Health Professionals

Table 1.1. Percent Ephedra Alkaloids in Twenty Herbal Products (Sagara et al. 1983).

Product	E	PE	ME	NE	Total
China 1	0.623	0.556	0.101	0.021	1.30
China 2	1.396	0.361	0.069	0.142	1.97
China 3	0.620	0.963	0.057	0.04	1.68
China 4	0.838	0.295	0.093	0.039	1.27
China 5	0.845	0.352	0.086	0.032	1.32
China 6	0.719	0.654	0.086	0.033	1.49
China 7	0.937	0.384	0.134	0.034	1.49
China 8	0.725	0.298	0.087	0.023	1.13
Pakistan	0.526	0.187	0.031	0.027	0.77
Russia	0.917	0.897	0.032	0.018	1.86
Japan	0.695	0.074	0.041	0.071	0.88
Average Alkaloid Content	58.3%	33.1%	5.4%	3.2%	100%

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Liu et al. (1993) conducted an analysis of 22 herb samples collected from herb shops throughout Taiwan using capillary electrophoresis. Considerable differences were noted in the relative content of ephedra alkaloids, even within the species used. The herbal products had been prepared using four ephedra species, E. sinica, E. intermedia, E. equisetina, and E. distachya. In some cases, the herbal shop had combined two ephedra species. As can be noted in Table 1.2, the average content of pseudoephedrine is slightly greater than ephedrine with these two alkaloids accounting for about 90% of the total ephedra alkaloid content.

The authors examined the relative content of ephedra alkaloids as related to the anatomic location within the herbal plant. It was determined that the total content within the internode region is about four times the total amount in the node. It was also found that the thin-stemmed samples had a total alkaloid content about 1.5 times that in the coarse-stemmed samples. It was also found that the total amount of constituents in the powdered form was about five times as great as the herbal material in the fibrous form. Therefore, the ephedra alkaloid content would appear to be highest in products prepared with thin stems with less nodes and fibers that snap easily. No ephedra alkaloids were found in the underground portion of the ephedra plant.

Table 1.2. Ephedra Alkaloids Measured in 22 Herbal Products (Liu et al. 1993).

Original Plant	E	PE	ME	MPE	NE	NPE	Total
E. sinica	1.601	0.175	0.184	0.015	0.043	0.029	2.047
E. sinica	0.437	0.344	0.060	---	0.021	0.027	0.889
E. sinica	0.684	0.248	0.077	---	0.039	0.027	1.075
E. sinica	1.112	0.230	0.109	0.006	0.053	0.043	1.553
E. sinica	1.037	0.706	0.110	---	0.032	0.086	1.971
E. sinica	1.380	0.625	0.169	0.018	0.031	0.085	2.308
E. sinica	0.634	0.814	0.068	0.006	0.042	0.089	1.653
E. sinica	0.58	0.505	0.058	0.013	0.043	0.057	1.256
E. intermedia	0.248	0.785	0.038	0.012	0.024	0.068	1.175
E. intermedia	0.165	1.023	0.032	0.015	0.02	0.098	1.353
E. intermedia	0.156	0.808	0.024	0.029	0.027	0.067	1.111
E. intermedia	0.098	0.787	0.015	0.02	0.020	0.073	1.013
E. intermedia	0.248	1.402	0.036	0.032	0.030	0.106	1.854
E. intermedia	0.124	0.561	0.017	0.017	0.010	0.025	0.754
E. sinica + E. equisetina	1.045	0.834	0.138	0.010	0.036	0.087	2.150
E. sinica + E. equisetina	1.006	0.459	0.123	0.010	0.055	0.063	1.716
E. distachya + E. equisetina	0.513	0.394	0.128	0.036	0.002	0.044	1.117
E. distachya + E. intermedia	0.238	1.028	0.028	0.025	0.018	0.070	1.407
E. sinica + E. intermedia	0.041	0.848	0.011	---	0.007	0.081	0.988
E. sinica + E. intermedia	0.556	0.740	0.099	0.015	0.023	0.052	1.485
E. sinica + E. intermedia	0.268	1.120	0.038	0.013	0.032	0.098	1.569
E. intermedia + E. equisetina	0.079	0.389	0.013	0.008	0.016	0.031	0.536
Ave. Concentration	12.250	14.825	1.575	0.300	0.624	1.406	30.980
Ave. % Alkaloid Content	39.5%	47.9%	5.1%	1.0%	2.0%	4.5%	100%

E = ephedrine; PE = pseudoephedrine; ME = methylephedrine; MPE = methylpseudoephedrine;
NE = norephedrine; NPE = norpseudoephedrine

Betz (1995) reviewed the literature on composition of dietary supplements and concluded that the alkaloid content of commercially available ma huang varied from 0.018 ‚ 3.4% with ephedrine (E) representing 70%, PE 26%, and ME 4%. The data pertaining to alkaloid content for four species are listed in Table 1.3.

Table 1.3 Percentage Ephedra Alkaloids in Four Common Ephedra Species (Betz et al. 1995).

	E		PE		ME
Species/variety	% in plant	Relative % of EA	% in plant	Relative % of EA	% in plant	Relative % of EA
Ephedra sinica	0.8	70	0.3	26	0.05	4
Ephedra equisetica	1.25	66	0.6	32	0.04	2
Ephedra intermedia	0.3	25	0.9	74	0.01	1
Ephedra intermedia v. tibetica	1.1	79	0.1	7	0.2	14
Average	.86	60	0.48	35	0.075	5.25

Reference: Betz (1995).

From the data in Table 1.3, the relative percentage of ephedra alkaloids is 60% ephedrine, 35% pseudoephedrine, and 5% methylephedrine. No PPA or norpseudoephedrine was reported. Note that the relative amount of pseudoephedrine in E. intermedia is greater than ephedrine.

White et al. (1997) assayed a typical ma huang product and determined that the ephedra alkaloid content consisted of 76% E, 19.2% PE, and 4.7% ME. They also reported very low variability in the ephedrine content of a random sampling of 32 capsules of the product tested. The Food and Drug Administration (FDA) analyzed the composition of a popular dietary supplement and determined that the content of the samples was similar to that reported by White et al. The FDA reported concentrations in two analyses as: 57% E, 30% PE, and 13% ME for one product and 57% E, 38% PE, and 5% ME for the other (FDA 1995). No PPA was listed as an ingredient.

Betz et al. (1997) conducted a series of analytical assays while at the FDA to determine the ephedrine alkaloid content of nine commercial herbal dietary supplements that contained ephedra. FDA field investigators at retail health food outlets throughout the United States had purchased the products. The FDA chemists analyzed the herbal products using g -cyclodextrin capillary GC/mass spectrometry and GC/matrix isolation/Fourier transform infrared spectroscopy. No synthetic isomers were found in any of the dietary supplements analyzed. Two products did not list ephedra on their labels, and the FDA chemists detected no ephedra alkaloids. In the other seven products, considerable variability was found in alkaloid content, ranging from 0.3 to 56 mg/g. Betz et al. (1997) reported the following levels of ephedra alkaloids (mg/g) in the nine products (commercial name not identified in report) (Table 1.4).

Table 1.4. Levels of Ephedra Alkaloids (mg/g) Found in Nine Commercial Herbal Products (Betz et al. 1997).

Product	E	PE	ME	NE	Total
A*	8.7	4.2	2.2	ND	15.11
B**	---	2.7	---	---	2.7
C	---	---	---	---	---
D	0.5	4.7	---	0.1	5.3
E	---	---	---	---	---
F	0.3	---	---	---	0.3
G	38.9	4.4	0.9	0.1	44.5
H	---	---	---	---	---
I	55.6	---	---	---	55.6
Average Alkaloid Content	84.2%	13.0%	2.5%	0.2%	100%

* Seven samples were analyzed and average value is presented.

** Four samples were analyzed and average value is presented.

--- Not detected or below detection limits.

From the data in Table 1.4, the relative percentage of ephedra alkaloids is 84.2% ephedrine, 13.0% pseudoephedrine, 2.5% methylephedrine, and 0.2% PPA. No norpseudoephedrine was detected; 0.2 mg/g of methylpseudoephedrine was found in product G.

Hurlbut et al. (1998) evaluated the ephedra alkaloid content of six herbal products using a solid-phase extraction cleanup and liquid chromatographic method with UV detection. The studies, jointly conducted by the FDA and Metropolitan College of Denver, developed the methodology for efficiently separating and accurately measuring seven possible ephedra alkaloids. The analytical method was tested with five purified alkaloids injected into matrixes with the result that 90% of the alkaloids were recovered with a relative standard deviation of 4.4% for alkaloid spikes between 0.5 and 16 mg/g. Following validation and perfection of the analytical method, analysis was performed on six herbal products, four on-shelf products and two raw products, that were ma huang extracts. In addition to determination of the ephedra alkaloid content of the products, the authors also conducted a comparison of the alkaloid recovery with the alkaloid content claimed by the manufacturer on the product label, and a validation of the analytical procedures and results by a second laboratory. The results of these tests are provided in Table 1.5.

Table 1.5. Analysis of Ephedra Alkaloids in Commercial Dietary Supplements, Comparison with Label Claims, and Intra-laboratory Comparisons (Hurlbut et al. 1998).

			Recovery
			mg/g		% of
Herbal Producta	Laboratory	Label claim, mg E/g	E	PSE	label claim	RSD, %
Product 1, finished product	1	15	14.8	0.4	98.5	4.7
Product 1, finished product	2	15	15.2	<0.5	101	5.2
Product 2, raw product	1	60	58.9	<0.4	98.2	6.3
Product 3, raw product	1	60	56.9	b	94.8	15
Product 3, finished product	2	60	59.1	2.8	98.5	5.6
Product 4, finished product	1	20	20.8	6.10	104	6.2
Product 5, finished product	1	25	20.9	<0.4	83.7	4.5
Product 6, finished product	1	10.6c	7.78	2.54	97.4	1.5
Product 6, finished product	2	10.6c	7.93	2.53	98.7	5.0

^a Finished products were on-shelf products; raw products were ma huang extracts.

^b PSE analysis not performed.

^c Unit of label claim is mg alkaloids/g.

As can be seen from Table 1.5, there are very few inter-laboratory differences, which validates the methodology and these analytical results. In addition, the variance between the amount of alkaloids measured and the manufacturer's claims on the label are reasonably close (± 5%), except for one sample, which appeared to have about 14% less ephedra alkaloids than claimed.

It should be pointed out that Gurley et al. (2000) found considerably greater variation between the measured alkaloid content and label claims for several commercial herbal products. They also found some substantial lot-to-lot variations for the same product. Gurley demonstrated minimal variation overall, however, because the major formulators had already employed Good Manufacturing Practices (GMP). Nevertheless, the variations demonstrated by Gurley et al. should be validated, and if the extent of the variation is found to be unacceptable, procedures should be introduced on a wider industry basis to assure compliance with labeling. Most major manufacturers of herbal products already have the means to assure production of a standardized product as well as the laboratory facilities to measure lots to determine compliance with labeling. Such GMP procedures should be instituted by all manufacturers of herbal products.

Gurley et al. (1997, 1998a, and 2000) conducted a series of analytical measurements of commercially available ECDSs, including those just described. Twenty products were analyzed by HPLC, of which 19 contained (-) ephedrine, which was the most common alkaloid found (Table 1.6). The quantities of the various ephedra alkaloids varied considerably and ranged from 1.09 to 15.33 mg per capsule. The second most common alkaloid was (+)-pseudoephedrine, which was present in 16 of the products and ranged from 0.16 to 9.45 mg per capsule. Nine of the supplements contained measurable amounts of (-)-methylephedrine. The least prevalent alkaloids were (+)-norpseudoephedrine and (-)-norephedrine, with quantities consistently below 0.5 mg/dosage form. Three products contained only (-)-ephedrine. One product did not list ephedra on the label and no ephedra alkaloids were detected.

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Table 1.6. Ephedra Alkaloids Measured in Twenty Herbal Products (Gurley et al. 2000).

Product	E	PE	ME	NE	NPE
A	11.27	1.38	---	---	---
B	3.03	0.53	---	---	---
C	1.09	0.16	---	---	---
D	2.84	1.49	0.28	0.17	0.31
E	13.57	0.81	0.20	0.19	0.21
F	---	---	---	---	---
G	12.78	9.45	0.61	0.25	0.38
H	8.10	---	---	---	---
I	9.34	---	---	---	---
J	9.58	1.10	0.18	0.16	---
K	10.14	1.49	0.22	---	---
L	2.58	3.37	0.33	0.20	0.42
M	15.33	3.11	---	---	---
N	8.90	1.37	0.39	---	---
O	11.60	---	---	---	---
P	8.53	3.44	---	0.19	0.20
Q1	6.25	8.44	0.20	---	---
Q2	2.63	7.52	2.71	---	---
R1	9.70	1.47	---	---	---
R2	9.72	2.17	---	---	---
S1	9.08	1.84	0.22	---	---
S2	2.51	5.29	2.58	---	---
T1	9.91	2.81	---	---	---
T2	14.23	4.31	---		---
Average Alkaloid Content	72.8%	23.2%	3.0%	0.4%	0.6%

--- - Not detected or below detection limits.

From the data in Table 1.6, the relative percentage of ephedra alkaloids is 72.8% ephedrine, 23.2% pseudoephedrine, 3.0% methylephedrine, 0.4% PPA, and 0.6% norpseudoephedrine.

Summary. Several analytical studies have been conducted to determine the ephedra alkaloids present in ECDSs. The studies appear to have analyzed those dietary supplements primarily sold and used in the United States. From the data provided in Table 1.7, it can be observed that the range for combined ephedrine and pseudoephedrine content was 87-100% with usually about 3-5% methylephedrine. In over half of the referenced reports, no other ephedra alkaloids were reported or the levels were negligible (0.2-4.5%).

Table 1.7. Summary of Ephedra Alkaloids Measured in Herbal Products

No. Products Surveyed	E	PE	E+PE	ME	MPE	NE	NPE	Reference
4	60%	35%	95%	5.3%	-	-	-	Betz et al. (1995)
9	84%	13%	97%	2.5%	0.2%	-	-	Betz et al. (1997)
1	57%	30-38%	87-95%	5-13%	-	-	-	FDA (1994)
1	76%	19%	95%	5%	-	-	-	White et al. (1997)
6	94%	6%	100%	-	-	-	-	Hurlbut et al. (1998)
20	73%	23%	96%	3%	0.0%	0.4%	0.6%	Gurley et al. (2000)
22	40%	48%	88%	5%	1.0%	2.0%	4.5%	Liu et al. (1993)
11	58%	33%	91%	5%	-	3.2%	-	Sagara et al. (1983)

- None detected or below detection limits.

1.3 Use of PPA (Norephedrine) or Norpseudoephedrine Data in an Evaluation of ECDSs

The FDA has relied heavily on the literature on PPA as a basis for proposed regulatory actions on ephedra-containing dietary supplements. The Ephedra Education Expert Panel has concluded that use of PPA data in a hazard evaluation of ECDSs is not scientifically appropriate. ToxaChemica, International, concurs with this conclusion. Specific information relating to this issue is provided in various sections of this report. The following are the three primary reasons why it is inappropriate to utilize PPA data in an analysis of the safety and efficacy of ECDSs:

• PPA is rarely found in ECDSs.
  Ephedra in dietary supplements used in the United States has a composition of ephedra alkaloids primarily consisting of 87-100% ephedrine and pseudoephedrine. Methylephedrine may be available in about half of ECDSs. No other ephedra alkaloid, including PPA or norpseudoephedrine, is found in most products, and if it is present, the amount is very minimal (usually 0.1-0.3mg/capsule). See Section 1.2. When compared to the amount of PPA often taken in decongestant preparations (150 mg/day in an adult), the relevant amount of PPA in ECDSs (when it is present) is less than 0.02% of the amount in the typical decongestant.
• PPA has different pharmacologic activity than ephedrine or pseudoephedrine.
  There may be a tendency in some hazard evaluations to lump all ephedra alkaloids together and consider that they all have the same hazards and risks. As pointed out by Karch (2000), "this is both foolish and misleading as it implies that the toxicity of all the enantiomers is equivalent, which is clearly not the case." He has further concluded that: "The pharmacokinetic and toxicokinetic behavior of any isomer cannot be used to predict that of any other ephedrine isomer." As indicated in Section 2.3, there are major differences between PPA and the two primary constituents of ephedra, ephedrine and pseudoephedrine. We support Dr. Karch's analysis and also conclude that it is medically and scientifically inappropriate to assume that all ephedrine enantiomers, and for that matter all ephedra alkaloids, are equivalent in their pharmacologic, pharmacokinetic, and toxicologic properties. See Section 2.3.
• In healthy individuals, ephedrine is only minimally metabolized to PPA.
  Demethylation is a biotransformation pathway for both ephedrine and pseudoephedrine with PPA and norpseudoephedrine the resulting metabolites. However, this pathway is ineffective in the metabolism of these agents due to the innate stability of the chemicals, their short residence time within the body, and rapid elimination via the urinary system. Several studies have demonstrated that only 4-6% of ephedrine is metabolized to PPA under normal circumstances, and the extent of metabolism of pseudoephedrine to norpseudoephedrine appears to be even less. The exception to this minimal biotransformation occurs in situations where a person has a disease (e.g., nephrosis) that alters the pH of the urine resulting in highly alkaline urine. In this case, both ephedrine and pseudoephedrine can be reabsorbed via the kidney tubules and re-circulate through the liver with an increase in metabolism to PPA or norpseudoephedrine.

Summary. PPA is a sympathomimetic as are ephedrine and pseudoephedrine, and in fact it is widely used in OTC pharmaceuticals. However, there are some substantial differences in the clinical uses of these agents. It should be obvious from the data presented in Section 1.2 that a safety evaluation of ECDSs, considering the individual ephedra alkaloids that are contained in the dietary supplements, should be based on primarily ephedrine and pseudoephedrine. Methylephedrine is present in about half of the surveyed products but usually no more that 5% of the total alkaline content. PPA, norpseudoephedrine, and methylpseudoephedrine, are infrequently present in ECDSs, and when present, they are in such miniscule amounts (usually <1.0%) that they should not be considered further (see Table 1.7).

