Paul forwarded a reader comment to me yesterday, and I thought the subject was worth exploring in depth:

I’m curious to know your opinion on the negative effects of Rutaecarpine? There are a lot of reliable (!?) anecdotal reports of liver enzyme issues. A quick search finds multiple studies, including human, of this compound inhibiting liver  microsomes.

Rutaecarpine is in products like BSN No Xplode (which many of the anecdotal evidence is against).

I’d be really interseted in your thoughts/comments and could provide an interesting article.  Most people will never come across this information, but we need supp companies to omit ingredients if dangerous.

I certainly don’t disagree with that last sentence!  Of course, therein lies the problem that many pro-regulation-types have with the industry.  Simply put, a lot of supplement ingredients have virtually no track record w/respect to health and safety, let alone efficacy.  So we’re treading into murky water, both scientifically AND philosophically. 

Let’s take care of the science part first…

I reviewed NO-Xplode about a year ago.  I gave it a trial run, and generally liked the effects, although I also made note of a few things that gave me pause…for example, I drew attention to certain ingredients that I thought were less than desirable (CEE, glycocyamine, guanidinopropionic acid) and described it as “overly complicated”.  Personally, I think the latter is an understatement, although I’ve seen worse (*cough* Anabolic Halo *cough*).

Rutaecarpine is one of the ingredients in the “NO Meta Fusion” blend.  I had nothing to say about it at the time, and now that I’ve done more digging, I’m still not sure it really merits a lot of attention, per se. According to BSN…

Rutaecarpine is an alkaloid extracted from the fruit Evodia Rutaecarpa. Rutacarpine stimulates nitric oxide production. RC-NOS also helps to counter the vaso-constricting effects caused by caffeine consumption.

Indeed, rutaecarpine does appear to be a vasodilator, thus, so far, so good.

What little we know about rutaecarpine appears to be fairly positive.  In-vitro and rodent studies show it has cardioprotective and anti-hypertensive effects;  it reduces platelet aggregation and also exerts gastroprotective effects.

It also has another, more interesting property, however… it can alter the activities of certain cytochrome P-450 enzymes responsible for drug metabolism.  For example, rutaecarpine can alter the pharmacokinetics of caffeine, theophylline and acetaminophen.  In particular, it appears to affect the activity of CYP1A2, although it’s not entirely clear in which direction.  Some research describes it as an inducer; whereas it’s described as an inhibitor elsewhere.

So interesting stuff… But in the meantime, is there anything here to implicate rutaecarpine as a hepatotoxic agent? Does its ability to alter the activities of cytochrome P-450 enzymes make it dangerous?

Lemme digress for a moment, to make one thing clear: although we’re talking about the liver, we’re talking about different enzymes from the ones in those “anecdotal reports”.  The cytochrome P-450 enzymes discussed above aren’t the same ones you measure in a blood test, which are alanine aminotransferase (ALT) and aspartate aminotransferase (AST).  There are other liver function tests too, but these are the ones considered to be the most sensitive indicators of disease/injury.

Is there a connection, though? At least one person seems to think so. He’s Lt. Col. James Freese, 509th Medical Group Medical Director at Whiteman Air Force Base.

Two dangerous items on the market are NO-Xplode™ and Clenbuterol™. NO-Xplode™ is marketed as an extreme nitric oxide and creatine surge. The bottle states it will amplify mental focus, performance, strength and training intensity.

It does this by dilating the blood vessels – allowing an increase in blood flow to the muscle. Sounds good, but that is not all it does.

The bottle does list the ingredients, one of which is a NO-Xplode™ Proprietary Blend: 20,500mg worth of ingredients.

Unless you go on-line and dig fairly deep, you will not find out what exactly is in the “proprietary-blend” ingredients.

Don’t worry; this has been done for you. One of the “hidden” ingredients in this blend is an herb called rutaecarpine. This ingredient is an alkaloid isolated from the traditional Chinese medicine, evodia rutaecarpa.

Studies have shown that this ingredient, rutaecarpine, can affect the P-450 enzyme system of the liver. Bottom line, it can cause serious damage to your liver and lead to devastating consequences.

We found out about it’s affect on the liver when we found abnormally elevated liver enzymes on a few patients during routine evaluation and laboratory testing, which there was no apparent explanation or exam findings to correlate the lab results.

After more in depth questioning, we found the patients had been using the supplement. After one month of remaining off NO-Xplode™, the livers had completely returned to normal.

(emphasis mine)

Unfortunately, this account raises some questions…just because the Lt. Col.’s mind is made up about the cause, doesn’t mean mine is.  How many is “a few”?  How elevated is “abnormally elevated?”  Did his patients display other symptoms besides elevated enzymes?  Were there other NO-Xplode users who didn’t have elevated enzymes? 

