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Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor which was originally studied for its effect on Parkinson’s and Alzheimer’s. Unfortunately, its exploration for these indications were limited because the research subjects started losing too much weight. Since then, tesofensine has been studied as a way to treat obesity via its ability to reduce appetite. This molecular compound indirectly stimulates the cholinergic system and showed to be more successful than other weight loss agents. Tesofensine (TE) increases transmission of 3 monoaminergic neurotransmitters in the brain. These neurotransmitters are serotonin, norepinephrine, and dopamine which help regulate energy balance and are linked to obesity and depression. On average, its 6-month weight loss results from a phase 2b clinical trial resulted in a weight loss of around 25 pounds. TE research has shown a pronounced effect on appetite sensations and a slight effect on energy expenditure. Both effects can contribute to the strong weight reducing effect.
Tesofensine (also called TE) is a novel norepinephrine, dopamine, and serotonin reuptake inhibitor (triple reuptake inhibitor) that was initially developed for the treatment of neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease. As it turns out, the benefits of tesofensine extend further to include increased weight loss, even for people who do not undergo dietary changes. Tesofensine is now in phase III clinical trials as a weight loss aid.
What is Tesofensine?
Tesofensine is a member of the class of medications known as “triple reuptake inhibitors.” It prevents the presynaptic reuptake of neurotransmitters norepinephrine, dopamine, and serotonin. This leads to an increase in the effects of these neurotransmitters.
Tesofensine is a member of the phenyltropane class of drugs, which were originally developed to reduce cocaine dependency. In fact, this class of drugs arose as a result of efforts to disassociate the stimulant properties of cocaine from the factors that cause it to be addictive. In other words, the phenyltropane drugs are designed to stimulate the central nervous system without creating addiction.
It should come as no surprise, given their origins, that compounds like tesofensine have profound effects on neurotransmission, particularly dopamine, which is responsible for reward and craving behaviors. Research shows that tesofensine has no potential for recreational abuse, suggesting that at least some of the goals of efforts to dissociate the properties of certain stimulants have been achieved[1].
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Tesofensine Structure
Amino Acid Sequence: Not a peptide
Molecular Formula: C17H23Cl2NO
Molecular Weight: 3.277 g/mol
PubChem CID: 11370864
CAS No: 195875-84-4 (Deprecated: 402856-42-2)
Alternative Names: TE, NS-2330
Source: PubChem
How Does Tesofensine Work?
Given its ability to increase dopamine levels, tesofensine was originally developed for the treatment of Parkinson’s disease. During clinical trials, however, a significant “side effect” of weight loss was consistently noted. Because the compound proved to be inferior to existing medications in the treatment of neurodegenerative disease, but nearly twice as effective in promoting weight loss as any existing compound on the market, the decision was made to pivot to trials on weight loss[2].
The ability of tesofensine to increase levels of neurotransmitters in the brain does not directly account for its ability to increase satiety and feelings of fullness. Neither does this factor account for the hypothesized ability of tesofensine to alter energy balance and increase metabolism. At this point, the exact reason that tesofensine is such an effective weight loss agent remains unclear.
It was originally thought that tesofensine was a relatively balanced reuptake inhibitor, increasing levels of dopamine, norepinephrine, and serotonin in roughly equal proportions. This turns out to not be the case. After more extensive study, it was found that tesofensine is much more effective in boosting norepinephrine levels than serotonin levels. It is better at boosting both of those neurotransmitters than it is at boosting dopamine levels[3]. This difference may explain why the drug wasn’t particularly successful in the treatment of Parkinson’s disease.
Tesofensine activity is not, however, strictly limited to the neurotransmitters just described. Research shows that it is also an indirect potentiator of cholinergic neurotransmission. Of course, this is why the drug was originally of interest in Parkinson’s disease and suggests that its dopamine effects might be more nuanced than is currently understood. Tesofensine appears to promote cognition, learning, and memory via the cholinergic pathway. This pathway ultimately leads to increased BDNF levels in the brain[3]. BDNF stimulates neuron growth and has been shown in previous research to benefit people with depression, cognitive decline, and certain neurological conditions.
Tesofensine and Weight Loss
So, just how effective is tesofensine when it comes to weight loss? Phase IIB clinical trial results indicate that tesofensine produces about 12.8 kg (~28 pounds) of weight loss over six months when administered as a 1 mg dose to people who have a 300 kcal deficit in their diet. When compared to placebo, this is a 6-fold increase in weight loss[4]. Compared to currently available FDA-approved weight-loss medications, tesofensine is twice as effective. The average weight loss in all other clinical trials of currently available drugs was just 3-5 kg of reduction over 6 months. In other words, people lose twice as much weight with tesofensine as they do with any currently available weight-loss aid approved by the Food and Drug Administration.