2.0 Pharmacokinetics and Metabolism of Ephedrine Alkaloid-Containing Dietary Supplements

2.1 Absorption, Distribution and Elimination

Gurley et al. (1998b) studied the pharmacokinetics of botanical ephedrine (Escalation and Excel) and synthetic ephedrine in a randomized, crossover study. Two botanicals and synthetic ephedrine (25 mg ephedrine capsule) were administered in gelatin capsules to ten healthy human volunteers. Another herbal product (Up Your Gas) was administered in tablet form. Plasma levels were measured at various intervals over an 18-hour period. The doses of ephedrine varied slightly but ranged from 23.6 - 27 mg ephedrine. The results indicated rapid absorption for all products although the product administered in tablet form had slightly slower bioavailability than those administered via gelatin capsules. Elimination was consistent with a one-compartment first-order model with half-life of approximately five hours. The authors concluded that ephedrine, when administered as the unprocessed raw ephedra, had similar pharmacokinetics (absorption and distribution) to those observed for a single-ingredient ephedrine capsule. White et al. (1997) found that ephedrine followed a similar one-compartment, first-order kinetic model for elimination.

Gurley et al. suggested that ma huang toxicity has usually been related to accidental overdoses of the herbal products. However, they are of the opinion that since the pharmacokinetics of botanical ephedrine and "conventional ephedrine" do not differ significantly, the apparent toxicity of ephedrine from herbs could be related to factors of product marketing, such as lot-to-lot variability with some lots having excess ephedra alkaloids, perhaps greater than indicated on the label.

Ephedrine is highly absorbed when taken orally in tablet form, is widely distributed via system circulation, and is eliminated largely unchanged (Dollery 1991; Hoffman and Lefkowitz 1990; Meyers et al. 1980; White et al. 1997). According to Kanfer et al. (1993), pseudoephedrine is also highly absorbed from the gastrointestinal tract after oral administration with no presystemic (gastrointestinal) metabolism.

Wilkenson and Beckett (1968b) studied the metabolism and excretion of ephedrine in three subjects at two dose levels of 20.48 and 25.0 mg. They confirmed the rather complete absorption of ephedrine following oral intake of ephedrine in tablet form. The absorption and elimination kinetics for ephedrine could be described as a single first-order process following a lag period, although there was considerable inter- and intra-subject variations in both lag time and the rate constant for absorption. The lag times ranged from 0 to 18 minutes in the three subjects with a suggestion of longer lag time at the higher dose level.

They also determined that while there was considerable variability in the time for peak plasma level (range of 1.75 to 4.02 hours), the plasma elimination T 1/2s were basically the same for all three subjects, approximately 3 hours (range of 2.52 - 3.63 hours). The kinetics of absorption and elimination of pseudoephedrine is basically the same. Kanfer et al. (1993) found peak plasma concentrations of 1.39 and 1.97 hours after administration of 60 or 120 mg of pseudoephedrine-containing syrups. The plasma half-life was listed as approximately 6 hours, somewhat longer than seen with ephedrine. Welling et al. (1971) had previously obtained similar results when they administered ephedrine (25 mg) in either syrup or capsule form to three healthy males with an average urinary pH of 6.3. They found that peak urinary excretion rates ranged from 0.75 to 1.25 hours with elimination half-lives ranging from 5.33-6.12 hours.

It appears that the form in which ephedrine and pseudoephedrine are ingested may have minor influence on the rate of absorption. White et al. (1997) found that absorption of ephedrine is slower when ingested as the ma huang herb than if the ephedrine is given in a pure form, although there was little effect on the elimination half-life. In those studies, which involved 12 subjects, the time to peak plasma levels was 3.9, 1.69, and 1.81 hours for ma huang capsules, ephedrine tablets, and ephedrine solution, respectively. The corresponding elimination half-lives were 5.2, 5.74, and 6.75 hours. Gurley et al. (1998b) also found slightly slower absorption of ephedra alkaloids from pills than from gelcaps.

The pharmacokinetics of pseudoephedrine have been widely studied with many comparisons of immediate-release tablets and sustained- or controlled-release tablets (see review by Kanfer et al. 1993). Pseudoephedrine appears to have similar pharmacokinetics to ephedrine in that it has high gastrointestinal absorption with no presystemic metabolism and minimal hepatic metabolism. Only 1% of pseudoephedrine was demethylated to norpseudoephedrine. It is eliminated largely unchanged in the urine (Kanfer et al. 1993). The T_max (peak plasma concentrations) for immediate-release tablets generally ranged from 1.5 to 3 hours. For sustained- or controlled-release tablets, a T_max usually ranged in the 4-6 hour range. Kanfer et al. found that the T_max was 1.39 and 1.97 hours following oral administration of ephedrine containing syrups, at 60 and 120 mg respectively. When an even higher dose was administered (180 mg), the time to peak plasma level increased to 3 hours. This indicates that there may be dose-dependent differences in absorption of pseudoephedrine. Kanfer et al. observed that absorption of pseudoephedrine appears to be faster from a syrup formulation as compared to immediate-release tablets.

Several investigators have measured peak plasma levels of ephedrine after ingestion of ephedrine tablets with results as follows:

• 22 mg given orally to 10 asthmatic patients resulted in an average peak plasma level of 79.4 (range of 52.7-138.4) ng/mL (Costello et al. 1975).
• 24 mg of oral ephedrine seldom resulted in peak plasma concentrations greater than 100 ng/mL (Midha et al. 1979).
• 23.6-27 mg ephedrine (oral as ma huang products), tested with 10 subjects, produced maximum plasma ephedrine levels of 73.4-100.1 ng/mL (Gurley et al. 1998b).
• 19.4 mg ephedrine (oral as 1556 mg ma huang) resulted in a peak plasma level of 81 ng/mL. (White et al. 1997).
• 50 mg ephedrine given to six healthy women resulted in mean peak plasma levels of 151 ng/mL, approximately two hours after ingestion (Vanakoski et al. 1993).
• 7.5 g ephedrine resulted in a peak plasma level of 23 mg/mL 1.5 hours after ingestion (Backer et al. 1997).
• 2.1 g ephedrine ingested resulted in plasma levels of at least 5 mg/mL. The level of ephedrine was 15 mg/g in the liver (Backer et al. 1997).

Excretion of ephedrine and pseudoephedrine is primarily via the urinary system but may be dependent on the pH of the patient's urine (Karch 2000). Wilkenson and Beckett (1968a) confirmed the slower elimination with alkaline urine by studies with three subjects in which they altered the pH of the urine and studied the elimination kinetics. Acidic urine at pH 5.0 was maintained by administration of ammonium chloride tablets while alkaline urine at pH of 8.0 was controlled using sodium bicarbonate. Ephedrine was administered both orally and intravenously over a period of one minute. Maintaining the urine alkaline resulted in a decrease in the 24-hour excretion of ephedrine and an increase in PPA compared to that found if the urine was acidic. The reason for this slower elimination in alkaline urine is apparently due to reabsorption of ephedrine back into the body from the kidney tubules with increased opportunity for hepatic metabolism of ephedrine to PPA.

Changing the pH of the urine has a similar effect on the elimination of pseudoephedrine. Elimination half-life increases as the pH of the urine increases, due to the extensive reabsorption of pseudoephedrine via the renal tubules. When the urine pH is 5-5.6, the T_1/2 is about 2-3 hours versus 16-21 hours with urine pH 8. Brater et al. (1980) determined the effect of urinary pH on pseudoephedrine elimination in a series of 15 urinary analyses (8 patients) given 30 mg tablets of SudafedÒ at different pHs of the urine. They found that increasing the urinary pH (from 5.6 to 7.4) had a dramatic effect on elimination and resulted in an increase in T 1/2s from 1.9 to 21 hours. The mechanism for the pH differences in elimination is the same as for ephedrine; that is, the decreased ionization of the drugs in alkaline urine results in enhanced reabsorption of the drug by the renal tubules and its recycling back through the body.

Stomberg et al. (1992) measured the effect of exercise on the pharmacokinetics of ephedrine and did not find any difference in the absorption and time to peak concentration as related to exercise. In this study, six healthy volunteers received 50 mg ephedrine orally 20 minutes before a 50-minute aerobic treadmill exercise and in a control session. The plasma peak levels and time to peak were 155± 16 ng/mL and 190± 45 minutes for ephedrine + exercise as compared to 168 ± 37 ng/mL and 127± 45 minutes for the ephedrine and no exercise group. An increase in heart rate and systolic blood pressure was observed two hours after the ephedrine-only administration. Exercise abolished the systolic blood pressure response to ephedrine. Diastolic blood pressure was not affected by the treatments.

Vanakoski et al. (1993) determined that heat exposure in a sauna results in more rapid absorption and earlier peak of the plasma concentration. In this study, six healthy non-smoking 21-year old women were treated with 50 mg ephedrine or placebo via gelatin capsule 20 minutes before going into the sauna. The women were subjected to the sauna for three 10-minute sessions, separated by a 10-minute cooling session. Blood plasma measurements were made periodically from 15 minutes to 24 hours after drug administration. The highest mean plasma concentration of 151 ng/ml was reached in two hours in the control session (room temperature), as compared to 173 ng/ml by 89 minutes for those in the sauna room. There were no differences between the elimination half-lives and AUC values.

Summary. Several studies demonstrate that the principal ephedra alkaloids (ephedrine and pseudoephedrine) are similar in the pharmacokinetics of absorption and elimination. Ephedrine is readily absorbed and is excreted primarily unchanged in healthy individuals with a serum half-life of 2.7 to 3.6 hours. Pseudoephedrine is also readily and completely absorbed and has a serum half-life of about 1.5-2 hours. Thus, both agents are rapidly absorbed and rapidly excreted from the body with no known storage depots. It should be realized, however, that a change in the pH of the urine, from the normal acidic to alkaline pH, as can occur in diseased conditions, can increase the half-life for elimination of the agents from the body. Heat exposure such as from a sauna can result in quicker absorption and shorter time-to-peak plasma concentration of orally consumed ephedrine. However, it does not appear that exercise causes any change in the pharmacokinetics of ephedrine after oral intake.

2.2 Biotransformation

Ephedrine can undergo metabolism primarily by demethylation to PPA although theoretically some oxidative deamination and aromatic hydroxylation could occur. Considerable confusion appears to exist as to the relative amount of metabolism that normally occurs with ephedrine ingestion. Sever et al. (1975) indicated that about 13% (range of 8-20%) of ephedrine is demethylated to PPA with perhaps 5% deaminated to benzoic acid and its conjugates. They did not find evidence that hydroxylation had occurred. In their studies, they synthesized ¹⁴C-radiolabeled ephedrine and administered the material at a dose of approximately 25 mg orally to three males of unknown age and health status. While there was no attempt to regulate the urinary pH, they did record the pH of the 24-hour urine sample, which apparently was in the normal acidic range. In the Sever et al. studies, the ephedrine metabolites were identified following either alkaline or acid extractions and analyzed by paper chromatography and reverse isotope dilution procedures. While two major peaks were identified as ephedrine and PPA, another small peak appeared in some chromatograms if the procedure was preceded by a preliminary extraction of urine at acid pH.

Sever found considerable variability among his subjects with the percent conversion to PPA 7.7, 11.3, and 20.1, resulting in the average of 13% PPA. However, the literature contains other reports that indicate the amount of ephedrine that is converted to PPA is far less and that virtually all ephedrine is excreted largely unchanged (Goodman and Gilman 1990, Meyers et al. 1980, among others). Beckett and Wilkenson (1965) reported a 4.3% metabolism of ephedrine. Baba et al. (1972) also found only 4.0 and 4.3% metabolism to PPA using two different analytical methods. Similarly, Basalt and Cravey (1997) reported that only 4% of ephedrine was metabolized to PPA.

Wilkenson and Beckett (1968a) confirmed that changing the pH of the urine from acidic to alkaline results in considerably slower elimination kinetics, probably due to reabsorption of ephedrine back into the body from the kidney tubules with increased opportunity for hepatic metabolism of ephedrine to PPA. Indeed, changes in the pH of the urine from 5.0 to 8.0 resulted in an increase in PPA from 7.2 to 24.4% in one patient, 2.9 to 10.9% in another, and from 8.1 to 19.4% in the third subject. This averages out to be an increase from 6% PPA production in normal urine to 14% if the urine is alkaline (at pH8) as can occur in some diseased conditions.

A major biotransformation pathway for pseudoephedrine is demethylation, with norpseudoephedrine as the resultant metabolite. However, as in the case of ephedrine, the degree of metabolism is quite small, only 1-6% as reported by several investigators (Kanfer 1993). Two other studies (Bye et al. 1975; Lai et al. 1979) also reported negligible (<1%) metabolism of pseudoephedrine to norpseudoephedrine. No information was found as to whether increased metabolism of pseudoephedrine occurred when the T 1/2 increased with alkaline urine.

It is concluded that only a small amount of ephedrine (4-6%) is metabolized to PPA in healthy humans with normal kidney function. The level of metabolism of pseudoephedrine to norpseudoephedrine appears to be even less and essentially negligible. For both ephedrine and pseudoephedrine, altered kidney function or increases in urinary pH can increase the elimination half-lives leaving the drugs to circulate in the body for a longer period of time. At least for ephedrine, the amount metabolized to PPA can increase. This increased T 1/2 and increased metabolism can affect the biological activity and possible side effects of the agents, whether received in the form of a pharmaceutical preparation or if ingested via dietary supplements.

Summary. A biotransformation pathway for both ephedrine and pseudoephedrine is demethylation, with PPA and norpseudoephedrine the resulting metabolites. However, metabolism is normally inefficient with only 4-6% of ephedrine metabolized to PPA and only negligible metabolism of pseudoephedrine to norpseudoephedrine. However, a change in the pH of the urine from the normal acidic to alkaline pH, as can occur in diseased conditions, can increase the degree of metabolism. This is the result of increased kidney reabsorption of the agents with increased opportunity for their hepatic metabolism.

2.3 Basic Pharmacologic Activity of Ephedra Alkaloids

The knowledge of sympathomimetics has been advancing with better biochemical tools to research cellular, biochemical, and especially macromolecular functions. It has become clear that there are subtle but important differences in the mechanisms and cellular interactions that are responsible for neurological differences in various biochemicals and xenobiotics. The long held view that there were basically two types of receptors, known as alpha (a ) and beta (b ) receptors, has given way to an understanding that there are several forms of these receptors. The next level of understanding was that there were at least two forms of the alpha- and beta-receptors, referred to as a 1, a 2, and b 1, b 2. Indeed, recent research has shown that there are additional forms of these receptors, including a 3, and b 3, and that these receptors may vary with specific cells and their location within the nervous system. As research continues, a better understanding of chemical interactions with the neuroreceptors will continue to evolve.

While it is not the intent of this document to provide a state-of-the-art review of sympathomimetic neuroreceptor activity, it should be clear that many different types of neurological activity may result, depending on the specific neuroreceptors involved. In the review by Love (FDA 1997), she provides a reasonably accurate discussion of the situation as was known at the time the FDA report was drafted, and she provided a table illustrating some of the differences in adrenergic activity of ephedrine, pseudoephedrine, and PPA.

The Love report also compared the receptor activity of those agents with norepinephrine. It can be immediately observed that there are important differences in the relative alpha and beta-receptor activity of PPA versus ephedrine and pseudoephedrine. As would be expected, the types of neurostimulation likewise differ, as does the potential for adverse effects. We have further reviewed this subject and conclude that it is inappropriate to assume that all ephedra alkaloids, and in fact all ephedrine enantiomers, are equivalent in their pharmacologic and pharmacokinetic properties.

The same structural features that give ephedrine greater affinity for b receptors also give it less affinity for a receptors. In general, the larger the group attached to the terminal amino group, the greater the affinity to bind to the b -receptor, and the lesser affinity to bind to the a -receptors (Bravo 1988). This explains why PPA has a much more marked affinity for a -receptor than b -receptor and thus has a greater pressor potency than l-ephedrine or d-pseudoephedrine.

The two asymmetric carbon atoms present in the ephedrine molecule allow for the existence of four different enantiomers of ephedrine. These enantiomers are the 1R,2S-ephedrine, the 1S,2R-ephedrine, the 1R,2S-pseudoephedrine and the 1S, 2S-pseudoephedrine isomers (Vansal and Feller 1999). The 1R, 2S-ephedrine isomer (l-ephedrine) and the 1S,2S-pseudoephedrine isomer (d-pseudoephedrine) are the only isomers found in Ephedra sinica to any significant extent. Both of these enantiomers have been synthesized and are present in OTC products such as cold and asthma remedies.

Pharmacologically, there are distinct differences in the pharmacologic and pharmacokinetic properties of ephedra alkaloids (Chua and Benrimoj 1988). The 1R, 2S-ephedrine (l-ephedrine) found in the herb and used as the synthetic chemical is a direct and indirect-acting isomer, having an action on both a and b receptors. The synthetic 1S, 2S-pseudoephedrine (d-pseudoephedrine) is an indirect-acting isomer having an action on both a and b receptors. Phenylpropanolamine (PPA), which is administered as a racemic mixture, is a direct and indirect-acting isomer having a definite action on a receptors but a weaker action on b receptors. Thus, phenylpropanolamine has decided pressor activity but no bronchodilatory properties. Phenylpropanolamine is not a bronchodilator. Phenylpropanolamine is a minor metabolite of ephedrine and is only found in ma huang in small concentrations.

Phenylpropanolamine, l-ephedrine and d-pseudoephedrine, at sufficient dose levels, can elevate blood pressure but only l-ephedrine and d-pseudoephedrine increase heart rate (Drew et al. 1978). L-ephedrine, and to a lesser extent d-pseudoephedrine, has sufficient b 2 activity to cause bronchodilation. However, the d-pseudoephedrine differs from the l-ephedrine in that its pressor, cardiac, mydriatric and central stimulant effects are relatively weaker than those seen with l-ephedrine (Craker and Simon 1987).

Chua and Benrimoj (1988) concluded that d-pseudoephedrine was less potent than l-ephedrine with only half of l-ephedrineís bronchodilator activity and only one-quarter of l-ephedrineís vasopressor effect. Both isomers appear to have the same potency as nasal decongestants. Pseudoephedrine is predominantly an indirect-acting sympathomimetic agent with lesser b -adrenergic activities than l-ephedrine.

OTC formulations may contain up to 30 mg of l-ephedrine, and doses up to 60 mg generally do not increase blood pressure. Doses of 60 or 90 mg of l-ephedrine cause an elevation in blood pressure (171/99 mmHg-mean) with only small increases in heart rate (Pentel 1984). However, it has been reported that doses of 50 mg have caused a 17 mm of Hg increase in systolic blood pressure (Bye et al. 1974).

