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This is the final post in which randomized, clinical trials of the potentially active ingredients in the branded drink Souvenaid are reviewed. (For background on Souvenaid's development, go here, here, here, and here.) 

The remaining components to be examined in the nutritional supplement are phospholipids, choline, and uridine monophosphate (UMP).

In the case of UMP, a directed PubMed search reveals no randomized, controlled trial of the RNA nucleotide in Alzheimer disease. Therefore the rationale for assessing UMP in cognitive dysfunction appears to extend solely from animal studies (for instance, see a 2008 rat study by anchor author Wurtman, who is also coauthor of the recently published Souvenaid study).

The rationales for giving phospholipids or choline to AD patients are either 1) to bolster the integrity of neuronal membranes by providing the necessary building blocks, or b) in the case of choline, to supply a precursor for the neurotransmitter acetylcholine, which is deficient in AD. 

Barring the negative studies of lecithin,* a potential source of both phospholipids and choline, there are at least 9 randomized, controlled trials (published from 1986 to 2003) of these substances in dementia. Six studies, from the 80s and 90s, assessed the specific phospholipid phosphatidylserine; 3 studies assessed choline alfoscerate or citicoline. Most of these studies enrolled outpatients with mild-to-moderate AD. General study features are tabulated here:

Intervention	N	Duration	Outcome in a Nutshell
Phosphatidylserine
1986	42	6 wk	Trend toward improvement or significantly improved
1986	No abstract	—	—
1992	51	3 mo	Improvement observed in milder disease
1992	33	2 mo	Mixed improvement
1992**	40	6 mo	PET-correlated cognitive improvement
1994**	70	6 mo	Temporary improvement
Acetylcholine precursors
1993	126	?	Significant improvements with choline alfoscerate
1999	30	3 mo	Citicoline associated with improvements in APOE ε4 carriers; effect more pronounced in mild disease and associated with physiologic changes
2003	261	6 mo	Choline alfoscerate improved cognition or delayed cognitive decline

Cumulative data from the relatively small, controlled studies of phosphatidylserine in AD suggest that whatever cognitive improvements exist, they are short lived.

The most compelling support for the use of choline (ie, choline alfoscerate) comes from a sizeable, randomized, placebo-controlled, 6-month study performed at the Instituto Nacional de la Senectud in Mexico City. Cognitive assessments, performed with the ADAS-cog and other well-recognized tests, showed either a significant delay in cognitive decline or actual cognitive improvement. 

Nevertheless, these impressive results must be replicated. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; PET = positron emission tomography.

* A directed PubMed search reveals at least 5 studies of lecithin in AD, published from 1981 to 1987. Among the 3 small placebo-controlled studies in which an abstract is provided, none showed clinical improvement with supplementation (treatment duration, from 10 weeks to 6 months), despite a rise in plasma choline levels. These search results omit at least 8 trials of the defunct cholinesterase inhibitor tacrine, in which lecithin was provided as standard treatment.

** Treatment options were phosphatidylserine or pyritinol, a vitamin B6 analog.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

Vitamin E and other antioxidants are included in the branded, nutritional drink Souvenaid, which is being developed as a treatment for Alzheimer disease. However, well-controlled clinical data to justify their use in AD or mild cognitive impairment (MCI) are scarce, and positive trial data require qualification.

The most prominent (and confounding) trial in which vitamin E was assessed in AD was the Alzheimer Disease Cooperative Study, published in 1997 in the NEJM. In this multicenter US study, 341 patients with moderately severe AD received randomized selegiline (10 mg/d), vitamin E (2000 IU/d), both, or placebo in a double-blind fashion.

In the unadjusted analysis, there were no significant differences among the 4 treatment arms with respect to the combined primary outcome of death, institutionalization, loss of the ability to perform basic ADLs, or severe dementia at 2 years. However, the trial results had to be statistically accommodated, because the mean baseline MMSE score of placebo-treated patients, despite randomization, was significantly higher than those of other enrollees. "[A]nd this variable," the authors predictably concluded, "was highly predictive of the primary outcome."

And so an adjusted analysis was performed, in which the investigators observed significant delays in the combined primary outcome with all 3 randomized treatments—selegiline, vitamin E, and both—when compared with placebo.

