EPHEDRINE AND ITS SUBSTITUTES

EPHEDRINE AND ITS SUBSTITUTES

Ephedrine is a molecule found in many plants that was sold widely as a sports supplement to enhance workouts, cause weight loss, and best of all, melt fat. It also was sold as an herbal (and safer) substitute for Ecstasy (methylenedioxymethamphetamine, MDMA). Ephedrine has been banned since 2004 (a ban upheld in 2007), although it sometimes crops up on the Internet in some forms including herbal teas, in Chinese herbal remedies, and in a chemically synthetic form as an asthma treatment. Ephedrine is an effective medicine for treating asthma and has been used medically as such in appropriate doses for thousands of years because it acts as a mild stimulant to the sympathetic nerve endings to dilate bron­chioles, increase heart rate and blood pressure, and raise blood glucose. However, this drug does not enter the brain well and at best causes a jit­teriness that most people find discomfiting even when used in appropri­ate amounts for the treatment of asthma. At higher doses, ephedrine causes an arousal and anxiety state that most people find unpleasant, although some report positive feelings with the arousal. Relative to other stimulants, these effects are mild.

These characteristics explain why ephedrine, especially at excessive doses, can be mistaken for MDMA and is popular for improving athletic performance. Ephedrine increases heart rate and blood pressure and can give the feeling of greater physical activation, which can be mistaken for improving athletic performance. If high enough doses are taken, these effects are associated with some increase in arousal and anxiety, so the users can "feel" a drug effect. But in fact, ephedrine does nothing to improve muscle development.

There may be some truth to claims that ephedrine can help contribute to weight loss due mainly to its effects on the body to facilitate fat breakdown and increase energy production, but the effects are minor. Ephedrine and ephedrine/caffeine preparations have been tested on obese humans and have been found to have a modest benefit (one well-controlled study reported a five-pound weight loss in two months, and a total of ten pounds of weight lost in five months).

The FDA banned ephedrine because of many (thousands) reports of adverse events including milder side effects like tremors, headache, insomnia, nausea, vomiting, fatigue, and dizziness as well as a number of deaths in young, healthy people who experienced heart attacks or strokes (especially when using this drug while exercising).

Numerous substitutes for ephedrine have entered the marketplace. Some of these are relatives of ephedrine (p-synephrine), and some are plant prod­ucts whose active ingredients aren't known or listed (Hoodia, Cha de Bugre). Three common ingredients are beta phenylethylamine (PEA), p-synephrine (the active ingredient in bitter orange), and dimethylamylamine.

Beta phenylethylamine is a drug that works very much like ephedrine and so has very similar effects: it raises blood pressure and heart rate due to the release of norepinephrine. In addition to its ability to mimic sym­pathetic stimulation, it also stimulates "trace amine receptor 1," a minor receptor that exists throughout the body through which it constricts arteries and probably has other actions. Unlike ephedrine, PEA enters the brain, and at high doses it causes the release of dopamine and norepi­nephrine and causes stimulant-like behavioral effects. Normally, these effects are limited by the rapid metabolism of PEA by monoamine oxi­dase in the liver and in the brain. Little is known about how high PEA levels get when humans ingest pharmacologic amounts as supplements: there has been almost no investigation of this.

PEA has another unique characteristic: it is a natural constituent of the brain (albeit a minor one), and over the years scientists have measured levels in the urine and blood of patients with a variety of disorders includ­ing ADHD, schizophrenia, depression, and Parkinson's disease in the hopes of understanding whether there is a link there. These research find­ings are mixed between speculations that it is beneficial (lifting depres­sion after exercise) or harmful (contributing to the acceleration of dopamine neuron death after monoamine oxidase therapy). So is PEA a natural therapy or dangerous sympathomimetic? We don't know. It is certainly physiologically and behaviorally active, based on a few studies. However, the same caveat exists for this supplement as for many others: you are not guaranteed to get the dose that is advertised, and sometimes not even the molecule that is advertised.

p-Synephrine is a simpler story. This is a very close relative of the nasal decongestant m-synephrine, better known as phenylephrine. It was used as a drug in the 1920s but has not been marketed for many years. However, its source as a dietary supplement is usually from immature (green) Seville oranges. It is used primarily for weight loss and as a component of sports supplements. It has been used in traditional Chinese medicines for diges­tive problems. Its main well-characterized effect from the old animal stud­ies of the sympathetic nervous system is to raise blood pressure, probably by stimulating the alpha-adrenergic receptor for norepinephrine, and per­haps through the weak inhibition of norepinephrine uptake. This effect has been observed in humans in some but not all studies. Its effectiveness as a weight-loss agent is in the eye of the beholder: reviewers who acknowl­edged their association with its marketing have taken a more positive view of the "modest" weight loss and benign side-effect profile than reviewers without a conflict of interest. Most studies of both its effectiveness as a weight-loss agent and its cardiovascular effects have been conducted on supplement mixtures containing caffeine, so it is hard to know the efficacy of the p-synephrine mixtures that are widely marketed. It would be logical to assume that the benefit-risk profile is similar to ephedrine.

DMAA is marketed as a constituent of rose geranium, although formu­lations may have geranium extract or synthetic DMA A. It is currently under investigation by the FDA, which has contested its existence as a natural product in geranium and, hence, questioned the freedom to mar­ket it under the protection of natural-product legislation. The purified molecule was used as a nasal decongestant for decades, ending in the 1970s. Like p-synephrine, its main action is as an alpha-adrenergic ago­nist that constricts blood vessels and raises blood pressure. There is little scientific evidence that it lowers weight or improves muscle mass. Fur­thermore, the first few reports are starting to trickle in of healthy young people experiencing strokes when using DMAA/caffeine combinations during heavy workouts—exactly the scenario that resulted in ephedrine casualties.

Finally, these drugs are often sold in complicated mixtures containing caffeine. Combinations of ephedrine and similar stimulants with caffeine are much more likely to lead to effects on the heart and circulation, jitter­iness, anxiety, and arousal than either drug does alone. Furthermore, the potential for overdosing is high given the free availability of both drugs. The effects of ephedrine and PEA can be exaggerated, leading to danger­ous increases in blood pressure in patients taking monoamine oxidase inhibitors for the treatment of depression (Marplan, Nardil, Parnate).

These are just three examples of the continual challenge users face in evaluating the effectiveness and safety of herbal drugs, especially those used as sports supplements when people are working out. Manufacturers are not required to prove efficacy or safety. If all that happens is that you waste your money on an ineffective product (which might have placebo value for you), then it isn't a big problem. But with drugs that simulate the effects of norepinephrine on the heart and blood vessels like many of these sports supplements, the outcomes of taking excessive amounts can be catastrophic.