Problem is, there are A LOT of things that can elevate liver enzyme levels:

Mild to moderate elevations of the liver enzymes are commonplace. They are often unexpectedly encountered on routine blood screening tests in otherwise healthy individuals. The AST and ALT levels in such cases are usually between twice the upper limits of normal and several hundred units/liter.

One of the most common cause of mild to moderate elevations of these liver enzymes is fatty liver. In the United States, the most frequent cause of fatty liver is alcohol abuse. Other causes of fatty liver include diabetes mellitus and obesity. Chronic hepatitis C is also becoming an important cause of mild to moderate liver enzyme elevations.

What medications cause abnormal aminotransferase levels?

Pain relief medications such as:

  • aspirin,
  • acetaminophen (Tylenol),
  • ibuprofen (Advil, Motrin),
  • naproxen (Naprosyn, Naprelan, Anaprox, Aleve),
  • diclofenac (Voltaren, Cataflam, Voltaren-XR)), and
  • phenylbutazone (Butazolidine)

Anti-seizure medications such as:

  • phenytoin (Dilantin),
  • valproic acid (Depakote, Depakote ER, Depakene, Depacon),
  • carbamazepine (Tegretol, Tegretol XR, Equertro), and
  • phenobarbital

Antibiotics such as:

  • tetracyclines, [for example, tetracycline (Achromycin)]
  • sulfonamides,
  • isoniazid (INH) (Nydrazid, Laniazid)
  • sulfamethoxazole (Gantanol),
  • trimethoprim (Trimpex; Proloprim, Primsol)
  • nitrofurantoin (Macrodantin; Furadantin; Macrobid),
  • fluconazole (Diflucan ) and some other anti-fungals, etc.

Cholesterol lowering drugs such as:

  • lovastatin (Mevacor, Altocor),
  • pravastatin (Pravachol),
  • atorvastatin (Lipitor),
  • fluvastatin (Lescol),
  • rosuvastatin (Crestor),
  • simvastatin (Zocor), and
  • niacin

Cardiovascular drugs such as:

  • amiodarone (Cordarone),
  • hydralazine (Apresoline)
  • quinidine (Quinaglute, Quinidex), etc.

Other drugs:

  • Anti-depressant drugs of the tricyclic type

With drug-induced liver enzyme abnormalities, the enzymes usually normalize weeks to months after stopping the medications.

A fast food diet can also elevate the values seen in liver function tests.  So can lifting weights…

Liver function tests are significantly increased for at least 7 days after weightlifting among men used to moderate physical activity, but not used to performing weightlifting on a regular basis. In accordance with these results, and in order to exclude potential exercise-related effects on liver function tests, it is important to impose training restrictions on weightlifting for at least 1 week before the start of clinical trials. Furthermore, the study also illustrates the importance of considering weightlifting and probably other types of intense muscular training as causes of asymptomatic elevations of liver function tests in daily clinical practice. This will reduce the risk of erroneously attributing changes in liver function tests to a drug effect.

If these guys were taking NO-Xplode, they were almost certainly pumping some iron, too. How did Lt. Col. Freese eliminate the influence of their workouts on their tests? 

These are the sorts of things you have to consider before drawing a definite “cause and effect” conclusion.  Maybe he did, but he doesn’t say so, and it’s risky to assume…

Especially since his chain of reasoning is missing a few links.  In essence, he’s arguing that…

  1. rutaecarpine affects the activity of drug-metabolizing enzymes in the liver
  2. patients with elevated liver function test values were taking a supp with an unknown amount of rutaecarpine in it
  3. therefore, the supplement causes liver damage

1 and 2 are true enough, but 3 doesn’t quite follow.  There are two problems with this:

  1. as noted above, transiently elevated liver enzymes in otherwise asymptomatic people may not actually reflect significant liver damage
  2. lots of things can affect the activity of drug-metabolizing enzymes, yet don’t necessarily (to my knowledge) cause elevated liver function tests or are hepatotoxic per se.  Grapefruit is a classic example.

So sorry, doc, but I just don’t see a straight line between what rutaecarpine does in-vitro, and what you’re insisting it does in-vivo.

