Tesofensine

Tesofensine

Tesofensine is a novel triple monoamine reuptake inhibitor from the phenyltropane family of drugs, a weight-loss promoting agent of remarkable efficacy with a considerable mood enhancing and nootropic potential. At first, it was developed for the treatment of Alzheimer’s and Parkinson’s Disease, yet failed to produce satisfactory improvement in these conditions, leading to discontinuation of further investigation after preliminary trials.However, patients who took part in the original studies consistently reported significant weight loss; furthermore, this “adverse event”seemed more marked and prevalent in the obese and overweight.

And so, the tesofensine research took a new direction, and soon yielded outstanding results, proving the new candidate drug for the treatment of obesity superior to all medications currently approved by FDA (US Food and Drug Administration) for the same applications.

Over a six-month period, patients lost an average of 12.8 kg on the 1 mg dose, 11.3 kg on the 0.5 mg dose and 6.7 kg on the 0.25 mg dose, compared with a 2.2 kg loss in the placebo group.

As of now, it is in phase III of clinical trials, and while it’s approximately twice as efficient in facilitating weight loss as the most commonly prescribed weight-loss inducing drugs, it has a similar safety profile.

The specific mechanisms by which tesofensine promotes weight loss are not yet fully studied, but are believed to be a combination of central and peripheral factors. By increasing norepinephrine it reduces overall appetite, while raising serotonin to adequate levels controls food cravings; according to a recent study, tesofensine actually silences GABAergic neurons in the lateral hypothalamus, a brain region vital for feeding.

Clinical trials have shown that tesofensine increases resting energy expenditure, most likely due to increased norepinephrine signaling, which is possibly also responsible for how this compound affects metabolism in favor of fat oxidation over carbohydrate oxidation. Dopamine reuptake inhibition, on the other hand, might decrease the relative reward associated with eating compared to alternative activities.

Existing evidence suggests that the level to which it raises dopamine is not high enough to cause pleasure in itself and thus can be considered non-addictive (its self-administration does not tend to increase in drug addicts), which is an advantage over typical dopaminergic agents with weight-loss promoting properties.

Other than altering the levels of the three key monoamines in the brain, tesofensine indirectly potentiates cholinergic neurotransmission and as such could be beneficial in terms of cognitive faculties, predominately memory and learning. It has been demonstrated that sustained treatment with tesofensine leads to an increase in BDNF, and might have an antidepressant effect.

The latter hypothesis calls for extensive studies, as its confirmation could mean a valuable alternative for those suffering from MD, who do not respond well to the widely prescribed anti-depressants either due to only partial therapeutic success, intolerable side effects (apathy, sexual dysfunction). Essentially, tesofensine could be the “light-weight” first line treatment for multiple types of depression, given that it potentially addresses multiple neurotransmitter deficits.

Benefits of taking tesofensine

• fast and safe weight loss;
• better control over binge-eating, habitual snacking, etc.;
• lessened preference for foods high in sugar and carbohydrates;
• healthier metabolism;
• potential pro-cognitive effects;
• increased BDNF;
• possible anti-depressant.

Side effects

• dry mouth;
• headache;
• nausea;
• insomnia;
• diarrhea;
• constipation;
• increased heart rate.

Interactions

• MAOIs (probably except B-selective doses of selegiline);
• bupropion;
• SSRIs / SNRIs;
• clomipramine, imipramine.

Contraindications

• severe renal impairment (medical consultation advised for dose adjustment)
• severe liver impairment (medical consultation advised for dose adjustment)
• age < 18 (use in children discouraged, medical consultation advised to decide whether to use it in adolescents, lack of clinical data)

Dosage

Based on clinical trials, the typical dosage ranges from 0.25 mg to 1 mg taken orally once daily, in the morningwith or without food.

Tesofensine has a half-life of 9 days, therefore it takes time to achieve steady plasma concentrations (usually ca. 2 months of daily dosing).

The initial dose of tesofensine is 0.25 mg and might be increased to 0.5 mg after 2-4 weeks if it is well tolerated. One should be aware that further increase to 1 mg is associate with both greater outcomes and prevalence of side effects.

Abrupt discontinuation could potentially result in withdrawal symptoms.