Investigation of maternal and embryo/fetal toxicity of

Ephedra viridis and Ephedra nevadensis in sheep and

cattle
RICHARD F. KEELXR

AbStUCt
Ephe&a vMdi& and Ephe&a nevadknh were gw8ged at high The pressor amines in Qhedra include (-)-ephedrine, (+)-pseudo-
doea to pregnant livestock to determine whether there existed any ephedrine, (-)-norephedrine, (-)-N-methylpseudoephedrine, and
maternal or embryo/letal toxicity. E. viricls was tested in both (+)-norpseudoephedrine, (+)-N-methylpseudoephedrine (Brossi and
sheep and cows and waa toxic, and generally induced rumhl Pecherer 1970). They are very close in pressor amine activity and in
impaction, diarrhea, vomition or anorexia. E. m!va&nsis WY structure to the adrenal hormones epinephrine (adrenalin) and
tested only in sheep, but wry devoid of toxicity. Neither plant norepinephrine (noradrenalin) in which, contrary to the &hedra
induced apparent adverse effecta in unboro offiprhg of animal8 amines, there are hydroxyl groups on the phenyl moiety. Both
paged. They were normal at birth. adrenalin and noradrenalin have been found to induce birth
defects (teratogenic effects) in rabbits, rats, and chicks (Jost et al.
KeywordszEpheth spp., poiaonour planta
1969, Jost 1953, Gatling 1962, Hodach et al. 1974, Pitel and Ler-
Many plant genera contain compounds that are substituted man 1%2).
/I-phenethylamines. The phenethylamines are very active com- Because of the widespread ingestion of species of the @hedra
pounds biologically. Many are potent vasoconstrictors (pressor genus by livestock on western ranges in the U.S., and because of the
amines) and thereby greatly elevate blood pressure. In addition, use of these same species in preparation of herbal teas, I investi-
they may exert a variety of physiologic effects including accelera- gated the toxicity and teratogenicity in sheep and cattle of 2 of the
tion of heart rate, increased cardiac output, increased respiratory more common Great Basin species-@&e&a neva&nsir S. Wats.
volume, increased central vasomotor activity, and mydriasis. They and Ephedka viridis Coville an”d compared toxicoses induced to
are useful medicinally because of those as well as vasoconstriction levels of suspect toxins. This report describes the results of those
effects (Goodman and Gilman 1960). Of course,phenethylamines investigations.
are considered toxic at elevated doses as is the case with all physio- Materials and Methods
logically active compounds.
Some Ephedro species contain substituted /I-phenethylamines. phnt MaterhI
Composite samples from several dozen &hedra nevaaimti
The author h with USDA/ ARSI Poisonow Plant Research Laboratow, 1I50 East plants were collected at an elevation of about 1,460 m on the Lake
1400 North, L.qan, Utah 8&l.
Ihe author expresses a reciatioa to Ma. Jan Knight and Mr. Glenn Patterson, Bonneville benches of the Hogup and Terrace Mountains in Box
BLM Hankwille, Utah. Pp or advice on plants and collection sites; to Mr. Edwin Elder County, Utah, in August of 1981 (collections 8122,350 lb
Lambcrt and L.D. Balls for excellent t&nical assistance; and to Dn. Ward Crow&
Stan Allen, and Row Smart for advice and necropsies. dry weight total) and August of 1982 (collection 82-15,470 lb dry
Manuscript accepted 25 Augurt 1988.

