Wednesday, October 18, 2017

Cathine (Alvalin®) a Legitimate 'New Ephedra'? 9.1kg vs. 2.4 kg Weight Lost, 165% Greater Waist Reduction in Humans

You don't have to switch to eating pills, only. Don't worry. What you will still have to do, though, is to (a) clean up your diet, (b) stop eating everything in sight, and (c) achieve a caloric deficit. With its ability to reduce hunger and appetite, cathine may yet help you make that happen. 
Let's be honest: ever since the classic ECA stacks have been banned from the market, there are neither over-the-counter, nor prescription weight loss supplements/drugs that work. Scientists from the Technical University of Munich (Germany | Hauner 2017) believe they can change that. Not by inventing a revolutionary new compound, but by digging out a cousin of ... you guessed it: the good old ephedrine.

Cathine is the name of the agent that was originally launched in the 1970s for the short-term treatment of diet-related obesity. Cathine is an alkaloid originally isolated from khat leaves grown in East Africa and the Arab peninsula and is a stable metabolite of cathinone, which is the main psychoactive alkaloid of kath, the leaves of an Arabian shrub, which are chewed (or drunk as an infusion) as a stimulant.

The pharmacological action of cathine includes central (anorexia, increased alertness, increased sensory stimulation, hyperthermia) as well as peripheral effects (increased respiration and heart rate, constipation, urine retention)... in other words: it works pretty much just like ephedra alkaloids from ma huang or alternative sources of ephedra/ephedrine.
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Against that background, it is only mildly surprising that the N=241 subjects (75.9% women; mean age of all patients was 48.5 ± 10.4 years, the mean baseline BMI was 34.6 ± 3.4 kg/m²) the researchers recruited for their 24-week RCT lost up to four-fold more body weight when they had been randomly allocated to group #4, the high-dose cathine group:
  • placebo - 0 mg cathine per day,
  • low dose - 16 mg cathine per day, 
  • medium dose - 32 mg cathine per day, or 
  • high dose - 53.3 mg cathine hydrochloride 
The cathine came from a drug that is produced by RIEMSER Pharma who call their product Alvalin® and, you guessed it, financed the study.

The subjects did not get away without lifestyle changes and a 500kcal/d deficit, though

In contrast to the average fat burning supplement (that does not even work), cathine does not come with the promise to shed fat effortlessly. Lifestyle changes are just as necessary as a significant restriction of your energy intake. To be able to put the necessary changes into practice, ...
[...e]ach patient, independent of group allocation, received structured counseling sessions using an estab lished and validated intervention program which was adapted to the specific requirements of the study design. In addition, the recommendations were individually tailored based on the analysis of dietary protocols. The aim was to achieve an energy deficit of 500–600 kcal/day. The level of daily physical activity was assessed using a pedometer. Patients were recommended to increase their physical activity up to 5,000 / 10,000 steps/day, depending on baseline activity using a pedometer for self-monitoring" (Hauner 2017).
The primary outcome variable of this study was the previously discussed change in body weight after 24 weeks of treatment. For me, personally, the secondary end points, which included an intention-to-treat analysis of patients with weight loss > 5% and > 10%, as well as the changes in waist circumference (WC), waist-hip ratio (WHR), serum lipids and glucose, are yet at least as important; lastly, we must not forget, the most important question: Is kathine even save? Or are there adverse events such as increased blood pressure, heart rate, and QT interval, as they have been observed with other stimulants before.

Adherence is key and a weight loss drug that works increases adherence

As a SuppVersity reader you know that the #1 determinant of weight loss success is adherence - not just to taking the drug/supplement, but rather and more importantly to the lifestyle changes... and here, that's what the study at hand shows, cathine is just as effective as ephedra which had the impressive ability to help dieters stick to their caloric intake goals while preventing the dreaded reduction of energy levels that will eventually make you fall off the wagon.
Unlike other stimulants, cathine rather decreased the subjects' blood pressure. The heart rate, on the other hand, increased as expected.
Cathine is actually good for your heart health: When we're talking stimulants for weight, cardiovascular side effect can be a pain in the ass. Cathine in no real exception to this "rule", but it is at least noteworthy that typical cardiovascular side effects occurred only transiently on the high dosage (5x palpitations, 3x hypertension, 2x chest pain). Still, only two of the subjects in the high dose group dropped out because of adverse events (3 subjects in the placebo group did so, too).