But these data are at odds with results from a 3-part Italian study of vitamin E and donepezil (Aricept; Eisai/Pfizer), published sequentially in 2001, 2002, and 2003. Among 40 patients with moderately severe AD who received randomized vitamin E (2000 IU/d), latencies of P300 recordings (a very rough, electrophysiologic indicator of cognition*), and cognitive scores declined significantly at 26 weeks (when compared with donepezil treatment [5-10 mg/d]).

These findings are supported by follow-up results, in which P300 latencies and cognitive test scores deteriorated with vitamin E supplementation at 3 months in patients with mild AD (n = 30). Cognition also significantly declined in subjects with moderate-to-severe AD (n = 30) who received vitamin E. Other electrophysiologic indicators of cognition worsened in a smaller and much briefer (ie, 30-day) study of vitamin E and donepezil in patients with "mild dementia."

To assess the potential benefit of vitamin E supplementation to prevent AD, investigators at the Mayo Clinic conducted a randomized, double-blind, placebo-controlled study of 769 patients with amnestic MCI. The results, published in a 2005 issue of the NEJM, showed no significant delay in the development of AD at 3 years with vitamin E (2000 IU/d) or donepezil (10 mg/d).** The annual rate of progression from MCI to AD was 16%, a rate that has been subsequently confirmed. 

The most recent trial assessing vitamin E in AD was published last year. In this small Spanish study, 57 patients with AD were assigned to placebo or vitamin E (800 IU/d) for 6 months. Among the 33 study completers, investigators correlated a controversial measure of oxidative stress (reduced glutathione) with maintained cognition in vitamin E-treated subjects. The authors concluded that "supplementation of AD patients with vitamin E cannot be recommended without determination of its antioxidant effect in each patient."

The American Psychiatric Association, as of 2007, no longer recommends vitamin E for the treatment of dementia because of limited efficacy data and potential safety concerns. The latter relate to reports of increased cardiovascular and cerebrovascular mortality. However, these risks may not be relevant in AD patients, according to a recent, longitudinal survival study.

So these clinical data for vitamin E in AD or MCI leave us firmly nowhere.

But there are other potential antioxidants in Souvenaid: namely, selenium and vitamin C. What are the clinical data to support their use in dementing disorders?

There is one semi-controlled Polish study (1999) in which selenium (100 µg every other day) was compared with placebo and some proline-rich substance isolated from sheep colostrum [yeesh] in patients with mild or moderate AD (N = 46). Psychiatrists blinded to treatment determined that cognition stabilized in 13 of 15 selenium-treated patients at 1 year, vs 8 of 16 placebo-treated patients. (The sheep colostrum product reportedly improved or stabilized cognition in all 15 treated patients.)

Controlled assessments of vitamin C, aka ascorbic acid, in AD are virtually absent, at least by my search. An Italian AD study, published in 1995, used ascorbic acid as a reference standard. In a later Czech study, 50 mg of ascorbic acid was given daily to all AD enrollees. 

* Increased latencies suggest delays in neuronal transmission.

** However, the rate of progression to AD at 12 months was reduced with donepezil treatment, and the AChEI prevented full-blown dementia at all time points in carriers of 1 or more APOE e4 alleles--a known genetic risk factor for late-onset AD. More recent, controlled studies of donepezil in patients with amnestic MCI suggest that the drug delays the progression to AD among depressed individuals but has only a modest effect on cognition in a more inclusive population with MCI.

AChEI = acetylcholinesterase inhibitor; ADLs = activities of daily living; MMSE = Mini-Mental State Examination; APOE = apolipoprotein E.

Ingredients in the proprietary nutritional drink Souvenaid, which its developers claim work synergistically to rejuvenate neuronal synapses in Alzheimer disease, include several B vitamins. (For necessary background on Souvenaid development and negative trials of omega-3 fatty acids [another ingredient in Souvenaid] in AD, go here and here.)

The rationale for using vitamins B6,* B9 (folic acid), and B12 specifically in AD is to reduce levels of homocysteine, an independent risk factor for AD. However, a directed PubMed search provides little evidence of the benefit of oral B-vitamin supplementation in dementing disorders. A total of 4 randomized, double-blind, placebo-controlled trials were discovered, in which 1 or more of these vitamins were assessed in patients with AD.

