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science nutrition <strong>blog</strong>

By Robert Schinetsky


For those of you who pay close attention to the supplement industry newswire, the name of Dr. Pieter Cohen is quite familiar. For those of you less attuned to the inner workings of the industry, Pieter Cohen is an Associate Professor of Medicine at Harvard Medical School as well as a general internist at Cambridge Health Alliance in Somerville, Massachusetts who specializes in weight loss, preventive medicine, and dietary supplements.

Over the years, Dr. Cohen has spearheaded a number of studies investigating the hidden dangers of dietary supplements, most notably the inclusion (sometimes unbeknownst to the consumer) of “gray area” stimulants in pre workout supplements, fat burners, and weight loss support aids.

We’ve previously covered some of Dr. Cohen’s work in our article titled, NEW HARVARD STUDY! HIGENAMINE CONCERNS! Stimulant In Some Pre-Workouts And Fat Burners!. In that article we discussed a study in which Dr. Cohen and his colleagues tested a number of supplements for their higenamine content. Results of the study showed that, of the products

tested, the discrepancy between the listed dosage and the amount actually contained in the product ranged from <0.01% to 200%!

Most recently, Cohen and colleagues turned their attention to another stimulant that has become rather popular in pre workout and weight loss supplements -- isopropylnorsynephrine.

In line with previous studies, Cohen & friends sought to investigate whether the quantities listed on the individual supplements actually met what was inside the tub or not as well as if there were any other ingredients sprinkled” into the products that weren’t accounted for on the label.

But, before we get into Dr. Cohen’s latest work, let’s first briefly recap what isopropylnorsynephrine is.

What is Isoproylnorsynephrine?

Isopropylnorsynephrine (aka deterenol) is a pharmaceutical beta-agonist[1] and relative of p-synephrine -- a molecule with which many of your reading this are already familiar, and one we’ve discussed at length before on the blog in our article titled Stim Hype! Show Me the Science.

p-synephrine is an alkaloid that is structurally similar to ephedrine -- a popular stimulant and effective weight loss agent that’s been banned from use in dietary supplements.

Since p-synephrine is structurally similar to ephedrine, it possesses some of the beneficial aspects of ephedrine, such as increasing energy expenditure, post exercise oxygen uptake, and fat oxidation, and its effects are also enhanced when used in combination with caffeine.

But, the real upside to p-synephrine is that it doesn’t impact cardiovascular system parameters (e.g. increased blood pressure), which can’t be said of ephedrine. This is due to the fact that p-synephrine has extremely low binding affinity for α-1 and α-2 as well as β-1 and β-2 adrenoreceptors.[2]

However, p-synephrine does activate the β-3 adrenoreceptor , which leads to increased metabolic rate, lipolysis, and potentially even reduced food intake, and it’s from these actions that p-synephrine offers its performance-boosting benefits.

Regarding safety, studies have used doses up to 3 mg/kg of p-synephrine and not witnessed any adverse side effects.

So, what does this have to do with isopropylnorsynephrine?

Well, in vitro studies on isopropylnorsynephrine have found the compound to be a highly selective beta-agonist with no alpha-adrenergic activity.

Other research conducted in human cells indicates it may be a stronger lipolytic agent than p-synephrine[3], which would make it an appealing option for inclusion in weight loss supplements.

To date, only a single study (conducted in 1949!) investigated the effects of orally administered isopropylnorsynephrine in humans.[7]

Researchers investigated the effects of three different dosages of isopropylnorsynephrine[7]:

  • at 1 mg/kg, the stimulant was noted to have vasodepressor effects
  • at 2–3 mg/kg, it led to flushing, tingling of extremities and face, anxiety, decreased diastolic blood pressure and increased heart rate
  • at 5 mg/kg, isopropylnorsynephrine induced vomiting, hypotension, inability to sit up, blurred vision, palpitations, weakness and respiratory distress


Aside from the side effects mentioned above (not to mention the lack of safety data around the ingredient) -- there’s yet another problem with isopropylnorsynephrine -- research to date has not shown it to be naturally in bitter oranges (or any other plant in substantial quantities, for that matter), and thus, and cannot be considered as a naturally occurring alkaloid.[3]

Moreover, isopropylnorsynephrine has never been approved by the FDA.

In Europe, between1975 and 1982, it was used as an ophthalmological preparation for the treatment of glaucoma[4].

Stateside, following the ephedrine ban in 2004, a manufacturer submitted an application to the FDA to introduce deterenol into supplements[5]. However, the FDA responded that isopropylnorsynephrine doesn't qualify as a dietary supplement ingredient.

Despite these facts, supplement brands and manufacturers are still putting isopropylnorsynephrine into products (sometimes unbeknownst to the consumer). 

And, it is here that we circle back to the latest research by Dr. Cohen & colleagues...

The Study

The newest study by Dr. Cohen & friends sought to investigate the presence and quantity of stimulants in supplements labeled as containing isopropylnorsynephrine.[1]

All dietary supplements listing isopropylnorsynephrine (or one of its other monikers, such as deterenol or isopropyloctopamine) as an ingredient on the label were identified using the Google search engine.

If a particular product was sold in one flavor, the team of researchers purchased two samples, and in instances in which a product was available in multiple flavors, Cohen & colleagues purchased two samples of each flavor, when possible.

Supplements were purchased online in April 2018. The team excluded products if, upon inspection of the bottle following purchase, the actual label did not list isopropylnorsynephrine or one of its synonyms.