Furthermore, (a) the average blood pressure and heart rate changes were beneficial and harmless, respectively, and (b) classic risk markers of heart disease such as total cholesterol, and triglycerides improved significantly in all treatment groups.
With the drop-out rate during the active treatment period being "only" 25% and the vast majority of the 59 patients who discontinued the study coming from the placebo group (42.3%), cathine seems to be a legit successor to ephedrine, which has also been shown to increased compliance and, more importantly, the number of subjects who were disappointed with their results in the good dozen of RCTs on its weight loss effects.

In the 4 groups combined, 12 individuals withdrew due to adverse drug reactions (ADRs). 

That's tolerable considering the fact that cathine will probably have similar pro-sympathetic and thus potentially blood pressure and heart rate elevating "side effects". Overall, 178 patients completed the trial after 24 weeks - with unquestionably impressive results:
  • Figure 1: Changes in weight (kg) and waist circumference (cm) (mean ± SD) in the ITT (LOCF) population (n = 237). ITT = Intention-to-treat analysis; LOCF = last observation carried forward method.
    Mean weight loss (± SD) after 24 weeks was 6.5 ± 4.2 kg under 16 mg cathine, 6.2 ± 4.7 kg under 32 mg cathine, and 9.1 ± 5.4 kg under 53.3 mg cathine but only 2.4 ± 5.4 kg in the placebo group. 
  • The respective levels of weight loss in the completers’ analysis were 7.6 ± 3.7 kg under 16 mg cathine (n = 48), 7.0 ± 4.6 kg under 32 mg cathine (n = 49), and 9.8 ± 5.6 kg under 53.3 mg cathine (n = 47) versus 3.7 ± 5.0 kg under placebo treatment (n = 34). 
In both types of analysis, weight loss was significantly greater in the active treatment groups compared to placebo (each p < 0.02, ANCOVA with Tukey-Kramer Test).
  • In the ITT population, mean WC decreased over 24 weeks by 5.4 ± 7.2 cm under 16 mg cathine, by 5.1 ± 4.7 cm under 32 mg cathine, by 7.5 ± 5.7 cm under 53.3 mg cathine, and by 1.6 ± 5.9 cm under placebo treatment. 
Again, the differences between the three doses of cathine and placebo were statistically significant (each p < 0.01, ANCOVA with TukeyKramer Test).

Now, Alvalin® is not meant to be an over-the-counter supplement. Accordingly, an intention to treat analysis that would confirm that the average subject achieves a clinically meaningful weight loss of >5% or, even better, >10% over 24 weeks is all the more important.
Figure 2: Patients who lost >5% and >10% of their baseline body weight at week 24 (Hauner 2017).
The result was clearly dose-dependent with 78.3% of the subjects in the high-dose group losing more than 5% of their initial weight and 41.7% lost more than 10%. Moreover, significantly more individuals in the cathine treatment groups had a weight reduction of >5% and >10% than in the placebo group (each p < 0.01, chi square test).
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This is not a supplement: While the authors point out that cathine is one of the few first-generation amphetamine-like weight loss drugs that is still available ... it is a schedule III drug under the Convention on Psychotropic Substances in the US and as such only available w/ a prescription. It's still likely that some shady companies will (ab-)use it in their "supplements".

With that being said, the results are impressive. Even in the absence of DXA data the sign. reduction in waist circumference clearly indicates that much of the extra weight that was lost came from the subjects' body fat stores.

Moreover, the side effects were tolerable and the adherence (probably due to improved results and reduced hunger) was superior to the placebo = life-style intervention, only, study. If monitored by a doctor cathine could thus be a viable addition, but not a replacement for making the necessary life-style changes (including a reduction in food intake, folks).

Lastly, it shouldn't be forgotten that this is only study #3 on cathine in human beings, with Spranger & Dörke (1966) as well as Szelenyi & Bräuer's 1974 having conducted likewise promising, but overall unfortunately only poorly controlled trials 40-50 years ago | Comment!
  • Hauner, H., Hastreiter, L., Werdier, D., Chen-Stute, A., Scholze, J., & Blüher, M. (2017). Efficacy and Safety of Cathine (Nor-Pseudoephedrine) in the Treatment of Obesity: A Randomized Dose-Finding Study. Obesity Facts, 10(4), 407-419.
  • Spranger J, Dörken J (1966). "Kindliche Adipositas: Prüfung der Psychodynamik unter d-norpseudoephedrin." Monatsschr Kinderheilk 1966;114:394–396
  • Szelenyi I, Bräuer H (1974). "Kontrollierte Prüfung von d-Nor-Pseudoephedrin auf Effektivität und Unschädlichkeit." Wien Med Wochenschr 124:49–52.