Published in 2007, a Thai study enrolled 89 AChEI-treated individuals with mild-to-moderate AD, all of whom had normal folic acid and vitamin B12 levels. The daily, oral administration of B12 500 mg and a multivitamin containing B6 (5 mg) and folic acid (1 mg) provided no statistically significant cognitive benefits at 26 weeks (measured by using the 11-item ADAS-cog); nor was the ability to perform activities of daily living (ADLs) affected. Negative clinical benefits were observed despite the reduction of homocysteine levels in treated AD patients.

A smaller UK pilot study, reported in 2008, revealed that folic-acid supplementation in 57 AChEI-treated AD outpatients improved the ability to perform instrumental ADLs and social behavior (a combined outcome) at 6 months; but daily folic acid did not significantly alter cognition (measured with the MMSE).

The same year, JAMA published results of an 18-month multicenter US study of 409 individuals with mild-to-moderate AD and normal folic-acid, B12, and homocysteine levels. Randomized, oral supplementation with B6 (25 mg/d), folic acid (5 mg/d), and B12 (1 mg/d) reduced homocysteine levels but had no effect on cognitive decline (measured with the ADAS-cog) in 340 "completers." Curiously depression was more likely to occur in supplemented patients.

Finally last year a multicenter Dutch study was printed, in which "vascular care" was assessed in 130 outpatients with AD and evidence of cerebrovascular disease on brain images. The combined, randomized treatment of aspirin, folic acid, and B6 provided no statistical benefits with respect to measures of cognition, dementia-related disabilities, or behavioral problems at 2 years. Rates of institutionalization were also comparable between patients who received vascular care and those who didn't. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; AChEI = acetylcholinesterase inhibitor (eg, Aricept [donepezil]); MMSE = Mini-Mental State Examination.

* It should be noted the B6 supplementation is associated with a dose-dependent peripheral neuropathy (for instance see Berger et al and Parry and Bredesen). The Food and Nutrition Board of the Institute of Medicine recommends that daily B6 intake should not exceed 100 mg.

Photograph: Atrophied brain of person with AD from National Institute on Alcohol Abuse and Alcoholism.

Developers of the proprietary drink, Souvenaid, claim its ingredients work synergistically to restore neuronal synapses in diseases like Alzheimer disease (for necessary background on Souvenaid clinical development, see yesterday's post). However, many of the individual components in the formula have been shown to be ineffective, or only marginally effective, in AD. Among these ingredients are omega-3 fatty acids—specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). One rationale for using DHA and EPA supplementation in AD is based on their potential to reduce disease-associated inflammation.

A directed PubMed search reveals exactly 1 randomized, double-blind, placebo-controlled study of DHA and EPA in AD. The 6-month study, with a 6-month open-label extension, was performed at the Karolinska Institute between 2001 and 2004 in 174 patients with mild-to-moderate disease who were receiving acetylcholinesterase-inhibitor therapy (eg, Aricept). Data were collected on cognitive decline, neuropsychiatric symptoms, weight gain, and plasma markers of inflammation and were parsed into 4 articles, published from 2006 to 2009.

Daily DHA (1.6 g) and EPA (0.6 g) supplementation did not affect cognitive decline (measured with the MMSE and ADAS-cog scales) at 6 months; however, in the subgroup with very mild AD (n = 32), supplementation was associated with a statistically significant reduction in the decline of the MMSE score. (This observation likely informed the enrollment of patients with very mild AD in the Souvenaid trial.)

Nor did DHA/EPA supplementation affect neuropsychiatric symptoms, the ability to perform activities of daily living (ADL), or caregiver burden at 6 months. In detailed subgroup analyses, however, supplementation reduced agitation in APOE ε4 carriers* (n = 125) and depression in APOE ε4 noncarriers (n = 49). Make of that what you can; I don't make much of it.

On the other hand, weight increased significantly with supplementation at 6 months and continued to increase for both treatment groups in the open-label extension phase. APOE ε4 noncarriers and high DHA plasma levels were independently associated with weight gain, reported the authors.