JOURNAL OF RANGE MANAGEMENT 42(l), January 1999 31

weight total). The collections included above-ground parts, excluding Results
woody material. Composite samples from several dozen &he&u
Ephedra viridis and Ephedra nevadensis differed markedly in
viridis plants were collected at an elevation of about 2,130 m on the toxicity at dosages gavaged (Table 1). E. nevadknsis was without
Eagle Bench of the Henry Mountains in Garfield County, Utah, in toxicity whereas E. viridis was quite toxic at all levels gavaged. In
September of those same years (collections 81-25540 lb dry weight sheep, both of the E. viridis collections, 81-25 and 82-23, induced
total, and 82-23,425 lb dry weight total). Those collections also ultimate clinical signs of ruminal impaction at all levels tested
included above-ground plant parts, excluding woody material. All (7-2lg/ kg/day) and in as little as 3 days at high doses. A few ewes
4 collections were returned to the laboratory and air dried for had evidence of diarrhea before impaction developed. In contrast,
several days. They were then ground to a fine consistency (to pass a E. nevaaknsis gavaged to sheep at 17.5g/kg/day for 30 days
15mesh screen) and stored at ambient temperatures for later gav- induced no clinical signs of toxicity. Only E. viridis was gavaged to
age. Portions subjected to chemical analysis were ground further in cows and induced at doses of 4-581 kg/day clinical signs of toxicity
a Wiley Mill to pass a 40-mesh screen. that included severe diarrhea, vomition, fecal mucus, and anorexia.
Six ewes gavaged E. viridis died during the course of the experi-
Chemkal Analysis
ments (Table 1). Two (3419 and 3498) died from among the group
E. viridis and E. nevadensis plant collections were subjected to gavaged collection 81-25 at 2lg/kg/day, one following 4 days of
tannin analysis by the Folin-Denis modification method of Bums gavage and one following only 3 days. The other 3 (3416,3103, and
(1963) using gallotanic acid as the standard to yield values for 3555) were gavaged Zig/kg for only 5 days each at which time
‘Yannic acid equivalents.” Values were-obtained at 700 rather than ruminal impaction became too severe to continue. In the group
725 nm. Samples were also analyzed for ephedrine, pseudoephed- gavaged collection 81-25 at 12g/kg/day, one died (2832) 46 days
rine, norephedrine, and norpseudoephedrine by gas chromato- after gavage began and another died (3433) 48 days after. Necropsy
graphy (GC) analysis of the purified total basic fraction of the plant established that both had impaction of rumen/ abomasal contents.
prepared as follows. Twenty g of plant material was moistened There were no other consistent gross pathologic signs in these 2
with 20 ml 2% Nas CGs and extracted for 2 days with 300 ml animals on thorough necropsy examination. The other 3 ewes
benzene. The benzene was removed by filtration, pooled with an (3501, 3590 and 2741) in thii group, gavaged collection 81-25 at
additional 100 ml benzene wash, evaporated to 10 ml, and parti- 12g/ kg/day, survived but had signs of rumen impaction the latter
tioned against 75 ml of 1% HCl(2X). The separated acid phase was 3/ 4 of the gavaging period. In a third group, 2 ewes (3653 and 3678)
then neutralized to pH 10 with 5% N&OH and partitioned against died from rumen impaction as a result of gavaging 7g/ kg/ day, but
100 ml benzene (2X). The pooled benzene was dried and the residue they received a different E. viridis collection (82-23). No deaths
taken up in ethanol for gas chromatography on an OV-17 column were induced by E. nevad2n.G in sheep nor by E. viridis in cows.
There was a very marked weight loss as judged from appearance
isothermally at 1200 C, and by temperature programming at lu)o -
in both sheep and cows during the course of gavaging E. viridis as a
170” C. Standards of ephedrine, pseudoephedrine, norephedrine,
consequence of anorexia. But careful measurements were made
and norpseudoephedrine were compared to plant extracts by GC