Doses of as high as 180 mg of d-pseudoephedrine produce no measurable effect on blood pressure or heart rate. The lowest dose of d-pseudoephedrine causing hypertension in four normotensive subjects was 210 to 240 mg, and the mean blood pressure from these doses was 155/98 mm of Hg (Pentel 1984).

No significant pressor effects were seen in normotensive subjects given 25 mg of racemic phenylpropanolamine. However, single doses of 37.5 mg or more of the racemic mixture given to normotensive subjects produced an elevation in blood in the supine position (Chua and Benrimoj 1988).

The binding affinities of the various ephedrine enantiomers clearly demonstrate that there are significant differences in the action of these isomers and that they should not be collectively considered to be one agent. Vansal and Feller (1999), utilizing CHO cells containing cloned human b receptors, demonstrated that l-ephedrine was the most potent of the four ephedrine enantiomers in binding to all three human b adrenergic receptors and had twice the binding affinity at b 1 and b 2 receptors of d-pseudoephedrine. Additionally, l-ephedrine showed the highest intrinsic activity on b 2 receptors and was most potent in binding to the b 1 receptor sites. All the other isomers of ephedrine are partial agonists on the human b 1 and b 2 receptor subtypes. Of the ephedrine isomers, l-ephedrine and d-ephedrine, the l-ephedrine isomer was more than 100 times more potent on both the human b 1 and b 2 receptors. Only l-ephedrine among the four ephedrine isomers showed any appreciable direct activity on the human b 3 adrenergic receptor. The b 3 adrenergic receptor is known to mediate lipolysis and brown fat cell thermogenesis.

Summary. It should be clear that different types and intensity of neurological activity can result from use of the different ephedra alkaloids, depending primarily on the specific neuroreceptors involved. Pharmacologically, there are distinct differences in the pharmacologic and pharmacokinetic properties of ephedra alkaloids. The binding affinities of the various ephedrine enantiomers clearly demonstrate that there are significant toxicological as well as pharmacological differences in the action of these isomers and that they should not be collectively lumped together and considered as one agent.

3.0 Approach to Hazard Evaluation of ECDSs.

It is a standard and accepted scientific practice, when conducting toxicity testing, epidemiology evaluations, or hazard assessments, that studies be designed so as to evaluate, wherever possible, the exact material or product of concern to which persons are exposed. However, testing each existing mixture in the environment or products of commerce is not always possible or practical. Evaluation of a mixture of potentially hazardous agents has long been a contentious issue for regulatory agencies. Mixtures often vary in composition, especially as they occur in the environment (e.g., ground water or hazardous waste dumps) or as they are present in natural food products such as cereals and other food products. In the absence of data on the testing of the specific product of concern (which may be a mixture of many ingredients), data pertaining to the hazards of individual ingredients can be employed in the hazard evaluation. Of course, using data from individual ingredients cannot account for the potential interactions that can occur among the various ingredients. While it is imperfect, analysis based on individual ingredients is an acceptable and current practice in risk assessments of mixtures.

Analysis based on data from specific ingredients in a mixture is an acceptable approach. However, it is not a commonly accepted scientific practice to include data from substances not actually in the mixture, merely on the basis that they may be in the same chemical class or have similar chemical structure. For example, one would not use benzene to evaluate a mixture that has phenol but not benzene, even though benzene and phenol are chemically similar, differing only in a hydroxyl group on the benzene ring. Only in unusual circumstances should data from structurally similar substances be employed, and then with extreme caution. To further emphasize this point, it would be fallacious and non-scientific for an epidemiology study to study a cohort of persons exposed to carbon tetrachloride (CCl₄) in order to assess the carcinogenicity of chloroform (CHCl3), which differs simply by a single chlorine molecule.

Numerous examples can be given to illustrate that a simple molecular rearrangement, even without substitution of any new molecules, can completely change the toxicity of a material. For example, rearrangement of a chlorine from the 2-position to the 1-position of 2,3,7,8-tetrachlorodibenzodioxin to yield 1,3,7,8-tetrachlorodibenzodoxin changes the toxicity from "super toxic," with an LD50 of 1m g/kg, to "virtually non-toxic," with an LD50 >15,000,000 m g/kg. This simple molecular rearrangement results in a 15 million-fold decrease in lethal toxicity. Two other commonly known illustrations of simple differences in molecular structure that virtually changed non-toxic chemicals to become toxic chemicals are: (1) carbon dioxide versus carbon monoxide and (2) ethanol versus methanol.

The National Research Council (1983) has stated that: "Similarities in molecular structure should be used for priority setting for testing only and not for risk assessment." Similarly, the U.S. Department of Health and Human Services Task Force on Health Risk Assessment (U.S. HHS 1986) acknowledged that "molecular structure is not highly predictive" and indicates that the weight given to such data is the least valuable for risk assessments, ranking last behind human clinical trials, epidemiology, animal studies, and in vitro studies. As pertains to ephedra alkaloids, Karch (2000), in his recent thorough analysis, has stated: "the pharmacokinetic and toxicokinetic behavior of any isomer cannot be used to predict that of any other ephedrine isomer." Further, Karch states: "To lump together all ephedra alkaloids . . . is both foolish and misleading, as it implies that the toxicity of all enantiomers is equivalent, which is clearly not the case."

To re-emphasize, it is clearly not scientifically acceptable to lump all phenylethylamines (chemicals with a benzene ring and ethylamine sidegroup) together in a hazard evaluation for ephedra alkaloids contained in dietary supplements. Whenever possible, the risk assessment for a mixture should be conducted on the specific mixture under evaluation, as there may be various types of interactions that can influence the bioactivity. In the absence of data on a specific mixture, risk can be evaluated on the basis of the individual components in the mixture. The general default position (and in the absence of mechanistic data to the contrary) is to consider the toxicity of the mixture to be additive for the individual components.

Thus, the appropriate procedure for a hazard analysis of ephedra alkaloid-containing dietary supplements would be to evaluate data pertaining to the actual supplements themselves when possible. When such data are not available, an assessment can be made on data that pertain to the actual individual components of the mixture.

The approach used by FDA to lump into an analysis of ephedrine-alkaloid dietary supplements all sympathomimetics, catecholamines, and other classes that function in or alter neurotransmission is not scientifically appropriate. As pointed out in several of the FDA references and by Karch (2000), there are great differences in pharmacologic action as well as toxicologic properties within these groupings. Some may act centrally while others may be peripheral or function at both levels. Some may act at the beta-receptors and others at the alpha-receptor sites or both.

As previously indicated, of particular concern is the emphasis placed by FDA on the use of data pertaining to PPA, in their literature support document to evaluate the hazards of ECDSs. PPA is at best only a very minor ingredient in some ECDSs and is not found at all in most others. The only known herb that contains a significant amount of PPA is Khat, a shrub native to the horn of Africa and cultivated in some African and Middle East nations. Both norpseudoephedrine and PPA can be found in about an 80:20 ratio in the dried leaves of Khat (Bruneton 1995). Chewing the leaves of Khat plants is a folk custom in some areas of the world but apparently is not practiced in the United States to any significant degree. In addition, as appropriately pointed out by the FDA and by Karch (2000), there are some major differences in adrenergic activity and in pharmacokinetics of PPA versus ephedrine and pseudoephedrine.

As explained in detail elsewhere, PPA differs in structure from ephedrine or pseudoephedrine in that it lacks the methyl group on the amino moiety. The presence of a methyl group on an organic molecule is widely known to drastically alter biological activity, in some cases resulting in increased activity and in other cases diminished activity, or in fact, a completely different bioactivity. The same is true for phenylephrine, which differs from ephedrine by a hydroxyl group substituted on the benzene ring structure. As emphasized by Hoffman and Lefkowitz (1990), substitution on the amino group and/or substitution on the aromatic nucleus can drastically alter the pharmacologic activity of chemicals having the basic phenylamine structure.

PPA and phenylephrine are not present in dietary supplements (except possibly in minute quantities in only a few products) and should not be included in a hazard evaluation of ephedrine alkaloid-containing dietary supplements. In addition, there are major pharmacological differences in PPA and ephedrine and pseudoephedrine. The metabolism of ephedrine to PPA is so minimal that it would have no influence on the toxic effects of ephedrine and cannot be used as justification for inclusion in the safety assessment.

Summary. The appropriate scientific method for hazard evaluation of ECDSs is to give priority to data based on the testing or clinical studies of the ECDSs. Data based on studies of the specific ephedra alkaloids, particularly ephedrine and pseudoephedrine, can be used to support the analysis.

4.0 Efficacy and Safety of Ephedra Alkaloid-Containing Dietary Supplements

4.1 Clinical Studies

The number of clinical studies of efficacy and safety in which ephedra-containing herbal supplements have been evaluated is limited but of considerable value in a hazard assessment. Details of the specific studies are provided in this section.

Jones and Egger (1993) reported the results of using an ephedra-containing herbal preparation in a weight loss program. The herbal product (Herbal BalanceÒ ) was given to obese patients as part of a multi-center open efficacy study of herbal appetite control agents. Nine patients (8 females) were treated for seven days with a regimen of two capsules per day for three days, then four capsules per day for four days. The patients were on a high protein, 1200 Kcal/day dietary program. Each capsule contained about 25 mg of mixed ephedra alkaloids. Thus, the ephedra alkaloid daily dose ranged from 50 - 100 mg. The diet/supplement program resulted in a significant reduction in hunger (47.22 ± 46.92 vs 20.29 ± 15.99), increase in satiety (116.78 ± 36.62 vs 140.71 ± 19.35), improvement in mood (120.78 ± 37.28 vs 150.43 ± 12.29), and increase in perception of increased energy (105 ± 33.29 vs 136.00 ± 14.07). A mean loss of 2.75 pounds resulted from the seven-day weight reduction program. These results are based on initial measurements and final 7-day measurements. It is not clear if this study was a double-blind placebo-controlled study as no placebo group data were provided. Thus, the relative contribution of the low caloric diet itself and that of the ephedra-containing herbal product cannot be assessed from the limited information provided in this abstract report. The presence or absence of side effects was not discussed.

Kaats and Adelman (1994) conducted a double-blind, placebo, crossover study using 100 subjects to evaluate the energy levels and weight control related to consumption of a ma huang proprietary herbal formulation (product name not identified). The test periods consisted of four weeks for each phase (placebo or herbal product). While on the herbal products the subjects had a significant decrease in body weight and body fat than the placebo controls with higher energy levels and greater appetite control. Twenty-two (22) percent of the herbal group lost from 11-29 pounds whereas none of the placebo group lost more than 10 pounds during the four-week period. The use of the herbal product did not cause significant changes in fat free mass, blood pressure or resting heart rates. The authors concluded that the herbal product contributed to the treatment of obesity without producing negative side effects.

Huber (1999, 2000) reported the results of ongoing studies on the benefits and risks of dietary supplements in weight management. Dr. Gary L. Huber, Texas Nutrition Institute, has conducted studies with five herbal products as listed in Table 4.1.

.

Table 4.1. Herbal Products Evaluated by Dr. Huber

Product	Ephedra/Caffeine Content and Recommended Daily Dosage
1. Lean-R-Gy: Thermogenic Weight Loss and Natural Energizer	24 mg ephedra/capsule; Daily dose = 48 mg ephedra/day
2. Trim-4-Life: Advanced Weight Management System	12 mg ephedra-equivalent per tablet; Daily dose = 24 mg ephedra-equivalents/day
3. Pro-Trim: a Remarkable Weight-Loss and Body-Fat Reduction Program and Nutritional Supplements	12 mg of ephedra and 33 mg of caffeine per tablet; Daily dose = 72 mg ephedra and 200 mg of caffeine per day
4. Metabolize and Save	36 mg ephedrine and 120 mg caffeine per capsule; Daily dose = 1 capsules 3x/day (108 mg ephedrine) and/or 2 capsules 3x/day
5. Metabolite	36 mg ephedrine per capsule; Daily dose = 1 capsule 3x/day (108 mg ephedra/day)

.

In Study No. 1 (Huber 1999), studies were conducted with Products No. 1, 2, and 3 with consumption for six months and clinical examinations and measurements on a 4-week schedule. The results with these products were compared with results obtained using the same basic experimental design with the physician-prescribed pharmaceutical products, Phentermine (30 mg/day), and SibutramineÒ (10-15 mg/day) and data previously obtained with the Phentermine/Fenfluramine ("Phen-Fen"). The study involved a group of over 400 obese middle-aged persons with an average weight of 259.6 ± 14.0 for males and 191.3 ± 14.0 for females and age of 40.5 ± 2.0 for males and 44.0 ± 2.0 for females. All products were effective in promoting weight loss with the ephedrine/caffeine combination more effective than ephedrine alone. Phen-FenÒ was the most effective but its use has been discontinued due to toxicity concerns. The results of the efficacy tests were as follows:

Herbal Product/Pharmaceutical	Excess Weight Loss (%)
1. Lean-R-GyÒ	19.6 ± 8.8
2. Trim-4-LifeÒ	24.6 ± 7.5
3. Pro-TrimÒ	28.8 ± 6.5
4. Phen-FenÒ	46.8 ± 8.1
5. Phentermine	16.5 ± 3.1
6. SibutramineÒ	15.4 ± 4.0

An extensive monitoring for potential adverse reactions was conducted during the six month study. The side effects observed with the ephedrine-containing herbal supplements were, in general, less frequent and less severe than those side effects observed with the physician-prescribed pharmaceuticals.

Dr. Huber arrived at the following primary conclusions from this study:

• All three ephedra-containing herbal products were efficacious and resulted in an enhanced and sustained reduction of unwanted excess weight.
• The rate of response to specific dietary supplements was variable with no product inducing a uniform response in all subjects.
• The response rate for weight reduction was comparable to or better than the response to currently available physician-prescribed pharmaceutical agents that are used to control weight.
• The amount of excess weight loss was better for dietary supplements than with physician-prescribed pharmaceutical agents.
• The products were safe, as there was an extremely low frequency of side effects, none that were significant adverse effects.
• The prevalence of potentially adverse side effects in the treated groups was not statistically different from the untreated population.
• Neither systolic nor diastolic blood pressure increased while the patients were on ECDSs. In contrast, small decreases in both systolic and diastolic blood pressure were observed in all dietary supplement treatment groups.
• An initial increase in apical pulse rate was observed; however, it was transient and did not increase significantly in any group or subject.

In the Second Study (Huber 2000), a double-blind, placebo-controlled ongoing study, 120 patients were randomly assigned to one of five groups (21-26 per group), which will be studied for six weeks. Dr. Huber presented the interim results of the study at the HHS meeting on ECDSs in Washington, D.C. on August 9, 2000. Two dose levels of the Metabolize and SaveÒ are employed. Thus the study consists of the following test groups:

• Metabolize and Save - 1 tablet 3x/day
• Metabolize and Save - 2 tablets 3x/day
• Metabolite - 1 tablet 3x/day
• Protrim - 3 tablets 3x/day
• Placebo - 3 or 6 tablets 3x/day

Another group of obese, untreated, patients were followed for comparative purposes. The patients in this study were not placed on special diets but were advised as to good eating habits and proper exercise programs.

At the end of approximately six weeks, all test groups consuming the dietary supplements showed weight loss whereas the placebo group had an increase in weight. The weight loss in the experimental groups were as follows:

Product	Weight Loss (average pounds lost per week)
Metabolize and SaveÒ - 1 capsule 3x/day	- 1.6
Metabolize and SaveÒ - 2 capsule 3x/day	- 2.1
MetaboliteÒ	- 1.8
ProtrimÒ	- 2.9
Placebo	+0.6

.

Thus, after the six weeks period, those patients receiving Metabolize and Save® weighed 10.6 pounds less than they would have had they not received the dietary supplement. A comparable weight reduction was observed with Metabolite - 11.5 pounds. The weight reduction observed with Protrim was even greater, approximately 18 pounds lost in the six-week period.

An extensive survey was conducted to detect virtually any type of adverse effect. In general, the dietary supplements exerted beneficial effects rather than adverse effects. For example, as compared with the placebo group, the groups on dietary supplements had decreased fatigue, decreased blood pressure, decreased cystitis and urinary frequency, decreased muscle, back, or joint pain, decreased impotence or delayed/altered orgasm, decreased sleep disorders, decreased anxiety, decreased agitation, decreased depression, and decreased sinusitis and rhinitis. The only adverse effects were minor in severity and consisted of increased dry mouths in the first two weeks (same after six-weeks), slight increase in heart rate at two weeks (but not at six weeks) in groups 2 and 3, increased insomnia at two weeks but not at 6 weeks, and constipation at two weeks with three products, which was not observed after six weeks.

The conclusion reached by the study director was that the ideal rate of sustained weight loss of one to two pounds per week was attained. No serious adverse effects were observed and in contrast, there was a diminution of symptoms generally associated with undesired excess weight. On the average, the blood pressure, heart rate, or other cardiovascular manifestations were not significantly increased. The author cautioned, however, that the small number of subjects and limited duration should be considered. In addition, the obese patients were screened for other serious illness or medical complications as is common in most clinical studies.

Nasser et al. (1999) have conducted an eight week, double-blind, placebo-controlled efficacy trial of an herbal supplement containing ma huang and guarana. Sixty-seven subjects began the study and consumed 72 mg/day of ephedrine and 240 mg/day of caffeine. Twenty-one subjects dropped out during the study, 11 in the dietary supplement group and 8 in the placebo group. The dietary supplement was effective in that the weight loss was -8.7± 7.5 pounds in dietary supplement group versus 1.8 ± 5.4 pounds in the placebo group. There was also a decrease of body fat (-2.5± 3.1 v 1.5± 5.4 percent) and a decrease in serum triglycerides (-15.7± 38.3 vs. 20.9± 50.8 mg/dL). The reason give for six dropouts in the supplement group was heart palpitation. Two others had an increase in systolic blood pressure. The reason for the other dropouts, including those in the placebo group was not provided. Side effects observed at the end of the eight-week study were more frequent in the dietary supplement group than in the placebo control group and consisted of insomnia (9 v 2), increased dry mouth (5 v 1), heart palpitations (2 v -2), and increased blood pressure (>20 points in the dietary supplement group). The authors concluded that the herbal supplement that they studied was effective in promoting weight loss but might also produce undesirable side effects in some subjects.