As expected, plasma levels of DHA and EPA increased with supplementation (n = 23). In addition, they were associated with reduced levels of some inflammatory cytokines (eg, interleukin-6).

* A genetic risk factor for late-onset AD.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; APOE = apolipoprotein E; MMSE = Mini-Mental State Examination.

Image of cod liver oil capsules from Wikipedia.

Last week, various mainstream news sources reported the positive results of a randomized, double-blind, placebo-controlled, multicenter study of Souvenaid, a proprietary nutritional drink, in people with mild Alzheimer disease. The objective of the trial, printed in the latest issue of Alzheimer's and Dementia, was to restore neuronal synapses by providing "rate-limiting precursors for membrane phosphatide synthesis, such as...uridine, omega-3 polyunsaturated fatty acids, and choline," which Souvenaid contains. Citing rodent studies, the authors claimed, "These nutrients synergistically increase brain levels of phosphatide molecules that comprise the bulk of synaptic membranes, and brain levels of specific synaptic proteins, suggesting that they also increase synapse formation" [emphasis added].

Yes, it'd be nice to have a boosted smoothie that wards off cognitive decline, but...

To the credit of at least one news source, mainstream coverage of the Souvenaid study was tempered by reports of AD experts' "disdain" for the trial and its results.

Among the criticism:

• The relatively short length of the study, 12 weeks. The generally accepted minimum duration of an AD trial is 26 weeks; most extend to 1 year or longer.*
• The lack of benefit when measuring cognition with standard tests, like the ADAS-cog.
• The potential conflicts of interest among the authors, given their intimate connections to the company that makes Souvenaid. Notably coauthor Richard J. Wurtman, of MIT, owns patents on "uridine, omega-3 fatty acids, and choline to treat brain diseases by enhancing synapses," according to the study disclosures.

A review of the study article reveals additional problems.

• Because one unnamed study site failed to comply with ICH-GCP guidelines, data from 13 individuals (~6% of the study population) were excluded from the efficacy analysis.
• At baseline, approximately 40% of enrollees scored 0, the lowest score, on the delayed verbal-recall test (Wechsler Memory Scale-revised), one of the 2 primary outcome measures. This skew in the study population required the authors to use a nonparametric analysis (eg, use general categories of better, worse, and unchanged), instead of the planned parametric assessment (that is, use mean score changes in the study arms). Furthermore it's not clarified that the percentages of 0 scorers at baseline were similar in the 2 treatment groups. If they were not, then the potential for enrollees to decline on the basis of assigned treatment would certainly be affected.

Finally, although the authors claim synergistic effects of Souvenaid's active ingredients on synapse restoration, many of the individual ingredients in the formula have been shown to be ineffective (or only marginally effective) in AD. Watch for upcoming posts at the Pathophilia blog that review these AD studies.

* A 12-week blinded extension phase was conducted (n = 161). No benefit was seen with respect to the 2 primary outcome measures, but immediate verbal recall was significantly better in the group receiving Souvenaid.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; GCP = good clinical practice; ICH = International Conference on Harmonisation; MMSE = Mini-Mental State Examination.

Photograph: Atrophied brain of person with AD from National Institute on Alcohol Abuse and Alcoholism.

Addendum: On the basis of the 12-week proof-of-concept study, the makers of Souvenaid are recruiting enrollees for a multicenter US study, called S-Connect. The trial, however, is not registered in the NIH database. The 40 US trial sites, 3 of which appear to be university affiliated, are listed here.

Seven Israeli infants who were fed a thiamine-deficient soy-based formula remain moderately to severely neurologically impaired at 5 years. Long-term impairment includes various degrees of mental retardation and motor, brainstem, or basal-ganglia dysfunction. The grave outcomes for these children, who displayed severe epileptic seizures during infancy, are presented in the latest print issue of Neurology.

A total of 20 Israeli infants were "seriously" affected after being fed the kosher baby formula, Remedia Super Soya 1—which was produced in 2003 by Humana, a German company, and imported by Remedia, an Israeli company. Infants quickly developed the known symptoms of cardiomyopathy or neurologic dysfunction that are associated with wet and dry beriberi, respectively. At least 3 infants died. Tests of the formula revealed negligible amounts of thiamine.