only on cows 3782 and 3325. These 2 animals lost 57 and 20 kg
analysis.
respectively. Cows and sheep gavaged E. nevadensis, however,
Animal Care and Administration of Plant Materials continued to eat normally and appeared to gain weight during the
Experimental animals were Hereford cows weighing an average gavaging period.
of 410 kg and crossbred ewes weighing an average of 56 kg. There were no marked trends (e.g., clinically significant declines
Ephedru plant material was administered by gavage in a water in RBC or WBC or elevations in the other parameters) in the 10
slurry at the dosage, stage of gestation, and for numbers of days sheep tested in mean concentrations of any of the blood parameters
indicated in Table 1. Dosages listed in Table 1 were the average measured (RBC, WBC, PCV, HGB, SGOT, SGPT, LDH, BUN,
dosages. There were some slight dosage adjustments (f20%) in nor GGTP) during the course of gavaging either E. viridis or E.
some animals in order to arrive at a maintenance dose that elicited nevudensis (Table 2). Individual animal variations in these para-
meters during the dosing period fell within about f 35% beyond
toxicity signs but did not result in death. Animals were provided
the pretreatment range values except for a rise in WBC and lower-
alfalfa hay, water, and salt ad libitum.
ing RBC in ewe # 2204 ascribable to a respiratory infection. How-
Experimental cows were bred to Hereford bulls and ewes to
ever, marked elevations of SGGT and LDH did occur in ewe 2832
Suffolk or Columbia rams with date of breeding considered as the and in LDH in ewe 3433 (Table 2) after those ewes were removed
beginning of day zero of gestation. Animals were observed for from treatment. They had been removed from gavaging at a little
clinical signs of toxicoses throughout the gavaging period and for a over l/2 the expected gavaging duration (Table 1) because of
few days thereafter. Offspring were examined at birth for congeni- severe ruminal impaction. Values for SGOT and LDH were 128
tal deformities. Thorough necropsies were performed on 2 of the and 1092 respectively in ewe 3433 and 181 and 1174 in ewe 2832.
ewes that died from toxicoses. They were selected because tissues These values were obtained after gavaging had ended but a few
were still reasonably fresh after death. days before their deaths. SGGT and LDH values did not elevate
For measurement of blood parameters, venous blood samples similarly in any of the other 8 ewes tested. Values measured 14 days
from each experimental animal so tested (ewes # 3501,3590,2741, after termination of dosing were essentially within pretreatment
2832,3433,3436,3434,3449, 3403, and 2204, and cows # 3782, ranges for surviving ewes.
3325,3753,3754, and 3825) were drawn 2 days prior to gavaging, There were no marked trends in the 5 cows tested in mean
and then periodically during the period of gavaging and at 14 days concentrations of any of the blood parameters measured (RBC,
after gavaging ended. Blood parameters measured singly by stand- WBC, PCV, SGOT, BUN, nor GGTP) during the course of gavag-
ard automated procedures (Abbott ABA 200 analyzer) in ewes ing E. viridis (Table 3). Individual animal variations in those
were red blood cell count (RBC), white blood cell count (WBC!), parameters during the dosing period fell within about f35%
packed cell volume (PCV), hemoglobin (HGB), glutamic-oxa- beyond the pretreatment range values except for one low BUN
loactic transaminase (SGOT), glutamic pyruvic transaminase values of 10.2 on animal 3782 ten days after dosing began. On
neither the 3 nor 24 day assays was the BUN for this animal outside
(SGPT), lactic dehydrogenase (LDH), urea nitrogen (BUN),
the pretreatment range.
gamma glutamyl transpeptidase (GGTP). Similar measurements
All lambs and calves born to ewes or cows gavaged either E.
were made for cows except that LDH, SGPT, and HGB were not
viridis or E. nevadensis were grossly normal and without notice-
measured. able birth deformities regardless of gestational period during which