This doesn’t necessarily put rutaecarpine in the clear, however.  While Evodia rutaecarpa has been used as a traditional medicine for centuries, its history doesn’t exclude the potential for adverse effects from isolated constituents taken in concentrated amounts.  Thus:

In the present study, adverse effects of rutaecarpine on immune functions were determined in female BALB/c mice. Rutaecarpine had no effects on hepatotoxicity parameters in mice, as measured by serum activities of aminotransferases. Meanwhile, rutaecarpine significantly decreased the number of antibody-forming cells and caused weight decrease in spleen in a dose-dependent manner… These results suggested that a single bolus intravenous injection of rutaecarpine from 20 mg/kg might cause immunosuppressive effects, and that rutaecarpine-induced immunosuppression might be mediated, at least in part, through the inhibition of cytokine production and cell cycle arrest in Go + G1 phase, and caused possibly by mechanisms associated with metabolic activation.

Despite the immunosuppression, in this particular study, rutaecarpine actually got a clean bill of health w/respect to those liver enzymes - lol. Of course, there’s always the possibility it could affect the metabolism of some OTHER, potentially toxic drug or compound, but there’s no proof of that yet…so it’s a conversation for another day.

In the end, more research needs to be done, but as an indictment of rutaecarpine, Lt. Col. Freese’s article fails…it provides far more smoke than fire.  Good thing too, as rutaecarpine is getting around these days.

Setting rutaecarpine aside, what about other evidence that NO-Xplode causes abnormal liver enzyme tests?  There are only some scattered, anecdotal postings on the subject (I counted 6, out of the links I was given, here, here and here), all of which suffer from the same deficiencies that plague Lt. Col. Freese’s report: no numbers (w/one, limited exception) and no context (i.e., diet, timing of the test vs. workouts; other supps possibly stacked w/it). 

And there aren’t that many of these reports, either.  Are users just not getting blood work done?  Or are they simply not seeing any reason to be alarmed?   Understandably, positive reports are harder to find, although I did turn this one up:

My experience with No Xplode has been incredible. I am HIV+ ( for 17 years )and was having a big problem with a lack of energy when weightlifting. I eat very healthily and eat to gain weight, so my energy problem did not stem from my diet. After all the years of being poz and taking the meds, I think I was just drained. Normal everyday activities were fine but I could last about 1/2 hour for a workout and I was done. I started No Xplode and actually trained a year to compete in physique at the Gay Games and won a gold medal and I attribute it to this supplement. I could not workout without it. Now I’ve started playing tennis and it gets me through 3 sets easily. I do bloodwork every 3 months and after 2 years of continuous use of No Xplode my liver function is normal and my health/bloodwork is the best it’s ever been.

Needless to state, this doesn’t invalidate the other reports, although it does call the universality of the phenomenon into question, methinks.

So where does this leave us?  Unfortunately, with more questions than answers.  On the bright side, I’ve seen no reports (either anecdotal or case histories) of any users diagnosed with drug-induced liver disease, which is certainly a potential outcome of chronic exposure to hepatotoxic agents.  Based on the limited (and poor quality) data, I’m tempted to conclude that any effects NO-Xplode has on liver function are either a) transient; b) relatively harmless; c) spurious; or d) occur within a small, uniquely sensitive population.

Nevertheless, I can’t be 100% sure…this is basically a judgement call, based on what I have in front of me – thus, I could change my mind as more info comes in. 

In the meantime, does NO-Xplode get a thumbs up?  Or down?

Under the circumstances, neither one. NO-Xplode works, but it’s definitely a “kitchen sink” supp – and the more ingredients you shove into a formula in order to make it look cutting edge and sciency (a definite marketing advantage, as Muscletech proves), the greater the potential risk of adverse interactions with other compounds in the formula; and/or other compounds in someone’s supp stack.

Ultimately, this is where the philosophy part comes in…in my opinion, this is not a desirable situation.  NO-Xplode may be benign (I hope!), but some other supps – whether already on the market or still on the drawing board – may not be.  But the powers-that-be are NOT going to make any changes in the way they do business unless they find compelling reasons to do so.  Those reasons will either come from the top down (i.e., tighter government regulation), or from the bottom up (i.e., market pressure from more demanding consumers).

I think y’all know which one I favor…

Personally, I think supplement consumers could do themselves a great big favor by doing one or more of the following:

  • buy supps that clearly list the amounts of each component on the label (Labrada SuperCharge Xtreme NO is a good example) – avoid “proprietary blends”.
  • choose supp formulas with a limited number of well-chosen ingredients backed by solid human and/or animal studies (as a former practitioner of the fine art of cell/tissue culture, I have HAD IT UP TO HERE with ingredients that have only cell culture studies behind them).
  • support companies that do basic safety and efficacy testing, and put their data front and center (Gaspari Novedex XT is a good example).

In the end, I’d like to see fewer questions like this, not more.  If nothing else, it will save me one hell of a lot of typing in the future. ;-)