In an accompanying editorial, child neurologist Marc Patterson reviews the effects of deficient thiamine, or vitamin B1, which cannot be synthesized or stored to any significant degree by humans. In addition to the long-described forms of beriberi, thiamine deficiency is also manifest in Wernicke encephalopathy and Korsakoff syndrome—amnestic conditions associated with inveterate alcoholism and diencephalic injury. Leigh disease, a metabolic pediatric encephalopathy associated with thiamine deficiency, is neuropathologically similar to Wernicke disease, minus the mammillary-body lesions. Infantile thiamine deficiency, itself, is very rare in developed nations and is seen primarily in infants who are breastfed by thiamine-deficient mothers. It has a better prognosis, however, than Leigh disease.

According to the Jerusalem Post, parents of the affected infants received substantial financial compensation from the formula manufacturer and the Israeli importer. The Israeli State Attorney's office is prosecuting 3 Remedia officials and 5 Health Ministry workers—including pediatrician Dorit Nitzan-Kaluski, the former head of the Food Service Division and coauthor of the 2005 report of the incident in Pediatrics.

Depicted chemical structure of thiamine from Wikipedia.

For some completely unknown reason, today's WSJ gives free publicity to Pamlab, LLC, a Louisiana company that sells an oral, "high-dose" vitamin B supplement for peripheral neuropathy. 

Treatment of neuropathy with various forms of vitamin B has been around for at least decades, and the promotion of B supplementation rears up periodically in the lay press (as in the case of today's WSJ) and mostly bottom-feeding medical journals. The popularity of vitamin B6 (pyridoxine), specifically, as a neuropathy treatment probably has its genesis in the use of the vitamin to reduce the risk of isoniazid-induced neuropathy when treating tuberculosis. We're talking Eisenhower era.

The problem is that clinicians forget (or never knew) that high-dose B6, itself, can cause a toxic sensory neuropathy, which was documented in 1983 in the NEJM. Reversible B6 neuropathies were also described in 172 women in 1987 who used lower vitamin dosages (mean, 117 mg/d ± 92). These clinical neuropathies were more likely to occur with longer durations of treatment.

Pamlab's supplement contains 25 mg of the active form of pyridoxine, with a recommended dosage of 1-2 tablets per day. This dosage is within the standard deviation of the B6 range reported in the 1987 case series. Pamlab says that its supplement (which is only available by prescription and costs a stunningly high $40-$70 per month) has been shown in unpublished clinical trials to improve foot sensation and pain, writes the WSJ. (The supplement also contains 2.8 mg of L-methylfolate [the active form of folate, or B9] and 2 mg of methylcobalamin [a form of B12].)

The WSJ also cites a Cochrane review from July, which concluded that there is currently insufficient evidence to use vitamin B supplementation for neuropathy. The Cochrane authors found only 13 randomized or "quasi"-randomized studies (N = 741) from the mid-1960s to 2005, which compared vitamin B supplementation with placebo in general peripheral neuropathy. A considerably fewer number of trials compared vitamin B complex with an active control. Placebo-controlled trials provided mixed efficacy results, and active-comparator trials suggested that vitamin B supplementation is less efficacious in the short term than other agents. (Specific forms of vitamin B, with the exception of thiamine, are not highlighted in the Cochrane abstract.)

Pamlab informed the WSJ of an unblinded study of its vitamin B supplement, which was presented last month by a podiatrist at an unidentified scientific conference. The NIH Clinical Trials database includes a randomized, double-blind, placebo-controlled phase 4 study of the proprietary product in patients with type 2 diabetic neuropathy. The study is currently recruiting patients at selected US locations.

Why the WSJ chose to showcase Pamlab's vitamin B product, without 1) having more definitive scientific information to support its use in neuropathy and 2) citing the risk of neuropathy with B6 supplementation, is a minor mystery. 

D'oh! Just when you thought you dodged an IOC bullet, the overseer of the Olympic Games announced yesterday that it will further analyze blood and urine samples collected from athletes at this summer's Beijing games. First on the retroactive testing list is Roche's long-acting red-cell booster Mircera.* But the IOC also warns that it will store the Beijing samples for 8 years to enable additional analyses when new drug tests become available.