For each product purchased, one container was analyzed by NSF International (Ann Arbor, MI), an independent not-for-profit organization that develops public health standards and certification programs, and one container by the Netherland’s National Institute for Public Health and the Environment.

The Findings

In total, 17 brands of supplements were analyzed.

The team identified NINE unapproved stimulants and eight different combinations of banned stimulants in supplements labeled as containing isopropylnorsynephrine.

However, isopropylnorsynephrine was NOT detected in four brands (24%) labeled as containing the drug. Still, all of the products tested were found to contain at least one non-approved or prohibited stimulant.

In addition to isopropylnorsynephrine, researchers also found the following stimulants in some of the products tested:

  • Phenpromethamine (Vonedrine)
  • Oxilofrine
  • Octodrine (DMHA)
  • BMPEA (often labeled as acacia rigidula)
  • 1,3-DMAA
  • 1,4-DMAA
  • 1,3-DMBA
  • Higenamine


Phenpromethamine was the second most common stimulant found in the supplements, appearing in four (24%) of the brands tested. However, only one of the products was labeled as containing the drug on the label, under the synonym n-methyl-beta-methylphenylethylamine).

For those of you not familiar with the drug, phenpromethamine was used in the U.S. as an inhaler drug for asthma until the FDA withdrew approval for the brand name version in 1971.

Furthermore, phenpromethamine has never been approved for oral use in the U.S. or in other countries, and its safety when taken orally lacks substantial research.

The stimulants identified in the products are NOT approved for oral use as ingredients in dietary and have been prohibited in dietary supplements by the FDA and/or prohibited in sport by the World Anti-Doping Agency (WADA).


Yet again, Dr. Cohen and colleagues have shown that when it comes to dietary supplements, not all are created equal. Oftentimes there is “more than meets the eye.”

By that, we mean that products may list certain compounds on the label, but when it comes to what is actually in the products (at least those discussed in the studies as well as the ones previously investigated by Cohen & friends), there is something(s) amiss).

Either products do not contain the actual ingredients that are called out on the label, and/or they contain other banned (and potentially harmful) substances.

The real victim in these instances is the consumer who is putting their trust in the brands to provide what they’re explicitly stating their product contains. Not only is their money being wasted (at best), but their health is also at risk.

One question that warrants further investigation from these findings is: who is to blame?

Is it the manufacturer not testing the raw materials they are sourcing (which could be tainted)?

Is it the supplement company for not double-checking the manufacturer and having their products 3rd-party tested?

Or, is it gross negligence on behalf of both parties?

Additionally, while this study was published in 2021, the products that were tested were purchased in 2018. Over the past three years, no doubt there have been changes to these products as well as others that weren’t included in the study, meaning that while the findings are interesting, they may not be valid today.

Nevertheless, companies are still using under-researched compounds like isopropylnorsynephrine and many others (either knowingly or unknowingly), which is putting the consumer at risk and contributing to the “stigma” the supplement industry has from time to time.

Consumers (especially drug-tested athletes) bear the burden of knowing what they put in their bodies, as they should, but when supplement companies sell products that don’t meet label claims, is the consumer really at fault?

At the end of the day, you, as the consumer, have the power to call for change by supporting brands and purchasing products that play by the rules and do NOT use banned substances.

Advanced Molecular Labs uses NO banned stimulants in any of our pre workouts supplements or weight loss support aids.

If you’re looking for a premium-quality supplement to boost energy, heighten focus, and increase performance (all while avoiding banned and/or potentially dangerous stimulants), check out AML Dopa Rush Cocktail

AML Dopa Rush Cocktail is a natural and non-habit forming way to naturally maximize dopamine levels to help increase energy, productivity, alertness, motivation, and mood.†

Click here to learn more about Dopa Rush Cocktail and what makes it the best dopamine supplement to maximize productivity and performance, safely and naturally

These statements have not been evaluated by the Food and Drug Administration.
These statements are not intended to diagnose, treat, cure, or prevent any disease.

© Published by Advanced Research Media, Inc., 2021

© Reprinted with permission from Advanced Research Media, Inc.


  1. Pieter A. Cohen, John C. Travis, Céline Vanhee, Dana Ohana & Bastiaan J.Venhuis (2021): Nine prohibited stimulants found in sports and weight loss supplements: deterenol,phenpromethamine (Vonedrine), oxilofrine, octodrine, beta-methylphenylethylamine (BMPEA), 1,3-dimethylamylamine (1,3-DMAA), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylbutylamine (1,3-DMBA) and higenamine, Clinical Toxicology, DOI: 10.1080/15563650.2021.1894333
  2. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev. 2011;2011:1– doi: 10.1155/2011/482973
  3. Mercader J, Wanecq E, Chen J, Carpéné Isopropylnorsynephrine is a stronger lipolytic agent in human adipocytes than synephrine and other amines present in Citrus aurantium. J Physiol Biochem. 2011 Sep;67(3):443-52. doi: 10.1007/s13105-011-0078-2. Epub 2011 Feb 19. PMID: 21336650
  4. Deterenol (DCI rec), Traitement de glaucome. In Index Nominum1978. Zurich: le Centre Scientifique de la Societe Suisse dePharmacie; 1977. p. 237
  5. Zhu B Premarket notification for a new dietary ingredient:betaphrine. Sept, 17, 2004.
  6. Marsh DF, Herring DA. The comparative pharmacology of the N-alkyl-1-(p-hydroxyphenyl)-2-aminoethanols. Arch Int Pharmacodyn.1949;78(3):489–498