Of course, it isn’t just the efficacy of tesofensine that makes it attractive as a weight loss agent. The compound is also easily administered by mouth just once per day. The side effect profile has also proved to be minimal in clinical trials, consisting mostly of dry mouth, headache, GI upset, and difficulty with sleeping. Both the dry mouth and difficulty sleeping show dose-dependent prevalence as well as attenuation over long-term use[4], [5]. So, it is possible to greatly mitigate these side effects by starting out on a low dose of tesofensine and then increasing it once attenuation has occurred.
Research shows that tesofensine produces the greatest weight loss when paired with dietary caloric restrictions and exercise. However, research shows that results can still be expected when tesofensine is taken and no differences in diet or exercise are encouraged. In one clinical trial, men treated with tesofensine lost weight despite the fact they were instructed to maintain their standard diet and levels of physical activity. These men lost 1.8 kg in two weeks when compared to placebo and reported higher feelings of satiety and fullness as well as decreased desire to eat. There was, additionally, evidence that men in the tesofensine arm of the study expended almost 5% more energy while they slept than those in the placebo arm. This correlates well with the additional finding that fat oxidation is increased by tesofensine[6].
One interesting aspect of tesofensine research in obesity has been the revelation that satiety appears to be centrally controlled and, perhaps, is harder to modify permanently than was once thought. The administration of tesofensine has a profound effect on satiety and hunger, thus greatly diminishing appetite. However, withdrawal of the drug, even after weight loss, results in an almost immediate return to baseline sensations. Reintroduction of tesofensine will suppress them again[7]. This suggests that appetite sensations are more permanent and ingrained than once thought and may, in fact, contribute to weight gain to a higher degree than once believe. In other words, it really isn’t a matter of willpower because some people are constantly being bombarded with signals that they are not full. Tesofensine is the first option to help quell those intrusive thoughts about hunger and the proof of its effectiveness is in the clinical trials showing significant weight loss.
Source: Nature
In the past, it has been noted that compounds affecting appetite generally lose their efficacy over time. The same is true of tesofensine, with its ability to stave off hunger diminishing (but never completely stopping) with prolonged use. That said, tesofensine shows drastically longer-lasting hypophagic effects than other weight reduction aids and, more importantly, shows substantial rebound to baseline after a short holiday. In other words, a short break from tesofensine restores its ability to suppress appetite and hunger[9]. No trials have been carried out looking at the long-term weight loss of cycled tesofensine, but there is good reason to believe that the drug, when cycled appropriately, may produce even greater weight loss than what has currently been observed.
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Tesofensine and Blood Sugar
Research in rats indicates that tesofensine can help to improve glycemic control in a dose-dependent manner. In basic testing of glucose tolerance, tesofensine greatly attenuates the insulin response. This means less insulin is released in response to a sugar load. How could this contribute to weight loss though?
Insulin is a major cause of fat deposition. When there is too much sugar to store in the liver or muscle, insulin crams it into fat storage. This is why high glycemic index foods, like white breads, lead to higher levels of fat deposition. They flood the body with sugars which insulin simply clears as quickly as possible. By attenuating this effect, tesofensine helps to lower fat deposition even in the setting of high blood sugar[9].
It is also true that the accumulation of fat creates a kind of self-reinforcing spiral. Once fat is deposited, it influences insulin signaling in a number of different ways that lead to additional fat deposition. This additional deposition then further stimulates fat accumulation.
Even worse, fat has been shown to be a source of inflammation, particularly once a certain threshold is reached. This inflammation has been linked to everything from insulin resistance and the development of diabetes to heart disease and even neurodegenerative conditions. By breaking this cycle of fat deposition and increased inflammation, tesofensine is helping to shift the balance of metabolism and give the body a fighting chance against adiposity.
Tesofensine and Brain Health
Despite the abandonment of tesofensine in the treatment of neurodegenerative diseases, there is still good evidence that the compound has beneficial effects on cognition, memory, and neurogenesis. Though the dopamine boosting effects of tesofensine appear to be too small to be relevant in the treatment of Parkinson’s disease, there is still interest in using the peptide to improve cognitive function in other settings.
Research in rats shows that tesofensine boosts expression of brain derived neurotrophic factor and, as a result, increases neurogenesis in the rat hippocampus[3]. BDNF plays several roles in the brain including boosting cell survival and reproduction in addition to increasing synaptic transmission. Research shows that BDNF signaling is altered in a variety of disease conditions including depression, schizophrenia, obsessive-compulsive disorder, and Alzheimer’s disease among others. Unfortunately, research into the direct delivery of BDNF into the central nervous system of humans and animals has not shown any benefit in various neurodegenerative diseases. This suggests that the role of BDNF is more complicated than science has revealed to this point. There is likely to be future research looking at not just the ability of tesofensine to influence BDNF, but the impact that this has on brain function, structure, resilience to injury, and perhaps even our abilities to learn and remember.