32 JOURNAL OF RANGE MANAGEMENT 42(l), January 1999

Table 1. Bffeets of @he&a spp. on corn and cwe~and their offqwlng.

Gestation Daily
Plant Animal period average Birth
material number aW?ed dosage (g/kg) Toxicity signs in the dam Pregnancy outcome wt (kg)
Cows gavaged
E. viridis
81-25 3782 10-36 4.9 Diarrhea, vomition, Delivered normal single at 24.5
anorexia, fecal mucus term
3325 lo-36 4.9 Diarrhea, vomition Delivered normal single 27.7
anorexia, fecal mucus at term
82-23 3753 40-70 3.9 Anorexia. vomition, Delivered normal single 29.1
bloaty at term
3754 40-70 3.9 Anorexia, vomition, Non-pregnant
bloaty
3825 40-70 3.9 Anorexia, vomition, Non-pregnant
bloaty
Ewes gavaged
E. viridis
81-25 3416 10-15 21 Ruminal impaction Delivered normal twins at 4.5.5.0
at term
3103 lo-15 21 Ruminal impaction Non-pregnant
3555 10-14 21 Ruminal impaction (died
at 14 days gestation)
3419 lo-15 21 Ruminal impaction Delivered normal single 5.9
at term
3498 10-13 21 Ruminal impaction (died
at 13 days gestation)
3501 1040 12 Ruminal impaction Delivered normal single 5.5
at term
3590 1040 12 Ruminal impaction Delivered normal twins 3.6,2.7
at term
2741 10-40 12 Ruminal impaction Delivered normal twins 4.5,4.1
at term
2832 10-26 12 Ruminal impaction (died at
56 days gestation)
3433 10-28 12 Ruminal impaction (died at
58 days gestation)
82-23 3650 30-60 5.3 Ruminal impaction Delivered normal single at 5.9
term
3653 30-35 7 Ruminal impaction (died
at 36 days gestation)
3678 30-33 7 Ruminal impaction (died
at 34 days gestation)
3661 30-60 5.3 Ruminal impaction Delivered normal twins 3.2,3.2
at term (one had equivocal
forelimb bowing)
3656 30-60 5.3 Ruminal impaction Delivered normal twins 3.6.3.2
at term
3687 30-60 5.3 Ruminal impaction Delivered normal twins 4.5,5.0
at term
3681 30-60 5.3 Ruminal impaction Delivered normal twins 4.3,4.5
at term
Ewes gavaged
E. nevadensis
81-22 3436 IO-40 17.5 No toxic signs Delivered normal twins 4.5,5.0
at term
3434 lo-40 17.5 No toxic signs Delivered normal twins 4.5,5.5
3449 IO-40 17.5 No toxic signs Delivered normal single 5.9
at term
3403 10-40 17.5 No toxic signs Delivered normal twins 4.5,5.5
at term
2204 1040 17.5 No toxic signs Delivered normal twins 5.0,5.5
at term
82-15 3692 30-60 17.5 No toxic signs Delivered normal twins 5.0, 5.3
at term
3684 30-60 17.5 No toxic signs Delivered normal twins 2.7,2.7
at term
3662 30-60 17.5 No toxic signs Delivered normal single 6.4
at term
3695 30-60 17.5 No toxic signs Delivered normal single 5.0
at term
3704 30-68 17.5 No toxic signs Delivered normal twins 3.0.3.2
at term
Table 2. Blood parsmeter muna and ranges from ewes1 during gwaging of Ephe&a spp. 8nd 14 days after g8~8gingbad ended.

