues with sleep and complete appetite wipeout and should monitor BP and HR