Summary. Five studies have been conducted to evaluate the efficacy and safety of dietary supplements. The durations of exposure were 7 days, 4 weeks, 6 weeks, 8 weeks, and 6 months, in which 9 different ECDSs were evaluated. A total of approximately 700 subjects consumed the products with ephedrine alkaloid dose range of 24-108 mg/day. All studies demonstrated the efficacy of weight loss, reduced hunger and other beneficial effects. Generally, side effects were minimal and consisted of loss of appetite, dry mouth, palpitations, fatigue, insomnia, and anxiety. While increases in heart rate and blood pressure were occasionally observed, they were generally mild in nature. No serious adverse effect was reported. In some cases, studies with physician-prescribed pharmaceutical products were studied concomitant with the studies of the herbal products. In general, the side effects were less with the ECDSs.

4.2 Case Reports

The number of case reports that pertain to adverse effects reported as allegedly due to consumption of an ephedrine alkaloid-containing herbal dietary supplements is quite limited. Since the concerns are primarily cardiovascular and neurological in nature, the case reports are described accordingly. The case reports are presented chronologically beginning with those first reported in the literature.

4.2.1 Cardiovascular Effects

Gorey et al. (1992). A 61-year-old immigrated Vietnamese man was treated for multi-organ effects, including hepato-renal failure, pulmonary emboli, peripheral arterial thromboembolism and consumptive coagulopathy. For three days before presentation, he had consumed a daily infusion of herbal medicine. The man had a history of atrial fibrillation and left cerebral hemisphere infarction of three months duration. Apparently the man had consumed numerous agents (including ephedrine) in the herbal concoction. The attending clinician opined that the acute hepatitis and oliguric renal failure may have been due to acute ischemia of these organs. No data were presented as to ephedrine in the blood or urine. There was no indication as to the dose of the herbal product, dose of ephedrine, or any other possible contributing conditions.

Pace (1996) reported on two cases in which adolescents developed hypertension and cerebral vasospasm after overdosing with a liquid ma huang-containing product (Amp II Pro-drops). This meeting abstract indicates that the recommended dose was 241 mg of the product, although the actual ephedra alkaloid content and composition was not provided. In the first case, an 18-year-old male had consumed over 861 mg of the product, which was nearly four times that recommended. In the other case, a 12-year-old girl ingested about 240 mg of the same product and was reported to have headaches and other minor symptoms, which had cleared up by the time of medical examination. In both cases the symptoms were minor and had resolved within a couple of hours.

Theoharides (1997) reported a case of a 23-year-old man that was found dead by his sister. The subject had jogged and lifted weights regularly. It was speculated by the sister that he had consumed a dietary supplement for about 6 months, although she did not think that any supplement had been taken within 24 hours of death. No ephedrine was in fact found in the blood; however, ephedrine was apparently found in the urine (16m g/dL). The diagnosis by the medical examiner was heart muscle necrosis with inflammatory cell response and early repair. Apparently an additional pathology examination was made by an unnamed pathologist who reached a different diagnosis consisting of myocyte necrosis with healing of 1-2-weeks, and fibrosis with no evidence of myocarditis. A request for an outside pathology review of the tissue slides to resolve the pathology diagnosis was turned down by the medical examiner's office (Karch 1999).

The author made two back-calculations in an attempt to estimate the peak blood level and thus ephedrine consumption based on post-mortem urine levels of ephedrine. In one case, he assumed that the urine level was about 5% of the blood level. In Theoharidesí second calculation, he estimated that the peak blood level would have been 3 mg/L (3,000,000 ng/mL). Theoharides concluded that the blood level would have been within the acute fatal range. Using the 5% urine/blood ratio, the peak blood level would have been about 320 m g/dL (3,200 ng/mL). Thus, in one case he estimated about 3200 ng/mL while in the other case, he estimated about 3,000,000 ng/mL. In either case those levels would have been exceedingly high and would indicate a severe overdose.

If indeed there is any credibility to Theoharidesí back calculations, it would substantiate that the decedent had an enormous intake of ephedrine. Using the generally agreed upon peak blood level of ~ 80 ng/ml after a 22 mg ephedrine dose (Costello 1975; Karch 2000, and others), this would mean that the patient would have consumed an enormous amount of ephedrine, 800-750,000 mg. Even with the obviously high level, Theoharides considered that this was not a case of acute poisoning but perhaps related to the chronic use of supplements.

Karch (1999), in a letter to the editor, presented numerous criticisms of the Theoharides paper. This included errors in referencing the existing literature and the discussion of the case facts. In particular, Dr. Karch pointed out the great uncertainties in extrapolating from postmortem urine levels to predict ante-mortem blood concentrations. It is obvious that there are too many uncertainties (including the calculations of blood levels and third party reporting of exposures) to have any confidence in an assignment of causality for the patientís medical problems.

Zahn et al. (1998) presented a case report of a 21-year-old male who had ingested four gelatin capsules of Herbal Ecstasy, which apparently contain ephedrine and caffeine. According to the patient, the package label did not include ephedrine as a constituent and none of the product was available for analysis. Apparently there was no blood or urine analysis to confirm that ephedrine had actually been consumed. The medical history did, however, indicate that the patient had consumed alcohol and marijuana. The patient had headache, dyspnea, diaphoresis, dizziness, and vomiting. He also had elevated blood pressure, tachycardia and increased respiratory rate. The association of this patient's adverse effects with ephedrine is highly speculative.

Zaacks et al. (1999) reported that a 39-year-old man with a two-year history of hypertension and one-month history of dyspnea was examined for mild respiratory distress, apparently related to myocarditis. The patient had taken 1-3 tablets of two different herbal products daily for three months along with pravastatin, furosemide, and various vitamin supplements. The patient had a history of hypercholesterolemia in addition to hypertension. The patient's recovery was un-eventful. The herbal products contained numerous ingredients with one product containing ma huang (~7 mg ephedra alkaloids/tablet). As indicated by the authors, there are numerous drug causes of myocarditis although they suspected that ephedra may have been involved in this case.

Summary. Six case reports (5 reports) have been published alleging cardiovascular effects related to use of ECDSs. None of the case reports clearly established that a dietary supplement had a causative role. In two cases there was clear evidence of multiple hazardous agents with only ancillary use of a dietary supplement. In two other cases, minor and transient hypertension and cerebral vasospasm were apparently associated with overdoses of 240 and 861 mg ephedra alkaloids as single doses. One case involved minor symptoms in which there was no information on the dietary product, dose or duration consumed and there were no data on blood or urine levels of any ephedra alkaloid. One well-publicized case involved the death of a young man with a diagnosis of heart muscle necrosis who had consumed an unknown quantity of a dietary supplement for about 6 months. However, he apparently had not consumed any dietary supplement during the 24 hours preceding death. Based on the author's calculations, the decedent must have consumed an extreme overdose of ephedra alkaloids. In addition, the man was an avid weight-lifter and routinely jogged. The report was effectively countered in the same journal that discounted the conclusions of the case reporter. Regardless, if ephedra alkaloids had a causative role, it would have been due to extremely large overdoses and acutely toxic levels.

4.2.2 Neurological Effects

Capwell (1995) reported that a 45-year-old man was restless, couldnít sleep, and was irritable after consuming ma huang for two months. The man was using "greater amounts" than recommended as a weight loss supplement. Within three days of hospitalization, the man recovered. There was a family history of bipolar illness. It is unclear what the author meant by "greater amounts" but one would assume that he was overdosing by exceeding the recommended dosage levels.

Doyle and Kargin (1996) reported that a 34-year-old man had temporary hallucinations and strange behavior after consuming ma huang over a 10-day period. His symptoms resolved rapidly after hospitalization. No data were presented on the actual product, dose or frequency of use.

Emmanuel et al. (1998) suggested that the use of dietary supplements might have mimicked the symptoms of mania in a 40-year-old woman. The woman had a history of bulimia and depression that coincided with menstruation. The diagnosis was premenstrual dysphoric disorder, mood disorder and bulimia nervosa and the woman was treated with Fluoxetine. However, in a five-month follow-up the woman admitted she had discontinued the Fluoxetine treatment and although her depressed mood had resolved, her episodes of bingeing continued. She apparently had been exercising three hours per day to lose weight and periodically, over the past year, used dietary products that contained ma huang, chromium picolinate, and caffeine. The authors suspected that the ma huang might have mimicked the symptoms of mania.

Jacobs and Hirsh (2000) described two cases of psychiatric complications that they attributed to the use of ma huang. In one case, a 27-year-old man had suicidal ideation and irritable mood, which apparently developed after a two-year history of the regular use of two ma huang-containing supplements to enhance his workout performance. He would not reveal the quantity and frequency of their use. The man had a history of depression with refusal to continue medical treatment. He also had a maternal family history of depression. In the second case, a 20-year-old man developed an acute psychosis and agitation. For several months, he had been ingesting two ma huang-containing dietary supplements along with ginseng, DHEA, creatine monohydrate, and copious amounts of coffee. While there was no apparent medical history, the maternal family history was positive for depression. In both cases, the conditions resolved quickly with treatment.

While not a case report, Gruber and Pope (1998) reported the results of interview with 64 women body-builders of which 36 (56%) admitted the use of ephedrine either as tablets or in herbal mixtures. Most had used ephedrine for over a year, some as long as 5-10 years, often in doses of 120 mg or more per day. All reported overdosing by using higher doses than recommended on the packaging. Some of the women indicated that they had to increase the doses to obtain the same desired effect. Seven of the women described to the authors what they interpreted to be "frank ephedrine dependence," as manifested by the need to increase the dose to achieve the desired effect and experiencing withdrawal symptoms when they stopped the use of ephedrine.

Vahedi et al. (2000) presented a case report of a 33-year-old man with cerebral infarct with no coagulopathy that had consumed multiple combinations of pills for six weeks. The pills contained ma huang, L-carnitine, chromium, creatine monohydrate, taurine, inosine, and coezyme Q10. He was an avid "body builder" and trained extensively for two hours each day. The subject also had a patent foramen ovale and had recently returned from a transatlantic air flight. He was consuming 40-60 mg ephedrine, 400-600 mg caffeine and 6000 mg creatine monohydrate daily for about six weeks before the stroke. The authors acknowledged that creatine has deleterious side effects and has been reported to cause renal dysfunction. They concluded that the sportsman used high doses of multiple combinations of energy supplements. It was unclear that ma huang had a causative role in the ischemic stroke.

Summary. There were no deaths in the six cases of neurological effects alleged to be related to consumption of ma huang or ECDSs. There was one serious event, cerebral infarct in a man that had consumed numerous drugs and supplements, including large levels of creatine and caffeine in addition to ma huang. The authors did not specifically consider that ma huang was the causative agent. In one case the person was consuming multiple drugs at the time. Another person obviously overdosed for about two months with the subject becoming restless, having insomnia, and being irritable. A third case involved acute psychosis and agitation in a patient that was on several different dietary supplements and copious amounts of caffeine. A fourth case involved a person that developed hallucinations and strange behavior after 10 days on a ma huang product. No information was provided on the product, dose taken or frequency. The final case was a person that developed suicidal ideation and irritation after two years of using ma huang to enhance workouts. There was no information on quantity and frequency of use. The person had a history of depression prior to beginning use of the dietary supplement. None of these cases provides a convincing argument for causation by ephedra.

4.2.3 Other Reported Adverse Effects of ECDSs

Catlin et al. (1993) reported that a 28-year-old woman developed erythroderma, which appeared about eight hours after she had ingested two herbal preparations, "fruitillaria" and "anti-virus," obtained from a Chinese herbalist. No information was provided regarding dose or duration of use. Since the woman had previous similar reactions to various cold preparations that contained pseudoephedrine and PPA, the tablets and the patientís urine were analyzed for ephedra alkaloids. Ephedra alkaloids were found in both the tablets as well as the patient's urine.

Nadir et al. (1996) described a case of a 33-year-old woman that was diagnosed with hepatitis, which seemed to develop within several days after taking a Chinese medicine product that contained ma huang. Initially a diagnosis of viral hepatitis was made but the condition worsened after taking the Chinese medical product again. Biochemical testing suggested that the hepatitis had an immune-mediated mechanism. It was considered possible that some ingredient or contaminant in the product may have induced the immune response. Her condition improved after she stopped consuming the product. The authors felt that the ma huang product contained some ingredient that caused the immune reaction, although it may not have been the ma huang itself. The report listed nine other non-ephedra-containing herbal medicines that have been associated with hepatotoxicity.

Powell et al. (1998) reported neprolithiasis in a 27-year-old man who had been consuming energy supplements, one containing ma huang and another with high protein, for nearly a year. The stone was removed and was found to contain ephedrine, PPA, and pseudoephedrine. The man had a congenital defect with only one kidney present. He was an avid weight lifter, had a diet excessive for sodium, calcium, and oxalate with poor fluid consumption. He also consumed high levels of ma huang extract (680-2040 mg EA/day) along with several medications, and he smoked.

Lee et al. (1999, 2000) conducted cytogenicity studies with ma huang extracts and reported that adrenergic antagonists and cytotoxicity correlated with ephedrine content. The cytotoxicity of the ma huang extracts in several cell lines could not be totally accounted for by their ephedrine content, suggesting the presence of other toxins in the extracts. Grinding was the significant condition enhancing the toxicity of the extracts. The Neuro-2a cell line demonstrated a relatively high sensitivity to the toxins in the herbal extracts. Based on the concentrations used in the cell studies, it is calculated that the Neuro-2a cells, at the IC50 concentration, were exposed to levels of ephedrine that were 5,000 times higher than that seen at peak blood levels after the oral administration of 20-25 mg. Likewise, at the IC50 concentration for the ground extract, the level of ephedrine that these cells were exposed to was 250 times higher that that seen at peak blood levels after the oral administration of 20-25 mg.

Summary. Three case reports of other than cardiovascular and neurological effects have been reported in the literature related to consumption of ECDSs. In one case, it appears that erythroderma was causally related to consumption of a Chinese herbal supplement that contained ephedra alkaloids. In the second case, hepatitis with an immune mechanism appeared likely due to use of an ephedra-containing dietary supplement. The third case consisted of nephrolithiasis in a man that had consumed very high levels of ma huang. Ephedra alkaloids were found in the kidney stones.

5.0 Efficacy and Safety Studies of Ephedra Alkaloids in Pharmaceuticals

The recognition that ephedrine and caffeine may be useful in weight control dates back to the discovery in 1974 by the Danish doctor, Dr. Eriksen, that treatment of asthmatic patients with a product composed of ephedrine, caffeine and phenobarbital may have caused an unintentional loss of body weight in his patients (Malchow-Moller et al. 1981). This finding was immediately recognized as a much-needed therapy for obesity and led to the widespread use of the "Elsinore" pill to treat overweight patients. However, due to cutaneous reactions, which were attributed to the phenobarbital component, the use of the Elsinore pill was replaced with other treatments, such as the "Do-Do pill" which combined only ephedrine and caffeine and which was also found to be effective in weight reduction and in increasing thermogenesis. The clinical studies of the principal alkaloids in the dietary supplement, i.e., ephedrine, pseudoephedrine, and methylephedrine, are discussed in this section.

5.1 Ephedrine

5.1.1 Clinical Studies

Evans and Miller (1977) studied the effects of ephedrine on oxygen consumption in fed and fasted subjects. Nine healthy volunteers were treated with 44 mg ephedrine, a 1.26 MJ liquid meal, or a combination of ephedrine+liquid meal. Oxygen consumption was measured over a 135-minute period after the treatment. Both ephedrine and liquid meal increased the oxygen consumption by approximately 13-14%. The combination of ephedrine plus the liquid meal had an even greater effect increasing oxygen consumption by 20%. This study confirms that ephedrine produces a thermic effect when given as a single dose.

Malchow-Moller et al. (1980, 1981) conducted a 12-week, placebo-controlled clinical study with 132 obese patients to compare the efficacy of two anorectic drugs, amfepramne (diethylpropion) and the Elsinore tablet. Each Elsinore tablet contained 20 mg ephedrine and 50 mg caffeine and was administered at a dosage of 2 tablets 3 times per day (thus a daily dose of 120 mg of ephedrine and 300 mg caffeine per day). The patients were maintained on a 1200 kcal/day diet during the study. The number of patients at the beginning and those that completed the 12-week study were: Elsinore pill (49 v. 38), diethylpropion (50 v. 39) and placebo (33 v. 31). Both the Elsinore pill and diethylpropion were effective in inducing weight reduction, 8.1 kg for Elsinor pill, 8.4 kg for the diethylpropion, and 4.1 kg for placebo. While the authors reported that there were no serious side effects due to the treatment, four patients withdrew from the study in both the Elsinore and the diethylpropion groups due to exaltation, tremor, and insomnia. The authors noted that the few side effects with the ephedrine/caffeine combination were transient, with no effects on blood pressure or heart rate. No cutaneous reactions were reported. It was concluded that both the Elsinore ephedrine/caffeine pill and diethylpropion were equally effective, with no strong reason to prefer diethylpropion.

Jensen et al. (1980) conducted a prospective, randomized, double-blind and placebo-controlled study of 12-weeks duration to compare the efficacy of the Elsinore tablet versus ephedrine alone in weight reduction of obese patients. Of the 64 patients in the study, 23 were assigned to the Elsinore group, 24 to the ephedrine group, and 17 were on placebo treatment. The age range was 35-40 years. The Elsinore tablet contained 20 mg ephedrine, 55 mg caffeine, and l mg phenobarbital, whereas the ephedrine tablet contained 20 mg of ephedrine only. Five tablets were administered each day for total daily doses of: Elsinore - 100 mg ephedrine and 275 mg caffeine, and ephedrine-only group with an ephedrine dose of 100 mg. Both the Elsinore and ephedrine-only treatments were effective in promoting weight reduction, with 7.9 kg and 9.4 kg, respectively. In the placebo control group, the weight reduction was less than 1 kg.

Pasquali et al. (1985) conducted a double-blind, placebo-controlled study to assess the effects of ephedrine on weight loss over a period of three months treatment. The initial 62 obese patients were randomly assigned to one of two ephedrine-treated groups and a placebo control group. The ephedrine treatments were 25 or 50 mg three times per day for total daily doses of 75 or 150 mg/day. The patients were also on a controlled diet of 1000 kcal/day for females and 1200 kcal/day for males. The study groups were identified as Group I (placebo control), Group II (75 mg ephedrine/day) and Group III (150 mg ephedrine/day). During the study, 16 patients dropped out due to various reasons, including one pregnancy, five for non-compliance with the protocol, and 10 due to side effects. There were 16 drop-outs, evenly divided among the three groups: 5 in Group I, 6 in Group II, and 5 in Group III.