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Tesofensine and Depression
A subcategory of brain health in which tesofensine may be helpful is depression. Research shows that exposure to stress can decrease BDNF levels in the brain and, if the exposure is prolonged, lead to atrophy of the hippocampus. This change in hippocampal structure has been directly linked to depression, especially major depression, and it is thought that existing treatments may be beneficial because they help to protect against or reverse these changes[10].
Tesofensine is known to improve BDNF levels and promote neurogenesis in the hippocampus, so it likely has anti-depressant properties. This, however, has not been the primary focus of research, as the compound was originally developed for its dopaminergic properties and then was discovered to have anti-obesity properties. All of that having been said, tesofensine offers a unique alternative to both anti-obesity and antidepressant applications because its properties cross both fields. It can be used as a standalone in either case, but the idea that it could have a “two birds with one stone” effect in the setting of weight loss and mood disorder is compelling[11]. This dual nature of tesofensine will likely make it a go to for people who struggle with weight and depression, two conditions that appear to have more than a few commonalities.
Tesofensine and Pain Management
The use of antidepressant medications in pain management is not new. Tri-cyclic antidepressants were among the first drugs available for treating mood disorders and have long been known to reduce nociception (pain perception), particularly in conditions like fibromyalgia. Research shows that the anti-nociceptive (anti-pain) properties of standard antidepressants, which affect only serotonin and norepinephrine, are enhanced by the addition of dopamine boosting agents[12]. Thus, there is speculation that triple reuptake inhibitors like tesofensine may provide benefits in pain management.
Tesofensine and Safety
Anti-obesity drugs have a long history of cardiovascular side effects. Fen-Phen is probably the most famous of the diet pills to have caused serious cardiac issues (e.g., heart valve damage) and though things have improved since 1997 when Fen-Phen was removed from the market, anti-obesity drugs are still hard on the heart. Sibutramine, for instance, has been associated with major cardiovascular events and was itself eventually withdrawn from the market in 2010[13]. The result is a death of options for treating obesity and feelings of hopelessness among those who seek relief. Phentermine, one of the ingredients in Fen-Phen can be used safely for short periods of time, but its reputation has produced fear and thus most people and healthcare providers are unwilling to use it.
To date, tesofensine has shown a substantially improved risk profile compared to other anti-obesity drugs. In particular, its central action on neurotransmitter reuptake as opposed to peripheral action of lipase inhibitors, amphetamines, and other compounds makes tesofensine unique[14]. There was some argument about trial design and whether side effects of tesofensine had been under reported[15]. The claim is that investigators did not list people with headache, migraine, stress, and depression prior to treatment as having those side effects if they experienced it during treatment. This is a valid criticism of the study design because a distinction should have been made between existing symptoms and new, but similar, symptoms. A change in trial design would likely have had no major impact on tesofensine side effect reporting.
Tesofensine Overview
Tesofensine is a novel inhibitor of the reuptake of serotonin, norepinephrine, and dopamine. By increasing levels of all three of these neurotransmitters, tesofensine increases BDNF expression patterns and promotes neurogenesis in the amygdala. None of this explains why it is the most effective weight loss agent developed to date, however. Research shows that tesofensine is at least twice as effective as any currently approved weight loss agent and with far fewer (and far less serious) side effects. While research is ongoing to get tesofensine to market as an anti-obesity drug, there is deeper research being carried out to understand how this molecule affects the sensations of hunger and satiety to produce weight loss. While tesofensine is proving to be a remarkable weight loss agent, it may yet prove to be even more remarkable by helping to elucidate the connection between the human brain and gut that controls eating behavior to begin with. With that knowledge, science could virtually eliminate obesity.
Tesofensine exhibits minimal side effects, good oral and excellent subcutaneous bioavailability in mice. Per kg dosage in mice does not scale to humans. Tesofensine for sale at Peptide Sciences is limited to educational and scientific research only, not for human consumption. Only buy Tesofensine if you are a licensed researcher.
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Article Author
The above literature was researched, edited and organized by Dr. E. Logan, M.D. Dr. E. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.
Scientific Journal Author
Arne Astrup‘s major current research is focused on the role of dietary macronutrients and glycemic index for body weight regulation, and the hormonal mediation of hunger and satiety by gastrointestinal peptides such as GLP-1, PYY, CCK etc.. In addition, I head the OPUS Centre, ‘Optimal well-being, development and health for Danish children through a healthy New Nordic Diet’, which ran from 2009 until 2014. The main objective is to develop a healthy and palatable new food and eating concept, and to examine how such a diet can affect mental and physical health in a Nordic population. Other active research includes studies of the role of dairy and bio-active food ingredients (various specific fibres) in aspects of human health and testing of pharmaceutical compounds for the treatment of obesity.
Arne Astrup is being referenced as one of the leading scientists involved in the research and development of Tesofensine. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Peptide Sciences and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Arne Astrup is listed in [2], [4], [7], and [15] under the referenced citations.
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