In Beijing, 4770 doping tests were conducted on blood or urine, covering the period from July 27th to August 24th. But only 6 out of approximately 11,000 athletes suffered sanctions as a result of positive tests, an unexpected, low number (Table). Therefore the IOC will retest samples with a recently validated assay for Mircera. The announcement comes on the heels of news this week that 3 more Tour de France racers tested positively for the substance.

Disqualified Athlete		Country	Sport	Highest Placement	Detected Substance
1	Lyudmila Blonska	Ukraine	Heptathlon	2nd	methyltestosterone
2	Igor Razoronov	Ukraine	Weightlifting	6th	nandrolone
3	Fani Halkia	Greece	Hurdles	—	methyltrienolone
4	Jong Su Kim	North Korea	Shooting	2nd	propanolol
5	Isabel Moreno	Spain	Cycling	—	Epo
6	Thi Ngan Thuong Do	Vietnam	Gymnastics	15th	furosemide

(IOC decisions regarding 3 other alleged Olympic doping cases, Belarussian hammer throwers Vadim Devyatovskiy and Ivan Tiskhan [testosterone] and Polish kayaker Adam Seroczynski [clenbuterol], are pending.)

* A pegylated version of recombinant erythropoietin.

Image of a freakishly bulked-up Lyudmila Blonska from Wikipedia.

In a welcome study of poorly regulated dietary supplements, investigators in Boston report the presence of toxic heavy metals—namely lead, mercury, or arsenic—in one fifth of US- or Indian-made Ayurvedic products. Results of a metal survey of these Internet-sold drugs were published in the latest issue of JAMA.

Among 199 of 230 randomly selected Ayurvedic medicines available for web-based purchase,* nearly 21% contained metals per x-ray fluorescence spectroscopy, wrote the authors, with no appreciable difference between US- and Indian-made products. Rasa shastra drugs—which combine herbs with metals, minerals, and gems—were significantly more likely to contain metals than non-rasa shastra products (41% vs 17%) and contained significantly higher median concentrations of lead (11.5 vs 7.9 µg/g) or mercury (20,800 vs 34.5 µg/g).

The amount of metals detected in metal-containing products consistently exceeded one or more standards for acceptable daily intake. These drugs were much more likely to be sold at US web sites (Table), and 75% claimed Good Manufacturing Practices, wrote the authors. In some cases, products were specifically recommended for pediatric use.

Product(s)	Manufacturer	US Web Site	Metal(s) Detected†
Prana-Breath of Life	Ayurherbal Corporation	By the Planet	Lead and/or mercury
AyurRelief, GlucoRite	Balance Ayurvedic Products	Balance Ayurvedic Products	Lead
Mahasudarshan	Banyan Botanicals	The Ayurvedic Institute	Lead
Kanchanar Guggulu, Shilajit	Banyan Botanicals	Banyan Botanicals	Lead
Acnenil, Bakuchi, Brahmi, Chairata, Cold Aid, Trifala Guggulu, Heart Plus, Jatamonsi, Kanta Kari, Licorice, Praval Pisti, Prostate Rejuv, Sugar Fight, Tagar, Yograj Guggulu	Bazaar of India	By the Planet	Lead, mercury, and/or arsenic
Energize	Bazaar of India	Bazaar of India	Lead
Hingwastika	Bazaar of India	Herbal Remedies	Mercury
Lean Plus, Neem Plus	Tattva's Herbs	Tattva's Herbs	Lead

These findings are consistent with those of a previous report, in which 20% of 70 Ayurvedic products made in South Asia and sold in Boston contained higher-than-regulatory amounts of lead, mercury, or arsenic. Scores of clinically symptomatic cases of heavy-metal intoxication due to the ingestion of Ayurvedic drugs have been reported since 1978.

* One web-based supplier of Ayurvedic products refused to fill an order for 14 products after recognizing that the purchasers were authors of a previous study.

† Measurement greater than reporting levels for x-ray fluorescence spectroscopy (ie, lead, ≥5 microg/g; mercury, ≥20 microg/g; arsenic, ≥10 microg/g).