Dropouts due to side effects occurred in all three groups, with two in group I (placebo), and four each in groups II and III. The subjects apparently took the initiative to spontaneously stop the therapy, primarily due to complaints of agitation, insomnia, constipation and headache. Among the dropouts were single patients in both Groups II and III due to dermal erythema, which reversed rapidly after cessation of drug treatment. The final size of the groups after three months was 12 in Group I, 7 in Group II, and 12 in Group III.

Weight loss was slightly greater in group III (10.21± 1.0 kg) although the other groups also lost weight (8.7± 1.0 kg in Group I and 8.7± 0.9 in Group II). The differences between groups were not statistically significant. Side effects occurred in all groups. While there was no significant differences in the incidence of side effects between Group I (placebo) and Group II (ephedrine, 75 mg/day), the incidence in Group III (ephedrine, 150 mg/day) was significantly greater. It is interesting that significant decreases in systolic blood pressure occurred in all groups. However, an increase in pulse rate was observed in patients receiving 150 mg ephedrine per day, which was not found in those that received 75 mg ephedrine per day.

According to the authors, all side effects were well tolerated and tended to disappear as the treatment period progressed. Interestingly, there were no side effects in any of the patients receiving ephedrine at a level of 75 mg/day during the third month of the study. Based on these results, it appears that 75 mg ephedrine/day (25 mg tid) is well tolerated, whereas 150 mg ephedrine per day (50 mg tid) appeared to cause side effects. This study did not confirm the value of ephedrine in promoting weight loss in unselected obese subjects.

Astrup et al. (1985) reported the effects of administration of ephedrine for three months in five healthy but overweight women. The women received 20 mg ephedrine chloride tablets one hour before meals, three times per day for a total daily dose of 60 mg ephedrine. The thermogenic response to ephedrine was determined again after the 4th and 12th weeks of treatment as well as 2 months after cessation of treatment. After 8 weeks of ephedrine treatment, indirect calorimetry was performed with placebo administration without the knowledge of the subjects. The average body weight had decreased by 2.5 and 5.5 kg after 4 and 12 weeks respectively. While there was no dietary change during the study, the energy intake was not specifically measured. The thermogenic effect of ephedrine was observed which appeared to increase during the chronic treatment with ephedrine. While the thermogenic response increased during chronic ephedrine treatment, it fell back to the initial baseline values 2 months after treatment ceased. Side effects were reported as minimal with no change in pulse rate but a slight and insignificant increase in blood pressure. Two subjects reported a transient hand tremor during the first 2-5 days.

Dulloo and Miller (1986) studied the effects of a single dose of ephedrine (22 mg) or a combination of ephedrine (22 mg) with caffeine (30 mg) and theophylline (50 mg) on the resting metabolic rate in 8 lean and 8 obese volunteers. All subjects were then given 3 tablets of the combination product during one treatment day, and effects on 24-hour energy expenditure were determined.

In the single-dose study, the combination was twice as effective as ephedrine alone in increasing metabolic rate and it normalized the defective thermogenic response to a meal in the obese subjects. In the 24-hour study, the combination had no effect on energy expenditure in the lean subjects but gave an increase of 8% in the obese subjects. No side effects were reported, and the authors conclude that combinations of ephedrine with methylxanthines could be useful in the treatment of obesity.

Pasquali et al. (1987) conducted a double-blind crossover randomized study to assess the effect of ephedrine on weight reduction during a two-month treatment period. The study used 10 adult overweight and obese women that had adapted to low-energy intake but had difficulty in losing weight with conventional hypocaloric treatment. The women were stabilized on a 1000 - 1400 kcal/day diet for one month, which was then supplemented with ephedrine hydrochloride (50 mg/day tid) or placebo, administered before each meal. Each pharmacological treatment lasted for 2 months. Weight loss was significantly greater during the ephedrine period (2.41 ± 0.61 kg) than during the placebo period (0.64 ± 0.50 kg). None of the patients presented clinically important side effects. Minor side effects were seen during the ephedrine treatment in four patients and consisted of mild agitation (2 patients), insomnia (3 patients), palpitation (2 patients) and giddiness (2 patients). One subject reported agitation, headaches and giddiness during both ephedrine and placebo treatments.

Krieger et al. (1990) conducted a double-blind, placebo-controlled study to determine the effectiveness and safety of a combined treatment of ephedrine, caffeine and aspirin in promoting weight loss. The subjects were obese men and women that had difficulty in losing weight in other weight loss programs. Twenty-nine subjects started on the program but five defaulted during the study due to difficulty in keeping follow-up appointments. The treatment group (ephedrine, caffeine, and aspirin) consisted of 11 patients who were given ephedrine in a dosage of 75 mg/day for the first 4 weeks, which was then increased to 150 mg/day for the final 4 weeks. The dose of caffeine and aspirin was 150 mg/day and 300 mg/day, respectively, throughout the 8-week treatment period. The placebo group (13 patients) received the same number of inert tablets as in the ephedrine treatments. The mean total weight loss was greater in the treatment group (2.2 ± 2.31 kg) as compared to 0.7 ± 2.02 in the placebo group. No differences were observed between the treatment and placebo groups with respect to resting heart rate, blood pressure, fasting plasma glucose, insulin, total cholesterol or HDL-cholesterol. The treatment group tended to report transient jitteriness and transient dry mouth, although the differences were not statistically significant. The reason for increasing the dosage at four weeks was on the basis that the initial ephedrine dosage was low, and since no effects on cardiovascular parameters had been seen with this triple-drug combination and 75 mg ephedrine/day, the dosage was doubled, which also failed to elicit side effects.

Astrup et al. (1990,1991) conducted a double-blind, placebo-controlled study of the thermogenic and cardiovascular effects of ephedrine, using six healthy, normal weight subjects, three men and three women, with an average age of 25 ± 1 years. The ephedrine was administered as single doses orally in gelatin capsules at doses of 10, 20, and 40 mg. There was a significant increase in energy expenditure following ephedrine treatment over that observed in the placebo-controlled group; however, the effect was not dose-related. There was a dose-dependent increase in plasma glucose, insulin, and C-peptide in the ephedrine-treated groups. Non-esterified fatty acid, plasma glycerol, sodium, and potassium levels were not affected. A dose-related increase in heart rate was observed during the three hours following ingestion of ephedrine, with the heart rate at 40 mg about 7 bpm greater than the placebo-controls. Side effects were minimal with no significant differences between ephedrine-dosed and placebo controls.

Horton and Geissler (1991,1996) compared the acute thermogenic response of lean, pre-disposed obese, and obese subjects treated with ephedrine alone or ephedrine+aspirin to that of a 1050 kj liquid meal (which was also provided to the drug-treated groups). Measurements in the changes in metabolic rate were measured for 160 minutes after the treatments in groups of 10 lean, 10-predisposed obese, and 10 obese subjects. A significant difference was observed between the level of thermogenesis following each of the three treatments in the obese group but not the lean in general. However, the greatest absolute rise in metabolic rate was produced by the ephedrine and aspirin treatment combined with the meal. The post-prandial thermogenesis was significantly enhanced by the ephedrine-aspirin-meal group only in the obese group. Side effects were infrequent, mild and of a stimulatory nature. While they appeared in greater incidence in the ephedrine and the ephedrine-aspirin groups than in the meal-only group, the differences were not statistically significant. The authors concluded that aspirin did not further the acute thermic effect of ephedrine and caffeine.

Astrup et al. (1992 a,b) conducted a six month, double-blind, placebo-control study to compare the effects of ephedrine with caffeine (E+C), ephedrine alone (E), caffeine alone (C) and placebo (P). The study plan consisted of a 2 x 2 factorial design under double-blind conditions using 180 obese patients that were placed on a 1000 kcal/day diet. The patients were treated for 24 weeks at total dosage levels of 60 mg ephedrine per day (E), 600 mg caffeine per day (C), 60 mg ephedrine + 600 mg caffeine per day (E+C), and placebo (P). The doses were divided and administered three times per day.

Weight losses at the end of the 24-week period were -16.6 kg in the E+C group, followed by -14.3 kg in the E group, and -13.2 kg in the placebo group. As a percentage of the original starting weights, the reductions of body weight were 17.5% in the E+C group, 15.3% in the ephedrine group, 13.1% in the caffeine group, and 13.5% in the placebo group. As can be observed, the greatest decrease in body weight was experienced with the ephedrine-caffeine combination with some loss in the ephedrine-only group. There was no difference between the caffeine-only and placebo groups.

Significant decreases were observed in systolic and diastolic blood pressure, blood glucose, triglycerides and total cholesterol in all groups. There were no significant between-group differences in these parameters or in blood counts, sodium, potassium, bilirubin, liver enzymes, creatinine, uric acid or urinalysis. Heart rates fell slightly in the E+C, C and P groups. In the E group, heart rate was marginally increased above baseline and significantly increased from the placebo group. The authors concluded that the combination of ephedrine and caffeine was effective in weight reduction in obese patients whereas ephedrine or caffeine alone were not.

Side effects in those completing the treatments were transient and occurred mainly in the first 4 weeks. After 8 weeks, the incidence and type of side effects was the same as in the placebo group. The primary side effects seen in the ephedrine and ephedrine-caffeine groups were insomnia, tremor, palpitation, and tachycardia. These conditions were also observed in the caffeine-only group. Insomnia, interestingly, was observed in the placebo group as well. The systolic and diastolic blood pressure fell in all four experimental groups to the same extent.

During the study, 39 patients (10 each in the E, E+C, and P group; 9 in the C group) withdrew or were withdrawn so that one hundred forty-one (141) completed the study. Withdrawals were due to the following reasons:

	E	C	E+C	P
Unwilling to continue	6	2	3	2
Lack of weight loss	0	1	0	0
Complication of obesity	1	1	1	0
Pregnancy	2	1	2	4
Non-compliance	0	1	1	3
Side effects	1	2	3	0
Other	0	1	0	1

Withdrawals were comparable for all groups. One patient withdrew from the ephedrine group due to depressed mood, insomnia, tremor and tachycardia. Two in the caffeine and three in the caffeine-ephedrine groups also withdrew due to similar conditions. All six recovered quickly after discontinuation of treatment. It was noted that tolerance to the typical ephedrine effects (insomnia, dizziness and tremor) developed rapidly during the study; however, no tolerance developed to the continuance of weight loss. The lack of effect of E+C on cardiac parameters also indicated that E+C treatment is not contra-indicated by moderate hypertension; in fact, subjects with resting diastolic blood pressures up to 110 mm Hg were accepted into the study. After treatment stopped at the 24th week, the study continued for 2 weeks to determine withdrawal symptoms. While the number of subjective withdrawal symptoms was similar in the E, C, and P groups, they were increased in the E+C group. The primary withdrawal symptoms consisted of headaches, hunger, and tiredness.

Astrup et al. (1992c) also compared the effects of ephedrine (60 mg/day) plus caffeine (600 mg/day) (E+C) and placebo (P), administered for a period of 8 weeks, on weight lost and energy expenditure. The study was conducted with 14 obese women that had been placed on a 1000 kcal/day diet. While there were no differences in weight losses, the E+C group lost 4.5 kg more fat and 2.8 kg less fat-free mass than did the P group. In addition, a decrease in 24-hour energy expenditure was seen in the E+C group, which was significantly less than that seen in the P group. Higher energy expenditure in the E+C group at day 56 could be completely attributed to an increase in fat oxidation. Three patients in the E+C group complained of insomnia, palpitations and tremor respectively; however, these symptoms were transient and disappeared by 14 days of treatment.

Pasquali et al. (1992) conducted a randomized, double-blind, crossover study with 10 obese subjects to determine the effects of ephedrine administration (150 mg/day) on energy expenditure, protein metabolism and levels of thyroid hormones and catecholamines. The patients had been placed on a 6-week very low calorie diet (VLCD) program (1965 kJ, 60 g of protein, 45 g of carbohydrates) prior to starting on the ephedrine. Ephedrine hydrochloride (50 mg three times a day by mouth) or placebo was administered during 2-week periods (weeks 2- 5 of the VLCD program). Five subjects began with ephedrine and five with placebo with the results analyzed separately in the two groups. While no differences were found for weight loss during the VLCD and drug treatments, ephedrine therapy resulted in a significantly lower daily urinary excretion of nitrogen (and, consequently, a better nitrogen balance) than placebo, independently of the drug sequencing.

There was no difference in daily urinary levels of 3-methylhistidine between the ephedrine and placebo treatments groups. The fasting resting metabolic rate (oxygen consumption, ml STP/min) fell significantly on the VLCD in both groups, an effect partially and significantly prevented by administration of ephedrine. The VLCD by itself significantly reduced the 24-hr urine levels of vanillylmandelic acid and homovanillic acid; however, these increased to pretreatment values during ephedrine treatment. No effects were seen on 24-hr urinary excretions of adrenaline, noradrenaline and dopamine, or on serum levels of thyrotropin, thyroxin, free tri-iodothyronine and free thyroxin, during the VLCD diet and/or ephedrine treatment. Ephedrine significantly prevented a further decrease in the serum triiodothyronine level and the serum tri-iodothyronine to thyroxin ratio during the VLCD. No side effects of any type were seen.

Toubro et al. (1993a,b) extended the studies described by Astrup et al. (1991) from the original 24 weeks to a total 50-week study period. Following the initial 24-week treatment, the patients were not treated but were observed for two weeks to detect for withdrawal symptoms. No withdrawal symptoms were observed. One hundred twenty-seven patients (127) from the original group participated in the second phase of the study, which consisted of an additional 24 weeks on the ephedrine (60 mg/day) + caffeine (600 mg/day) combination. Twenty-eight patients dropped out, which left 99 patients who completed the 50-week treatment regimen.

The authors concluded that the ephedrine + caffeine combination improved and maintained the total weight loss during the 50-week period and altered the composition of the weight loss by increasing the fat loss while preserving the lean body mass. Side effects were observed in many of the subjects with about equal distribution among the ephedrine, caffeine, ephedrine + caffeine, and placebo groups. The side effects were primarily mild central nervous system (CNS) and cardiovascular symptoms. They further concluded that the side effects were minor and temporary in nature with no serious withdrawal symptoms. Of the 28 that withdrew, only five were due to some side effects (two in ephedrine and three in caffeine groups), all minor in nature. The authors concluded that the ephedrine/caffeine combination was safe and effective in long-term management of weight. They further concluded that the side effects were minor and transient without clinically relevant withdrawal symptoms.

Jaedig (1993) described a study in which 18 premenopausal (ages 36-47 years), obese women were studied over a 12-week period for weight loss and thermogenetic properties when treated by a caloric restricted diet [supplemented with electrolytes (potassium, magnesium, or HPO4)] (Group 1), ephedrine and minerals (Group 2), or a placebo (Group 3). Six patients were included in each group. The ephedrine group lost an average of 11.3 kg as compared to 7.9 kg in the placebo and electrolyte groups. While the energy expenditure decreased in the placebo controls, it increased in Group 1 by 11.1% and in Group 2 by 6.7%. The results were considered consistent with (1) a relationship of enhanced total body potassium to energy expenditure, (2) the beneficial effect of ephedrine on body loss and increased energy expenditure, and (3) the beneficial effect of adding potassium to the diet to increase total body potassium and energy expenditure.

Daly et al. (1993) in a double-blind study with 24 obese subjects extended the studies previously reported by Krieger et al. (1990). The subjects were administered either a composite treatment of ephedrine (75 - 150 mg/day), caffeine (150 mg/day), and aspirin (330 mg/day) (ECA) or (P) placebo. The ECA group contained 11 subjects, and the P group contained 13. While the total treatment period was 8 weeks, the ephedrine dosage was 75 mg per day during the first 4 weeks, after which it was increased to 150 mg per day. The dosage of caffeine and aspirin was maintained at the original levels. No specific diets were prescribed, though dietary advice was given, and subjects were restricted to 2 cups of coffee or caffeinated beverages per day. Weight loss was significantly improved in the ECA group. No differences in self-reported appetite were observed between the groups, with about 50% of each group reporting a decrease in appetite. Side effects were negligible. In the ECA group, two subjects reported transient jitteriness, two dry mouths and two reported constipation, while in the placebo group one complaint of jitteriness was registered along with two with dry mouth and one with constipation. There were no significant differences in the frequencies of any side effects between groups, and the side effects did not persist in either group.

There were no significant differences in systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, glucose, insulin, total cholesterol or HDL-cholesterol between or within the groups.

Commencing 5 months after the first phase of this study, 9 of the 13 placebo subjects were treated with the ECA combination for another 8 weeks. One subject was unable to tolerate the higher dose of ephedrine due to jitteriness and mild hypertension; however, the subject admitted to having a previously undisclosed history of borderline hypertension. Three of the 8 subjects that completed the eight-week period reported transient dryness of the mouth. No other side effects were observed, with all cardiac and biochemical parameters unchanged.

In another phase to this study, six of the eight subjects that had participated in the second phase were followed for another 7-26 months with weight, blood pressure, heart rate, compliance, appetite and side effects assessed at monthly intervals during this period.

The weight loss continued in this phase of the study. While all subjects occasionally complained of dry mouth or constipation, blood pressure and pulse remained normal. Overall the ECA combination continued to be well tolerated. The authors concluded that the ECA combination worked well and showed excellent tolerance. They opined that this could have been partially the result of starting with a low dose of ephedrine (75 mg/day) and allowing tachyphylaxis to develop (to classical ephedrine effects) before moving to the high dose (150 mg/day). They also considered that the tolerance could also be attributed to a beneficial effect of the aspirin in the treatment regimen.

Geissler (1993) reported on acute studies of thermogenesis conducted in lean and obese human subjects that were treated with a meal containing ephedrine (30 mg), one that contained ephedrine (30 mg) and aspirin (300 mg), and that of a standard meal. No significant differences or side effects were observed among the three treatments. The authors concluded that the ephedrine treatment was well-tolerated.

Molnar (1993) conducted acute studies on thermogenic effects in obese adolescent children. Four groups were compared, one group of 27 subjects treated with ephedrine hydrochloride at a dose of 1 mg/kg lean body mass, a second group of four subjects administered aminophylline (3 mg/kg lean body mass), a third group of 20 administered ephedrine + aminophylline (same doses as in single treatment groups), and the final group of 20 that was given only water (200 ml). Thermogenic effects were determined after which 22 of the children from the ephedrine and aminophylline groups were given a one-week treatment with ephedrine (2x50 mg/day) or aminophylline (2x150 mg/day). Thermogenic effects were again determined, and children that had poor initial thermogenic responses to ephedrine remained poor responders after the one-week treatment course. No side effects were observed.

Vallerand (1993) studied the effects of an ephedrine/caffeine combination with or without added theophylline as a means to counteract the fall in body temperature of volunteers exposed to cold. The combination of ephedrine (1mg/kg) with caffeine (2.5 mg/kg) increased the average energy expenditure by 19% over the placebo group, and decreased the rate of fall of body temperature. The combination of ephedrine (44 mg), caffeine (60 mg), and theophylline (100 mg) increased energy expenditure by 17% over the placebo group during a 3-hour cold exposure. This was shown to result from the 28% and 10% increases in lipid and carbohydrate oxidation respectively. No mention was made as to side effects; however, the authors concluded that the combination of ephedrine with xanthines represented the best approach to enhancing cold thermogenesis and delaying the onset of hypothermia.

Pasquali and Casamirri (1993) tested the effects of ephedrine for treatment of obesity using oral doses of 75 or 150 mg/day for a period of three months. The study involved 46 obese patients, 14 males and 32 females, that were treated with a 4180-5016 Kj/day diet. After the three-month treatment period, the body mass index fell in all groups as follows:

However, the body mass loss was greater at one and two months for the ephedrine group, prompting the authors to conclude that ephedrine probably favors a greater weight loss than placebo, at least at the 150 mg/day dose level.

Some side effects were observed at the 150 mg/day level early in the study but disappeared with time and were well tolerated. The side effects consisted of agitation, insomnia, headache, weakness, palpitation, giddiness, tremor, and constipation. There were no effects on arterial blood pressure although patients treated with 150 mg/day experienced a small but significant increase in pulse rate when compared to the placebo group.

In another study, the effect of ephedrine was analyzed in a selected group of 10 low-energy adapted obese women with ephedrine treatment for two months via a double-blind, placebo-controlled study. Treatment was three doses of 50 mg ephedrine per day while the women were on a 4180-5852 Kj/day diet. Weight loss was significantly greater in the ephedrine treated group versus the placebo group (2.41 ± 0.61 vs. 0.64 ± 0.50). No significant side effects or changes in arterial blood pressure and pulse rate were found.

A third study was a randomized, double-blind, placebo-controlled study to test the effects of both ephedrine alone or ephedrine + caffeine combination in a group of 22 obese women with verified low daily energy intake and low resting metabolic rate (15% below that expected). The women were placed on a 4180-5852 Kj/day diet.

The weight losses in the 20 woman that completed the treatment were as follows:

The authors suggested that the results of this study do not support the added benefit of caffeine over ephedrine alone in weight reduction.

Nielsen et al. (1993) conducted a test with 8 obese and 13 normal weight volunteers for thermogenic responses to ephedrine and to cold exposure. This included repeat tests in 6 subjects from each group after aerobic training for 5 weeks. The single dose used in the ephedrine test was 1 mg/kg lean body mass. The thermogenic responses to both ephedrine and cold exposure were smaller in obese subjects than in normal controls. In both tests glucose levels increased in the controls but not in the obese subjects. Plasma catecholamine levels in all subjects increased more on exposure to cold than after ephedrine administration. The 5-week training course had no effect on the basal metabolic rate. While the thermogenic response to ephedrine tended to increase in all subjects, the response to cold exposure only improved in the normal control group. There was no indication of side effects even with the large dose of ephedrine used.

Breum et al. (1994) conducted a 15-week, double-blind study that compared the weight control effects of an ephedrine + caffeine (EC) combination and dexfenfluramine (DF) in the treatment of obesity. Fifty overweight (20-80% OW) patients (39 females) were treated with a combination of 20 mg ephedrine and 200 mg caffeine three times per day (daily dose = 60 mg ephedrine and 600 mg caffeine) for the 15-week period, while on a 5MJ/day diet. The DF group of 53 patients received 15 mg of DF on the same dose schedule. At the end of the 15-week period, both treated groups had lost considerable weight; however, the weight reduction with the EC group was greater than with the DF group (8.3± 5.3 kg vs. 6.9± 4.3 kg). The treatments had a beneficial effect of reducing the systolic and diastolic blood pressures to a similar degree. Some side effects were initially observed with both treatment regimens, but declined markedly during the first month of treatment. Of the 50 patients in the EC group, 38 completed the study with approximately 1/2 of the patients experiencing minor and transient side effects.

The most common effects were insomnia (8), twitching or tremor (5), nausea (5), and palpitation (4). Six patients decided to withdraw from the EC study due to the early side effects (two cases of abdominal pain and vomiting, one case of tremors, palpitations, and syncope, and three cases of vertigo, nausea, and insomnia). One death occurred in the study group, which was unrelated to the treatment. It was a 57-year-old male that was found to have a history of alcohol abuse. He was hospitalized during the third week of the study due to acute alcohol intoxication, which led to his death due to gastro-intestinal bleeding. Following the original study, a further 15-week open study was conducted using ephedrine with caffeine only. Of the original patients, 85 were included in the follow-up study. Weight loss continued with the ephedrine-caffeine combination. Blood pressure remained unchanged. While there were no serious side effects, transient effects were reported by 29 patients, of whom 20 had been in the original dexfenfluramine (DF) group.

The authors concluded that the EC treatment was effective in promoting weight loss while preserving lean body mass. They also concluded that, even with the possibility of minor side effects, that EC could be used as an alternative to DF in the long-term treatment of obesity. They also noted that the weight loss persisted in the EC group after it had plateaued in the DF group and that the weight loss continued in the open study following the double-blind study.

Buemann et al. (1994) conducted an eight-week study to compare the effects of treatment with a combination of ephedrine plus caffeine on weight loss and plasma lipids and lipoproteins. The study population was a group of 41 obese subjects placed on a low calorie diet (1000 kcal/day). The combined ephedrine (60 mg/day) + caffeine (600 mg/day) treatment produced a greater weight loss after 8 weeks than found in the placebo group. Total cholesterol declined in both groups with no significant difference between groups. HDL-cholesterol fell in the placebo group, but not in the EC group; the difference was significant. Plasma triglyceride levels also fell in the EC group but not in the P group. No side effects were noted. Further, the authors point out that the treatment with ephedrine + caffeine had a beneficial effect in that it abolished the decline in HDL-cholesterol due to dietary restriction.

Ingersleve et al. (1997) conducted a double-blind, placebo-controlled clinical study to determine how an ephedrine-caffeine combination (E+C) affected blood pressure in normotensive and hypertensive patients over a six-week treatment period. One hundred and thirty-six patients with body mass index of >25 kg/m² were treated with a combination drug (Letigen) three times per day with total daily oral intake of 60 mg ephedrine and 600 mg caffeine for six weeks. Some of the patients were hypertensive while others were normotensive. All were placed on a 5040 kj (1200 kcal) diet. One hundred twelve completed the treatment period. A significant mean loss of weight was observed in all groups of approximately 4 kg for each group. There was no increase in blood pressure in any of the treatment groups. In the normotensive group and most hypertensive groups treated with E+C, the systolic blood pressure was significantly reduced. The heart rate statistically increased in the E+C treated normotensive group by an average of 4.9 beats per minute. Side effects were observed in both the E+C groups and the placebo control groups. However, the incidence was greater (56%) in the E+C group v the placebo group (21%). Seven of the E+C group dropped out of the study. The most frequent side effects in the E+C groups were nausea, palpitations, increased perspiration, and tremors. Palpitations and nausea were also observed in the placebo group. No serious adverse events occurred. The authors concluded that the study did not support an assumption that E+C should cause rises in blood pressure, acutely or during short term treatment either in normotensive or hypertensive obese patients.

Shannon et al. (1999) studied the acute effect of ephedrine on 24-hour energy balance in a group of 10 healthy subjects using a double-blind, placebo-controlled crossover study. The dose of ephedrine was 50 mg given three times daily for a total dose of 150 mg/day. Energy expenditures and side effects were measured for 24 hours following the treatments. The energy expenditure was significantly greater (3.6%) in the ephedrine group than that of the placebo group (8965 v 8648 kj). Over 50% of the additional calories burned with ephedrine treatment were expended in the sleep time period, measured as 8.4% increase from that determined for the placebo group. Mechanical work was not different in the two groups. There were no dropouts from the study. While there were no serious adverse effects, mild stimulatory side effects were noted in greater incidence in the ephedrine group as compared with the placebo group. The most frequently reported side effects were difficulty sleeping, increased or stronger heartbeat, and decreased appetite. One placebo subject reported heart pounding and difficulty sleeping while another placebo subject reported palpitations and decreased appetite.

Bell et al. (1998, 2000), in a double-blind study, evaluated the effects of acute ingestion of caffeine (C), ephedrine (E), and a combination of caffeine and ephedrine (C+E) on time to exhaustion during high-intensity exercise (cycle ergometer). In the 1998 report, it was announced that the combination of caffeine and ephedrine significantly increased the time to exhaustion compared to a placebo control. Twelve subjects were studied using dose levels of 5-mg/kg caffeine, 1-mg/kg of ephedrine, or a combination of the caffeine and ephedrine at the individual dose levels administered 1.5-2 hours prior to the exercise. However, three of the twelve subjects (25%) experienced vomiting and severe nausea while engaged in the intense exercise after the C+E treatment. Additional studies, also using 12 healthy males, were conducted to ascertain if lowering the dose levels could provide the beneficial enhancement in ergogenic performance without the undesirable side effects (Bell et al. 2000). By lowering the dose levels of caffeine to 4 mg/kg and ephedrine to 0.8 mg/kg, the subjects were able to retain the enhanced ergogenic performance without the undesirable side effects. The time to exhaustion was 28.0 ± 9.3 minutes in the C+E group compared to 17.0± 3.0 minutes in the placebo control group. While the heart rates were slightly increased in the drug groups, the perceived exertion was lower. There were no differences in the respiratory gas exchange parameters.

Kalman et al. (2000) conducted an eight-week, double-blind, placebo-control study to determine body mass, body composition, metabolic variables, and mood states in healthy overweight adults. The study group consisted of 30 healthy, physically active adults with a body weight mass of greater than 27 kg/m². The subjects were treated twice a day with ephedra alkaloids (40 mg/day), synephrine (10 mg/day), caffeine (400 mg/day), or salicin (30 mg/day) for an eight-week period. The drug-treated group has a significantly greater weight loss compared to the placebo group (3.14 kg v 2.05 kg). The drug group also had a 16% decrease in body fat compared with only a 1% decrease for the placebo group. No significant changes in blood pressure, electrocardiograms, pulse rate, serum chemistry, or caloric intake were observed. Five patients dropped out of the study, none related to side effects but rather for personal reasons. The authors concluded that the treatment was safe to use and effective in reducing body weight and body fat.

Summary. Approximately 30 clinical studies have been conducted to evaluate the efficacy and safety in the use of ephedra alkaloids. The studies covered various periods of treatment ranging from a couple weeks up to 26 months. Most of the studies were 3-6 months in duration. Over 1100 patients were in these studies, most obese and treated for weight reduction. The dose levels usually were 60-150 mg ephedrine/day. Several studies combined caffeine treatment along with the ephedrine, usually at a dose of 600 mg of caffeine per day. Nearly all studies demonstrated the efficacy of ephedrine alone in weight reduction. Several other studies also demonstrated that ephedrine alone or in combination with caffeine enhanced thermogenic effects as well as ergogenic performance. It appeared that the combined ephedrine-caffeine treatment was superior to ephedrine or caffeine alone in weight reduction and ergogenic performance.

Some side effects were observed in most studies but were mild in nature and decreased as the studies progressed. No serious adverse events occurred in the entire group of clinical studies. One man died during treatment but his death was not considered related in any way to the dietary treatment. In some cases, patients dropped out of the study due to the side effects. In other cases, patients dropped out due to other reasons, e.g., the inconvenience of coming to the clinics and due to unpleasant taste of the treatment, etc. In general, however, the dropout rate was in the acceptable range and the studies were considered as satisfactorily meeting the study objectives. Overall, the studies demonstrated effectiveness of the products tested as regards weight control and ergogenic performance as well as assuring minimal and acceptable level of side effects.

5.1.2 Case Reports Involving Ephedrine in Pharmaceuticals

The toxicity of ephedrine has been recognized for many years. Indeed, as early as 1933, Chopra and Mukherjee summarized the toxicity of ephedrine and presented two case reports. The concern at that time was the widespread use of ephedrine in medical practice. As pointed out by Chopra and Mukherjee, the toxic symptoms appeared in patients that were given large and frequent doses. In both cases, the patients had overdosed on asthmatic preparations. They also reported individual differences in sensitivity and indicated that it was not clear whether habit formation actually occurs but that there may be increased tolerance with chronic administration and in some cases withdrawal-like symptoms with patients feeling uncomfortable when the ephedrine was discontinued.

Wu and Reed (1927) point out that ephedrine and epinephrine differ greatly in their psychological and undesirable effects. Ephedrine gave more complete and longer asthmatic relief while producing fewer side effects. In their review of 90 cases where ephedrine was used for treatment of asthma, when adverse effects were seen, they were considered due to overdosing in the patients.

5.1.2.1 Suicide or Accidental Fatal Overdose Cases Involving Ephedrine Pharmaceuticals

Garriott and Simmons (1985) reported three fatalities due to overdoses with ephedrine and caffeine in "Look-A-Like" drugs. All three cases were ruled as suicides. All involved young persons (19-23 years) that had apparently intentionally consumed large amounts of the Look-A-Like drugs in successful suicide attempts. The authors could not ascertain the actual doses, although they concluded that the doses were obviously large overdoses.

The drug concentrations in the body fluids and internal organs were as listed below:

	Case 1		Case 2		Case 3
	Caffeine	Ephedrine	Caffeine	Ephedrine	Caffeine	Ephedrine
Blood	343.9 mg/L	20.5 mg/L	147.0 mg/L	7.9 mg/L	129.9 mg/L	3.5 mg/L
Urine	21.2 mg/L	N.D. mg/L	43.2 mg/L	239.9 mg/L	-	-
Liver	670.4 mg/kg	150.9 mg/kg	199.9 mg/kg	51.3 mg/kg	57.8 mg/kg	10.2 mg/kg
Kidney	351.9 mg/kg	28.2 mg/kg	172.0 mg/kg	23.0 mg/kg	-	-
Brain	-	-	94.5 mg/kg	7.4 mg/kg	-	-

In addition, the authors reported two more lethal cases in young persons that had consumed large amounts of Look-A-Like capsules containing only caffeine along with ethanol.

Backer et al. (1997) presented a case in which a 28-year-old woman was found dead following consumption of extremely large amounts of ephedrine in a successful suicide. The blood level of ephedrine was very high, 11 mg/L. In addition, another drug, amitriptyline, was found in the blood. High levels of ephedrine were found in the brain (8.9 g/Kg), kidney (14 mg/Kg) and liver (24 mg/Kg). Some unabsorbed ephedrine tablets were present in the gastric contents. While the authors did not estimate the actual consumption of ephedrine, they indicated that the dose was probably in the range of 2-7 grams.

They based this on the following:

• the estimated lethal dose of ephedrine in man is about 2 grams
• 400 mg doses not known to cause serious toxic effects
• a woman survived a dose of 7.5 g and had a blood level of 23 mg/L, 1.5 hours after ingestion
• a 20-year-old woman survived ingestion of 7.5 g and had a plasma ephedrine concentration of 23 mg/L
• ephedrine blood concentrations in a series of fatalities observed with "look-a-like" combinations ranged from 3.5-20 mg/L
• a fatality after ingestion of 2.1 g ephedrine and 7.0 grams caffeine was accompanied by blood and liver levels of 5 mg/L and 15 mg/Kg respectively.

5.1.2.2 Cardiovascular Effects of Ephedrine in Pharmaceuticals

Hirsh et al. (1965), in a letter to the editor, reported subarachnoid hemorrhage in a 49-year-old woman taking an MAO inhibitor that was hospitalized for light-headedness, dizziness, weakness, and hypotension. She was administered oral ephedrine to counter the hypotension and soon afterwards suffered an increased blood pressure to 160 mmHg, and she developed headache, neck stiffness, and leg spasms which disappeared after a few days. Two weeks later she was diagnosed with psychiatric problems, which was felt secondary to subarachnoid hemorrhage. The author cautioned against the use of ephedrine along with MAO inhibitors.

Wilson et al. (1976) followed the cardiopulmonary and bronchodilation response of 45 asthmatics that used either ephedrine or a terbutaline for up to a year. Cardiovascular changes in the ephedrine group were minor and tolerance did not develop. There was no evidence of cardiac, hepatic, renal, or ophthalmologic toxicity.

Van Mieghem et al. (1978) presented a case report of a 35-year-old man with chronic asthma that had been using a cough mixture containing ephedrine for 20 years. Gradually he increased the dose until he drank a bottle every day (400 mg ephedrine) plus taking large intermittent doses of prednisone. He was admitted with symptoms of tachycardia, ventricular hypertrophy and generalized cardiomegaly. They concluded that a long-standing abuse with high doses of ephedrine might have been a contributing cause.

Banner et al. (1979) conducted comparison studies with a group of 20 patients with ventricular arrhythmia for the effects of ephedrine, aminophylline, and terbutaline sulfate. Ephedrine was administered orally at 25 mg ephedrine sulfate in a double-blind crossover study. No significant changes were observed in blood pressure, and there was only one case of tachycardia in patients treated with ephedrine.

To et al. (1980) presented a case report of a 32-year-old woman with symptoms of cardiac failure of 6 months duration, which was clinically diagnosed as congestive cardiomegaly of unknown etiology. Fourteen (14) months later it was discovered that she had been taking very large quantities of ephedrine-containing compounds for 10 years. She had been on ephedrobarbital, tabasan, and more recently phensedyl elixir. She was consuming three bottles of phensedyl elixir per day. Three bottles of phensedyl elixir would contain 540 mg ephedrine, 675 mg codeine, and 270 mg promethazine. The authors contributed the cardiotoxic effects due to chronic overdosing with ephedrine and codeine.