In honor of the upcoming Olympics and prompted by recent (alleged) doping incidents, here are the substances prohibited by the World Anti-Doping Agency (WADA). The list indicates that world-class athletes and trainers are highly enterprising in their search for (and cover-up of) that little extra edge.

Prohibited in and out of competition

1. Exogenous and endogenous anabolic androgenic steroids (AAS): A perennial favorite. Olympic athletes from East Germany, especially female swimmers, were systematically doped with AAS from 1965 to 1989, as were the obviously acned, female swimmers from China in the 1990s. According to sports medicine expert Ken Fitch, MD, AAS was the most frequently detected category of banned substances in athletes who participated in the last 2 Summer Olympics. Canadian sprinter Ben Johnson famously lost his gold medal from the 1988 games owing to the post-race detection of anabolic steroids. And last year, American medalist Marion Jones admitted to anabolic steroid use in preparation for the 2000 Olympics in Sydney. The use of designer AAS, which may evade current detection methods, has emerged as a particular problem during the last few years, writes Fitch.
2. Other anabolic agents: The β2 adrenergic agonist clenbuterol was allegedly detected in urine samples this month from US swimmer Jessica Hardy. Selective androgen-receptor modulators, investigational agents for the treatment of osteoporosis and muscle atrophy, are new to the WADA list as of this year. Tibolone is a postmenopausal hormone replacement therapy (HRT) with estrogenic, progestogenic, and androgenic properties. Also banned are the cattle-feed steroids zeranol and zilpaterol.
3. Other hormones and related substances: Doping with erythropoiesis-stimulating agents (ESAs) is notorious in endurance sports, like cycling and long-distance running. Also widely abused, human growth hormone (hGH) is reportedly taken frequently with AAS by doping athletes. However, a reliable test for distinguishing exogenous from endogenous hGH has been elusive, according to the literature, and physiologic levels of hGH can vary widely within and among individuals. Other banned endocrinologic agents include insulin-like growth factors, the new-to-me mechano growth factors (MGFs), gonadotrophins (luteinizing hormone, human chorionic gonadotropin* [in men only]), insulins, and corticotrophins.
4. β2 agonists: For example, clenbuterol. The use of inhaled anti-asthmatic drugs, like formoterol, salbutamol, salmeterol, and terbutaline, requires an Abbreviated Therapeutic Use Exemption.
5. Hormone antagonists and modulators: Here's disturbing enterprise. Athletes use agents indicated for hormone-receptor-positive breast cancer, like aromatase inhibitors (eg, anastrozole) or selective estrogen-receptor modulators (eg, tamoxifen), to produce an indirect androgenic effect. Also new to the WADA list this year are inhibitors of myostatin, an endogenous factor that limits the growth of muscle tissue.
6. Diuretics and masking agents: The general idea is either pee out the banned substance or dilute it. An example of a masking agent is epitestosterone, which is used to normalize the testosterone-to-epitestosterone ratio during traditional testing. According to Wikipedia, US runner Mary Decker failed a T/E ratio test in 1996. Other banned substances in this category, besides traditional diuretics, are probenecid, α-reductase inhibitors, and plasma expanders (eg, albumin).
7. Blood and blood substitutes
8. Gene doping: Circulating now is news of a German TV report that warns of gene doping (eg, stem cell therapy) offered in China.

Prohibited in competition

1. Stimulants: For example, amphetamine, ephedrine.
2. Narcotics
3. Cannabinoids: Not even in snowboarding, dude.
4. Nontopical glucocorticoids: Although intra-articular and similar local injections require an Abbreviated Therapeutic Use Exemption.

Prohibited in particular sports

1. Alcohol: With regard to the Olympics, alcohol levels greater than 0.10 g/L are prohibited in archery (ouch), karate (huh?), and shooting sports (bigger ouch).
2. β-blockers: The use of β-blockers is prohibited in archery (in and out of competition), bobsledding (but not luging?), curling (aw, somebody cares), gymnastics, shooting sports, skiing, snowboarding, and wrestling.

* Yes, the pregnancy hormone.

Photo: Qian Hong, winner of the 100-m butterfly at the 1992 Barcelona Olympics and possessor of killer triceps.