Wooten et al. (1983) reported that a 20-year-old man developed a subarachnoid hemorrhage and cerebral angiitis, which was considered, associated with overdose with "speed." He had also consumed LSD and marijuana. Ephedrine was found in the blood but not PPA.

Nadeau (1984) in an editorial reply criticized the report by Wooten et al., contesting the diagnosis of vasculitis and association of the condition with ephedrine abuse.

Stoessl et al. (1985) reported on two cases in which the patients had consumed street drugs and developed intracerebral hemorrhage and angiographic beading. In the first case, a 20-year-old woman took two capsules of a supposed amphetamine look-alike 12 hours prior to admission. While blood and urine toxic screens were negative, analysis of the capsules revealed the presence of ephedrine, PPA, and caffeine. The patient made a successful recovery. In the second case, a 23-year-old-woman had taken a "black beauty" as a "wake-up" pill about 15 hours prior to developing symptoms. No information was presented as to blood or urine levels of any drugs; however, analysis of ingested capsules revealed the presence of pseudoephedrine, PPA, caffeine, and a barbiturate. The woman made a modest recovery.

Chua and Benrimoj (1988) reviewed non-prescription sympathomimetic agents and hypertension. They concluded that the risk of blood pressure elevation with ephedrine might be greater in hypertensive patients although no study had been conducted to verify this. They claim that pseudoephedrine is less potent than ephedrine with half the bronchodilator and one-quarter the vasopressor effects. They concluded that pseudoephedrine had no appreciable effect on blood pressure of hypertensive patients.

Whittet and Veitch (1989) presented a case report of a 50-year-old woman with tachycardia, mild hypertension, palpitations and central chest pain. She overdosed with a nasal congestant every 1û2 hour, which contained ephedrine and xylometazoline that caused rhinitis medicamentosa. There was no evidence of myocardial infarction or other serious conditions.

Yin (1990), from the Peoples Republic of China, wrote a letter to the editor, in which he reported that a 68-year-old man with a 40-year history of chronic pulmonary disease had taken an OTC asthma preparation (for 10 years) that contained several drugs, including ephedrine. He apparently developed CNS vasculitis that Yin felt may have been linked to the OTC medication in some way.

Bruno et al. (1993) reported on three cases of cerebral stroke in which the patients had overdosed with ephedrine tablets in the form of "street drugs." The authors treated one case whereas the other two cases were found by a review of the cases available in a search of two state medical examinersí files (New Mexico and Connecticut) over a ten-year period. Case 1 was a 37-year-old man who had been overdosing on "speed" for at least three weeks. Case 2 was a 42-year-old man found dead who had a history of hypertension and drug abuse for 23 years. He also had severe atherosclerosis and arterionephrosclerosis. Traces of ephedrine were found in his blood. The third case was an 84-year-old woman who died of cerebral atherosclerosis. Association with ephedrine was based on a small amount in her blood with no information on the possible source. Bruno et al. concluded "[o]ur findings do not suggest that the use of ephedrine used according to the manufacturer's recommendation is a risk for stroke."

Gualtieri and Harris (1996) discussed a case in which a 28-year-old woman with chronic dilated cardiomyopathy had consumed ephedrine tablets for eight years. She was taking eighty 25 mg ephedrine tablets daily (2,000 mg/day), an obvious overdose.

Hirabayashi et al. (1996) presented a case report of a 69-year-old man who apparently developed coronary artery spasm after he had been administered ephedrine during spinal anesthesia. The ephedrine was administered after the patient had a sudden decrease in blood pressure and heart rate. Atropine did not resolve the condition so ephedrine was administered. This resulted in the tachycardia, increased blood pressure, and chest pain, which were corrected by nitroglycerin injection. The authors postulated that the ephedrine may have induced a coronary artery spasm based on the alterations in the ECG.

Lustik et al. (1997) described a case of a 42-year-old man who suffered coronary artery spasm while being prepared for femoral-popliteal bypass due to peripheral vascular disease. The man had been a chronic cocaine user for many years. The man also had glucose intolerance and was a smoker. During spinal anesthesia, the man developed slight tachycardia and a drop in blood pressure. Ephedrine was given IV, and the patient progressed to a more severe ventricular tachycardia. The authors considered the cause of coronary vasospasm due to prior cocaine use but cautioned regarding use of ephedrine in such cases.

Cockings and Brown (1997) described a case of myocardial infarction in a 25-year-old man with a history of intravenous drug abuse. In this case, the man had injected himself IV two hours prior to admission with a solution of a white powder ("On the Street") that the patient believed to be amphetamine. Laboratory analysis of the unused powder identified only ephedrine. The patient recovered within five days. The authors describe the case as an overdose with ephedrine and suggested that various other risk factors may have contributed to the myocardial injury, including contaminants in the syringe, insoluble particulate material and other myotoxins in the street drug. No information was provided as to the probable dose administered or the blood or urine level of ephedrine.

James et al. (1998) conducted a cross-sectional case-control study of pediatrics admitted to an emergency department with chest pain. Twenty-eight patients and twenty-six controls were surveyed at time of treatment for possible causes of chest pain. Marijuana was the most commonly reported drug used with ephedrine reported in five individuals.

Waluga et al. (1998) studied the cardiovascular effects of ephedrine, caffeine and yohimbine in a group of 27 obese but healthy women. Hemodynamic measurements were made at rest in a sitting position 90 minutes after administration of the drugs, for a period of 10 days. The study consisted of three groups, (a) the control standard hypocaloric diet, (2) a combined ephedrine (2 x 25 mg) plus caffeine (2 x 200 mg), and (3) combined ephedrine (2 x 25 mg) plus caffeine (2 x 200 mg) plus yohimbine (2 x 5 mg). The results supported the beneficial use of low caloric diet along with ephedrine and caffeine for obesity treatment. No undesirable effects on the cardiovascular system were observed.

Mourand et al. (1999) reported that a 44-year-old woman developed cerebral arteritis while under spinal anesthesia. The woman developed headache, vomiting, nausea, drowsiness, and hypotension immediately after the spinal anesthesia. To treat the hypotension, the woman was administered ephedrine IV and the woman subsequently developed hypertension. Even though the woman had symptoms prior to ephedrine administration, the authors nevertheless associated the cerebral arteritis to the ephedrine treatment.

Summary. Sixteen case reports were found that alleged cardiovascular effects related to ephedrine use. In nearly all cases, the effects occurred in persons that overdosed - often by use of street drugs that incorporated ephedrine, sometimes in conjunction with other drugs. In several other cases, the cardiovascular effects resulted during use of ephedrine as medical treatment, e.g., to counter hypotension during spinal anesthesia. In another case subarachnoid hemorrhage occurred when a patient, on a MAO inhibitor, was administered ephedrine in the hospital to counter hypotension and developed transient cardiovascular effects.

5.1.2.3 Neurological Effects of Ephedrine in Pharmaceuticals

Escobar and Karno (1982) described a case in which a 62-year-old man sought medical care for nervousness and insomnia with chronic hallucinosis. The man had a long history of psychotic problems and had undergone psychiatric hospitalization when he was 26. For nearly 40 years the man had been using copious amounts of nasal decongestants for a sinus condition. For the past 20 years, he had heard voices and experienced frightening images, usually at night. For the 5 years previous to his latest medical admittance, he had used a variety of decongestants, some of which contained ephedrine. More recently, he was consuming very large amounts (eight or more bottles per month) of the highest available concentration of oxymetazoline (Afrinâ ). The authors suggested that the chronic hallucinosis might be related to the large amount of nasal decongestants that he has used for many years.

Roxanas and Spalding (1977) described three cases of psychosis that they related to ephedrine abuse. One case was a 26-year-old man with delusions and hallucinations, which occurred three days after he had begun taking ephedrine (5 tablets twice each night) in order to keep awake at his job. On the third day he increased the frequency to 5 tablets three times per day. It was estimated that the total amount of ephedrine ingested in the three-day period was 750 mg. The man had a history of epilepsy and previous admissions to a psychiatric hospital for drug abuse. The second case involved a 26-year-old man with several monthsí history of odd behavior and aggressive outbursts. Three days prior to admission, he had consumed 20 tablets of ephedrine (300 mg) and became aggressive. While in the hospital he again became aggressive after taking 60 ephedrine tablets. He had a previous history of psychiatric hospitalization and drug abuse. The third case was a 30-year-old woman with a change in behavior over the previous two years. She had suffered from asthma since early childhood and had apparently been taking Tedral tablets "more frequently than necessary." The authors considered that the acute psychosis might have been aggravated by the abuse of ephedrine.

Herridge and aíBrook (1968) reported two cases of psychosis that they associated with ephedrine use. In the first case, a 65-year-old man was admitted to a hospital due to paranoid psychosis of two months duration. He had a history of chronic bronchitis, asthma and long-standing tuberculosis. He admitted to taking 200 ephedrine (60 mg) tablets a week for some years with an increase during recent weeks. Psychotic treatment corrected the psychosis within two weeks. In the second case, a 54-year-old woman with a 25-year history of severe chronic pulmonary tuberculosis, recurrent attacks of bronchitis and chronic asthma, and a 10-year history of depression with paranoia and hallucinations, was treated for psychosis. She admitted to having taken large quantities of ephedrine tablets (fifteen 30 mg tablets five times/day) for the past 20 years for her asthmatic condition. Within 4 days of treatment, the psychosis had disappeared with only mild depression remaining.

Whitehouse and Duncan (1987) described a case of a 59-year-old man with a schizoid personality who had consumed ephedrine for 25 years for chronic asthma. He had recently doubled his ephedrine intake to 360 mg daily, which seemed to coincide with his change in personality. The dose of ephedrine was reduced to 60 mg and the patient became symptom-free within 10 days.

Kane and Florenzano (1971) reported a case of a 19-year-old male student that was hospitalized for an acute paranoid psychiatric reaction, which appeared to be temporally related to the use of an asthmatic preparation containing ephedrine, hydroxyzine, and theophylline. The student admitted to taking the drug in greater amounts than prescribed, especially at night.

Mitsuya (1978) described three cases of addiction to asthmatic drugs, of which the main component was ephedrine. The period of abuse to ephedrine was 3-8 years, 200-250mg/day. Withdrawal of the antasthmatics resulted in disappearance of the psychotic symptoms within 2-4 days. No specific data on the cases were provided.

Tinsley and Watkins (1998) presented five cases pertaining to patients that they felt had become dependent or addicted to ephedrine. In the one case described in detail, a 33-year-old woman was admitted for inpatient treatment of stimulant dependence following an 18-month history of ephedrine use. During that 18-month period, she had increased her ephedrine use from two capsules (25 mg capsules) per day to about 60 capsules per day. Her attempts to discontinue use of ephedrine were not successful due to rebound somnolence and fatigue. Four other cases were listed in which ephedrine was used for 8 months to 2 years, with doses ranging from 1000 mg/day to 2500 mg/day. All four were also nicotine dependent, two were alcohol dependent, and one was cannabis dependent.

Summary. Seven reports have been published involving 15 individuals that developed neurological conditions allegedly related to ephedrine use. All cases involved overdoses or abusive use of ephedrine. Two reports described eight persons that suffered withdrawal symptoms after long-term, high-dose ephedrine use. No deaths were reported with quick recovery.

5.1.2.4 Dermal Effects of Ephedrine in Pharmaceuticals

Serup (1981) reported that a 25-year-old patient had exfoliative erythroderma, which he attributed to the long-term use of Elsinore pills, which contained ephedrine, phenobarbital, caffeine, minerals and vitamins. The dermal condition was triggered by use of ephedrine nosedrops five weeks after discontinuance of the Elsinore pills. The author was unsure as to whether the dermal reaction was due to ephedrine, phenobarbital or steroid rebound.

Audicana et al. (1991) reported delayed dermal hypersensitivity to ephedrine in a 68-year-old man on oral anticatarrhal drugs. The hypersensitivity was determined by a positive patch test.

Villas-Martinez et al. (1993) reported generalized dermatitis following the use of nasal congestants containing ephedrine, pseudoephedrine and PPA. Oral challenges were positive for sensitivity to ephedrine and PPA.

Garcia-Ortiz et al. (1997) reported that an 18-year-old woman twice developed nonpigmenting fixed exanthema following treatments with ephedrine (Fluidin codeina) and pseudoephedrine (Narine) containing medications. Patch tests were negative to both ephedrine and pseudoephedrine; however, the patient had a positive reaction with oral challenge to both ephedrine and pseudoephedrine.

Summary. Four case reports indicate that some persons develop dermal allergy or sensitivity to ephedrine. None of the skin conditions appear to be serious in nature. Considering the large number of persons that have taken ephedrine in the past, this number of reports would provide assurance that the incidence of allergic reactions to ephedrine is quite low.

5.1.2.5 Effects on the Urinary System Related to Ephedrine in Pharmaceuticals

Boston (1928) reported that six men who had been treated with ephedrine developed dysuria within 1-2 days. Improvement occurred with discontinuance of the drugs.

Balyeat and Rinkel (1932) presented a case of urinary retention in a 56-year-old man treated with ephedrine who experienced difficulty in urination, which improved with discontinuance of the treatment.

Glidden and DiBona (1977) reported urinary retention in a 12-year-old boy who was treated for about a year for asthma using ephedrine, phenylephedrine, and PPA medications. He had suffered from difficulty in urination during much of the time. Cessation of the ephedra alkaloids resulted in immediate cessation of the urinary problems.

Blau (1998) reported nephrolithiasis in a 24-year-old man who had taken 40-120 OTC ephedrine-containing tablets each day for several years. The stone passed and analysis revealed ephedrine content.

Assimos et al. (1999) reported that seven patients developed urinary stones who had consumed large amounts of guaifenesin and ephedrine as stimulants. The stones consisted of mainly guaifenesin with small amounts of ephedrine.

Summary. Of the five case reports of urinary tract effects, two involved the development of kidney stones in patients after long-term high-dose ephedrine use, some in conjunction with other drugs (e.g., guaifenesin). The other cases involved dysuria or difficulty in urinating while being treated with ephedrine. Improvement occurred rapidly with discontinuation of the ephedrine treatment.

5.2 Pseudoephedrine in Pharmaceuticals

5.2.1 Clinical Studies

Porta et al. (1986) conducted a study to evaluate the adverse effects of pseudoephedrine using a very large number of persons that had been prescribed pseudoephedrine. In this study, over 100,000 persons below age 65 years that used prescribed pseudoephedrine were followed to determine the incidence of serious adverse events that required hospitalization. The primary endpoints studied were directed primarily to cardiovascular (CVS) and neurological adverse effects. The main CVS events monitored were cerebral hemorrhage, thrombotic stroke, and myocardial infarction, whereas the neurological events evaluated were seizures and neuropsychiatric disorders. All other relevant hospitalizations were also evaluated to identify causal linkages to pseudoephedrine use. The study was conducted over an eight-year period (1976-1983). Hospitalizations that occurred within 15 days of using pseudoephedrine were included in the analysis. The most common prescriptions were pseudoephedrine syrup for children (6 mg/ml) and pseudoephedrine tablets (30 mg) for older children.

While there were 246 hospitalizations that met the criteria of 15 days after filling the pseudoephedrine prescription, causal association was ruled out in all but one case. In this single case, there was a history of intermittent fever for three days prior to admission. Based on the clinical evaluations, a causal connection even in this case was considered remote. The authors consider that these results provide substantial reassurance as to the safety of pseudoephedrine. However, they point out that the study would not have detected adverse events of a long-term nature or effects that might occur in persons older than 65 years of age.

Torfs et al. (1996) conducted a case-control study to determine the maternal medication and environmental risk factors for gastroschisis (congenital defect of abdominal wall). The study group consisted of 110 cases and 220 controls. The maternal medications and environmental exposures that occurred in the first trimester were evaluated. Elevated risks were found for many substances, including pseudoephedrine decongestants. An odds ratio (OR) of 2.1 (0.8-5.5) was found for pseudoephedrine which was not statistically significant. The OR for pseudoephedrine was less than that found for several commonly used drugs, including PPA (10.0), aspirin (4.67) and ibuprofen (4.00). Other environmental risks included solvents (OR=3.84) and colorants (2.27). The suggested mechanism for the gastroschisis is a compromise of the vasculature of the developing embryo.

Summary. In the only long-term clinical study found, an assessment was made of serious effects in a large study involving over 100,000 persons. No increased hospitalization rate occurred with the use of pseudoephedrine. There is a suggestion of a weak teratogenic effect (gastroschisis) due to exposure to pseudoephedrine in the first trimester.

5.2.2 Case Reports Involving Pseudoephedrine in Pharmaceutical Products

5.2.2.1 Suicide or Accidental Fatal Overdose Cases Involving Pseudoephedrine Pharmaceuticals

Salmon and Nicholson (1988) reported a suicide that involved high doses of pseudoephedrine along with other pharmaceuticals. This case involved a 22-year-old man who was found dead by his roommate who had not seen the victim for the prior 24 hours. The man had expressed frustration with his undergraduate studies, which presumably led to the suicide decision. The man apparently consumed large amounts of ActifedÒ (pseudoephedrine and tripolidine) and SominexÒ (pyrilamine or diphenhydramine). Several empty bottles were near the victim. When found, the victim was unconscious but still alive. Despite heroic measures, the victim proceeded into renal failure (considered secondary to rhabdomyolysis) and he died on the third day of hospitalization. Autopsy revealed diffuse hemorrhages in many organs, ischemic injury of the kidneys, which were interpreted to be consistent with disseminated intravascular coagulation. Although serum levels of drugs were not determined, the urinary levels of pseudoephedrine was 0.20 mg/mL and the level of diphenhydramine was 11.2 m g/mL.

McCleave et al. (1978) reported an unsuccessful suicide attempt by a 17-year-old youth who had consumed an unknown quantity of pseudoephedrine and choline theophylinate. When admitted, the youth had severe hypokalemia, tachycardia (130 bpm), dilated eyes, blood pressure of 135/70, hyperglycemia, and hyperinsulinemia. Treatment was successful and the patient was released two days later. The authors considered that both drugs could have contributed to the symptoms. The doses could not be determined due to the refusal of the patient to cooperate in the investigation. No information was provided as to blood or serum levels of pseudoephedrine.

5.2.2.2 Cardiovascular Effects of Pseudoephedrine in Pharmaceutical Products

Rosen (1981) reported a case with a 51-year-old woman who was admitted due to chest pains, with a diagnosis of coronary insufficiency. She had been taking several medications, including meclizine, diazepam, and Actifed (which contains pseudoephedrine). While in the hospital, the patient was administered Actifed along with nitroglycerin and other medications without any recurrence of the angina. However, following release she returned the same day to the hospital due to another anginal attack, which was quickly resolved with nitroglycerin treatment. She had apparently taken the Actifed tablets 40 minutes prior to this second onset of pain. There was no evidence of myocardial infarction. The authors felt that there was a temporal relationship of the angina to ingestion of Actifed tablets; however, they were puzzled by the lack of reaction to Actifed while in the hospital and considered that other factors may also have played a role in the anginal attacks.

Loizou et al. (1982) reported a case of intracranial hemorrhage that occurred in a 17-year-old girl that ingested 20 tablets each containing 60 mg of pseudoephedrine (total dose of 1200 mg) in an apparent suicide attempt. While she developed intracranial hemorrhage about 24 hours after ingestion of the pseudoephedrine, there was no evidence of associated hypertension. She rapidly recovered with no permanent effects.

Mariani (1986) provided a case report of hypertensive emergency that occurred in a 23-year-old man that had recreationally overdosed with Trinalin tablets three hours before going into severe hypertension (200/160 mm Hg.). The Trinalin tablets contained 120 mg pseudoephedrine and 1 mg azatadine per tablet. Since the man consumed seven tablets, the total dose was 840 mg pseudoephedrine. Treatment brought the blood pressure down within a few hours.

Chua et al. (1989) conducted a double-blind crossover study to determine the effects of single doses of pseudoephedrine in hypertensive patients. Blood pressures and heart rates were measured in 15 male and 5 female patients every 5 minutes for 30 minutes after administration of either 60 mg pseudoephedrine or a placebo. After a wash-out period of 2 weeks, patients were crossed over and the study repeated. Both placebo and pseudoephedrine caused increases in systolic, diastolic and mean arterial blood pressures, with decreases in heart rate. Changes were small, and there was no significant difference between treatments for effects on diastolic or mean arterial blood pressure. Pseudoephedrine increased systolic blood pressure more than placebo (5.0 ± 6.8 vs. 2.1 ± 6.0 mm Hg) while the fall in heart rate was greater with placebo (- 6.9 ± 4.7 vs. -2.5 ± 3.5).

Wiener et al. (1990) reported that a 28-year-old man developed coronary artery spasm and mild myocardial infarction following ingestion of 60 mg pseudoephedrine. The previous day he had ingested 30 mg of pseudoephedrine and had chest pressure, which resolved after several hours. The man was treated with nitroglycerin and had uncomplicated recovery.

Bradley et al. (1991) studied a group of 29 patients with controlled, uncomplicated hypertension to determine the effect of pseudoephedrine on blood pressure in these controlled patients. A dose of 60 mg taken four times per day for three days did not affect control of hypertension.

Beck et al. (1992) conducted a double-blind, placebo-control study to evaluate the safety of pseudoephedrine in 28 hypertensive patients. Patients were treated with 120 mg pseudoephedrine twice daily (daily dose = 240 mg) for three days. No change in any cardiovascular parameter was observed although there was an upward trend for blood pressure and heart rate. Even though the doses were large, pseudoephedrine treatment caused only minimal increases in measured cardiovascular parameters (systolic, diastolic, mean arterial blood pressure, heart rate). None of these differences reached statistical significance. There were indications of the minor differences between treatment and placebo groups, which started to disappear within the 3-day period of the study. Subjective side effects of the pseudoephedrine treatment consisted of mild to moderate sleep disturbances in 32% and 40% of volunteers at 48 and 72 hours, and some urinary obstruction in 27% and 20% of male volunteers at 48 and 72 hours.

Schneider (1995) reported a case of ischemic colitis in a 58-year-old woman who had taken a long-acting nasal congestant (containing 240 mg pseudoephedrine hydrochloride) daily for five days before developing symptoms. The author was unclear as to the cause of the ischemic colitis but considered pseudoephedrine as a candidate.

Derreza et al. (1997) reported on a 46-year-old man who was hospitalized due to acute onset of chest pain and other anginal symptoms. For 3 months, the man had been taking an OTC medication (4x/day) for sinus congestion, consisting primarily of acetaminophen and pseudoephedrine. He apparently had taken the medication 30-60 minutes prior to onset of pain. On admission, his blood pressure was slightly elevated with a normal heart rate. Although the clinical work-up did not find definite cardiac abnormalities, he was treated with nitroglycerin and suddenly developed a transient tachycardia which resolved spontaneously. Coronary angiography revealed atherosclerosis of 10-30% in the coronary arteries. It was noted that nitroglycerin caused unbearable headaches and had to be discontinued. He fully recovered and was free of anginal symptoms. While the authors allude to a myocardial infarct, the case write-up fails to provide information to that effect. It is also of interest that the man had partially occluded coronary arteries, was a heavy smoker, and had strong adverse reactions to nitroglycerin.

Dowd et al. (1999) reported four cases of ischemic colitis that were associated with ingestion of pseudoephedrine. All cases were in middle-aged women (37-50 years) that developed abdominal pain and bloody diarrhea, which was confirmed to be ischemic colitis. All women had taken cold-allergy medications within the week prior to onset of symptoms. All cases responded to supportive therapy and abstinence from pseudoephedrine. None had relapsed since discontinuing the pseudoephedrine (8-12 months).

Summary. Of the 10 cases reported, none involved cardiovascular deaths or long-term clinical problems. The most common adverse effect was ischemic colitis that occurred in five persons consuming oral pseudoephedrine at the recommended dose level. Two other cases of anginal pain were reported with use of high doses. Two cases involved overdosing with hypertension and one case of intracranial hemorrhage from which satisfactory recovery occurred. Three of the reports actually pertained to clinical studies to evaluate the safe use of pseudoephedrine at a dose level of 60 mg.

5.2.2.3 Neurological Effects of Pseudoephedrine in Pharmaceutical Products

Diaz et al. (1979) reported that a 37-year-old woman had developed a tolerance and possible addiction to a pseudoephedrine-containing medication (Sudafed). She began taking the medicine five years previous and gradually had increased the dosage. At the time of admission, she was ingesting 100-150 tablets each day. When she attempted to withdraw she felt fatigued and depressed with some visual aberrations, although there were no signs of psychotic thought processes. She was gradually withdrawn from the drug with no untoward effects.

Dalton (1990) reviewed a case in which a 13-year-old girl was presented for mixed bipolar disorder, which seemed to be triggered by overdosing with pseudoephedrine. She had taken eight 60 mg pills within a 1-2 hour period (total dose = 480 mg). Previously she had been taking one 60 mg pill per day without side effects. She was treated and discharged within two weeks. However, the psychotic condition returned seven months later without a history of taking the pseudoephedrine. It was noted that there was a family history of major depression (father).

Clark and Curry (1990) presented a case of a 19-month-old girl that had accidentally ingested 20 pseudoephedrine tablets (30-mg per tablet). Within 75 minutes she was brought to the emergency room with tachycardia (200 bpm). Approximately one hour after admittance, the patient suffered a generalized tonic-clonic seizure, which resolved spontaneously. The child responded to treatment and was released in two days.

Anastasio and Harston (1992) reported that a 39-week-old fetus developed tachycardia in a woman that had been taking a long-acting pseudoephedrine nasal decongestant (Sudafed LA) for seven days. The heart rate of the fetus was 175-185 bpm, which decreased to 150 bpm by the next day after discontinuing the product. The child was delivered successfully with no apparent abnormalities.

Clovis (1993) in a letter to the editor, reported that he had treated a woman for 25 years for recurrent bouts of paranoia. It was speculated that the frequency of attacks seemed to be seasonal and may relate to the use of a nasal decongestant that contained pseudoephedrine (Sudafed). Avoiding use of Sudafed seemed to reduce but not eliminate the paranoia relapses.

Wood (1994) reported that an elderly woman (72-years old) showed psychiatric disturbance, which he associated with use of a nasal decongestant that contained pseudoephedrine that she had been taking for four weeks. It was noted that she had previously suffered from a depressive episode and was treated with lithium, apparently with success. She also had a family history of bipolar illness (brother). Medication with the decongestant was stopped and the woman returned to normal state within two weeks.

Roberge et al. (1999) reported the examination and treatment of a 2-year-old male child that was acting bizarrely and drunk. Two days prior, the child was placed on treatment with Robitussin CF [which contains pseudoephedrine (PE)] and Dextromethorphan (DM) for respiratory symptoms. The child normalized within 4 hours in the ER without medication. According to the reporting clinicians, the child had been severely overdosed with 450% more DM than recommended and 225% more PE than recommended.

Soutullo et al. (1999) presented short summaries for three young girls (10, 13 and 15 years of age) that had various forms of psychosis, which appeared to have some relationship to use of ephedrine or pseudoephedrine products. In case 1, the 15-year-old had apparently overdosed with pills for recreational purposes. She in fact vomited 3 pills in the ER room. She was a marijuana and alcohol user with a family history of psychotic conditions (father and mother). Case 2, a 13-year-old girl had been taking Rondec-DM for a week for flu-like symptoms. She also was a marijuana user, which was detected in the urine along with pseudoephedrine, diphenhydramine, promethazine and benzodiazepines. Case 3 involved a 10-year-old girl with asthma that had been taking a pseudoephedrine-containing nasal decongestant (120 mg/day) for three weeks. The authors pointed out that their observations had several limitations, including the fact that the patients were taking different medicines combined with other medications and the possibility that steroids might have contributed to the psychotic syndromes.

Summary. The eight cases reporting psychiatric problems associated with pseudoephedrine were related to abusive use of ephedrine or long-term, high-dose treatment. No deaths or permanent disabilities were reported.

5.2.2.4 Dermal Effects of Pseudoephedrine in Pharmaceutical Products

Taylor and Duffill (1988) presented a case report of a 32-year-old woman with a history of recurrent pseudo-scarlatina, which was considered as a response to pseudoephedrine as well as other unknown substances. She had experienced 11 attacks over a 13-year period with no obvious cause identified, although codeine was suspected. On the occasion she visited the authors, she experience an attack soon after taking a little Nyal Decongestant Cough Elixir New Formula. She challenged herself again with the medicine and reproduced the attack within hours. A patch test with pseudoephedrine was negative. The woman believes that the original attack 13 years previous occurred at a time when she had taken Actifed.

Camisa (1988) reported that a 48-year-old woman developed erythematous plaques in various areas of the body on three separate occasions and had been on various medications including pseudoephedrine. Two years later she developed new patches which seemed to coincide with having taken pseudoephedrine two days previous. The eruptions cleared soon after discontinuance of the pseudoephedrine.

Tomb et al. (1991) presented a case of allergic dermatitis apparently due to the oral consumption of a pseudoephedrine product. The patient was a 65-year-old woman that presented with an acute bilateral eczematous eruption on the neck, trunk, and arms, which developed two days after taking one capsule of a pseudoephedrine-containing nasal decongestant (RhinalairÒ ). The patient had a history of allergic dermal reaction to a nasal decongestant. This occurred about 18 months prior to the reported event. The woman had been treated with a nasal decongestant that contained pseudoephedrine along with triprolidine and paracetamol, with a similar eczematous eruption.

The patient was patch tested with RhinalairÒ and had a strong positive allergic reaction. She underwent further patch testing two months later, which revealed strong sensitization to ephedrine and pseudoephedrine and slight reaction to phenylephrine. Three months later, she again developed skin reactions after treatment with another product (RinutanÒ ), which contained paracetamol, PPA, phenyltoloxamine diacid citrate, and other ingredients unrelated to ephedrine, pseudoephedrine or phenylephrine. The authors suspected sensitization to PPA for which they had not previously tested.

Cavanah and Ballas (1993) reported that an 18-year-old woman developed toxic shock syndrome, with skin rash, angioedema of hands and face, myalgia, orthostatic hypotension, among other symptoms. She had similar episodes on five occasions over the next year with no clear etiology. At the time of her last episode, she recalled that the symptoms seemed to appear at times she took OTC cold preparations although she had taken different products each time. A common component of the products was pseudoephedrine. Upon oral challenge with pseudoephedrine, she developed a rash and other symptoms, which confirmed the sensitivity to pseudoephedrine.

Hauken (1994) reported a case of fixed drug eruption, which a 41-year-old man related a history of four episodes of fixed drug eruption that occurred during the preceding 19 years. All seemed to occur after having taken medications containing pseudoephedrine. There was no indication that patch testing or oral challenge was performed.

Krivda and Benson (1994) reported that a 61-year-old man with a 4-day history of erythematous eruption had taken Vicks Formula 44D and noticed the reaction 9 hours later. The patient reported two previous episodes, one occurred two years previous after he had taken TheraFlu cold medication and the other occurred five years prior after he had taken Actifed tablets. While the authors concluded that pseudoephedrine was the inciting agent, no oral rechallenge was performed to confirm this.

Heydon and Pillans (1995) reported an allergic response in a 42-year-old man that had taken Seldane Decongestant (terfenadine and pseudoephedrine) and three hours later he developed angioedema of the tongue and erythematous reactions and desquamation of the skin. Approximately six months later, he had a similar reaction after taking Claratyne Decongestant, which contains pseudoephedrine and loratadine.

Rochina et al. (1995) reported scarlatina-like rash that occurred on two occasions after taking pseudoephedrine. While the patch test was negative, she had a positive oral challenge test.

Alanko et al. (1996) reported that a 26-year-old woman developed nonpigmented fixed drug eruption 10-12 hours after taking medicines for respiratory tract infection, including pseudoephedrine. Two months later, she took the same medications and developed similar eruptions. A patch test produced a positive but weak response to pseudoephedrine.

Garcia-Ortiz et al. (1997) reported that an 18-year-old woman twice developed nonpigmenting fixed exanthema following treatments with ephedrine (Fluidin codeina) and pseudoephedrine (Narine) containing medications. Patch tests were negative to both ephedrine and pseudoephedrine; however, the patient had a positive reaction with oral challenge to both ephedrine and pseudoephedrine.

Hindioglu and Sahin (1998) reported that a 10-year-old boy developed nonpigmenting skin reaction a few days after having consumed triprolidine and pseudoephedrine tablets. The boy developed the lesions again 4 hours after an oral challenge with pseudoephedrine.

Vidal et al. (1998) reported that a 27-year-old woman developed nonpigmenting skin eruption twice after taking tablets that contained pseudoephedrine, once six months before and the other on an unspecified occasion. Patch tests were negative for pseudoephedrine; however, she had a positive reaction following an oral challenge.

Anibarro and Seoane (1998) reported that a 19-year-old woman twice developed nonpigmenting fixed exanthema, which was temporally related to the use of pseudoephedrine medication (Narine and Iniston). Patch testing was negative although she reacted positive to an oral challenge.

Vega et al. (1998) reported on two patients that developed delayed generalized dermatitis, which appeared to be associated with pseudoephedrine medication. In both cases the men were elderly (64 and 73 years old) and had taken a codeine, chlorpheniramine maleate and pseudoephedrine medication known as Las Con Codeina. In both cases the rash developed 24-48 hours after taking the medication. The second patient took the medicine a second time a month later and developed similar lesions.

Summary. The 13 cases reporting dermal conditions related to pseudoephedrine use were primarily sensitization although one case was diagnosed as systemic contact dermatitis. The causal relationship of pseudoephedrine to the dermal conditions is considered confirmed in most of these studies.

5.2.2.5 Other Reported Effects

Franklin (1999) reported that a 21-year-old male had been consuming a pseudoephedrine product for weight loss. Subsequently, he was vaccinated for typhoid and Japanese encephalitis. Seventy-five minutes after receiving the vaccinations, while on a three mile run, the man collapsed and could not be resuscitated. The coroner reported that he had a moderately enlarged heart with early moderate atherosclerotic cardiovascular disease but no evidence of heart failure or thrombosis. The author opined that the cause of death could have been related to pseudoephedrine, typhoid vaccine, Japanese encephalitis vaccine, exercise, or a combination of all these factors, which could have contributed to central thermoregulatory system failure that likely caused his death.

Lyon and Turney (1996) reported a case of pseudoephedrine toxicity in a man with pre-existing chronic renal failure. The man was 39 years old with end-stage renal failure when he was treated for sinusitis with SudafedÒ tablets containing 60 mg pseudoephedrine three times per day for seven days. At the time of treatment with pseudoephedrine he was on routine hemodialysis. Due to the development of insomnia, anxiety, palpitations, and tachycardia (110 bpm), he discontinued the SudafedÒ . Four days later, since he was still symptomatic, blood was analyzed for pseudoephedrine levels, and revealed a level of 1.28 mg/L. This was well above the upper therapeutic range of 0.7 mg/L. As some of the drug would be removed by dialysis and since four days had elapsed, the authors estimated that the peak serum concentration in this patient probably exceeded 1.9 mg/L. Reference was made to a similar case reported by Sica and Comstock (1989) who reported that a 64-year-old man on hemodialysis accumulated pseudoephedrine during a seven-day course of 60 mg, three times per day use of a nasal congestant. The man apparently developed pseudoephedrine toxicity.

Matsuoka et al. (1985) reported a case of an aborted fetus (80 days of gestation) in a woman that had taken an overdose of Tedral when the embryo was at approximately 30 days of development. The doses of drugs consumed at the time were 100 mg pseudoephedrine, 520 mg theophylline and 32 mg phenobarbital. The congenital anomaly was truncus arteriosus of the fetal heart. The authors considered that the Tedral could have played a role.

Summary. One case report was published describing chronic renal failure following use of a pseudoephedrine product at approximately twice the recommended dose. Another case suggested that pseudoephedrine might have contributed along with numerous other factors in a congenital anomaly of the fetal heart.

5.3 Methylephedrine

No clinical studies pertaining to the efficacy and safety of methylephedrine were found in the published literature. Methylephedrine is used for pharmaceutical purposes in Europe. The manufacturer of Tossamin PlusÒ (Norvatis Consumer Health) indicates that the product contains 30 mg of d,l-methylephedrine HCl. The recommended daily dose is two pills per day. Assuming that the l-isomer is the only active form, a safe dose would thus be at least 30 mg/day.

6.0 References

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Respectfully submitted:

Norbert P. Page, D.V.M, M.S., DABT

Theodore M. Farber, Ph.D., DABT