RBC WBC PCV HGB SGOT SGP? LDH GGTP

(N/mm2) N/nut+) (%) (a/dl) (u/l) (u/l) (u/l) (u/l)
2 days
before 11.0 8860 15.4
Eavaging [8.3-13.21 [5780-MOO] [3&, [14.6-16.81 [35%2, [l l.ifi4.1, [3:%9] [14.:;5.4] [44.?:3.9,
3 days El nevademis 11.2 16.4
after [10.7-13.11 [702:?kO, [3::3] [15.7-16.91 [82%8] [12.::7.7] [31z3, [12.:;7.1, c49.Ez8.7,
waging
ban E. viridis r8.6-9ii.6, 9520 40 15.3 94 17.3 r33??58, 18.8 59.3
r6990_126OO] r35-431 113.8-16.61 r48-1241 r9.1-23.91 r14.O-24.31 r49.6-75.51
10 days E. nevademis 10.3 No Data 14.5 282 19.5
after [9.3-l 1.61 [762E6o, [4t?42] [5cz34, [14.4-14.61 [266-3141 [12.9-26.7 [49.::9.1]
wa@w
Man E. vin’dis r7.1%.3i 7700 43 No Data r42%9i 7.8 337 11.2 59.2
14770-i loooi r36-w r4.4-12.21 1283-4351 r6.o-15.11 r52.2-74.71
17 days E. nevademis 1959i80.5, [688:g70, [3&] 15.0 f637-51, 12.0 319 18.5 58.6
sftcr [14.4-16.01 [9.5-14.41 [286-3621 [13.3-21.21 [51.9-63.6]
gavaging
began E. vin’dir 9.0 7120 40 14.4 84 10.1 370 13.1 No Data
f8.1-9.81 f7010-103001 r35-461 rl2.9-17.21 r43-1391 rll.2-12.91 w-3091 rlzo-14.11
24 days E. nevademis No Data 13.0 312
after [5.0!;70.2, [62Ot?l!&O, [37%, [71?12, [9.9-15.81 [252-3601 [17.?;2.4, No Data
gsvs&g
began E. viridis 8.5 7860 38 No Data No Data 11.3 297 18.9 58.6
f7.1-10.11 f6880-89701 f35411 r4.9-17.71 r260-3381 117.620.91 145.2~65.21
30 days E. nevademis [3.:;5] [63~3?&30, [3”37401 13.9 [7tP97j 13.0 335
after 112.414.51 [8.7-14.41 [274-426] [21.:;8.2, No Data
gavaghrg
began E. viridis 8.5 8210 36 13.8 52 7.6 314 18.3 62.5
r7.2-lo.41 r5630-124001 r32-421 rl2.4-la.01 r42-621 yo-10.61 1266-3701 114.621.27 r49.8-72.61
14 days E nevademb [6.::9] [633230, [3;2, 14.3 12572, 11.0 289 27.8
sftcr [13/t-15.8] [8.7-12.81 [238-3351 [18.3-28.81 [47.::2.9,
rd$ng E. viridis 11.9 639 18.9 70.8
[7.59;.2] [65w??900, [33:7, [40?81] [8.2-15.21 [271-l 1701 [10.8-26.41 [48.2-l lo]
Then were 5 cwcs gavagcd E. nc~dorr~l~ (# 3436,3434,3449,3403 & 2204), and 5 ewes gavagcd E viridis (#3505 3590,2741,2832 & 3433). However, 2 on 4 viridh (f 2832 B
3433) were not gavaged beyond 16 and 18 days respectively. E viridisdata for the 24 and 30day periods does not mcludc those 2 WCS. Data from all ewes are mcluded in the 14
days after gavaging period, however.

Table 3. Blood parameter meann amI ranges from COWSI

during pvaging of Ephedw viriws.

RBC WBC PCV SGOT BUN GGPT

(N/m@ (N/mm21 (o/o) (u/l) @g/ 1oocc) (u/l)
2 days before 7.3 6470 r3?5Oi 71 20.5 16.1
gavaging f6.48.11 r5700-69701 rss-911 rl7.2-23.01 rll.0-27.91
3 days after 7.4 7080 74 21.5 16.4
gsvazing began r7.0-7.71 f6580-78401 r37”-zsoi 161-951 rl5.9-25.n rl2.3-25.41
10 days after 7.7 7810 43 78 17.1 14.8
gsvazina bearm r7.3-7.91 17120-86901 f39-481 145-931 rlo.2-24.21 12.3-19.81
24 days after 6710 19.8 14.3
gavaging began [6.;<.9] [5510-82401 [37:2, $679, [ 16.0-24.61 [12.6-17.01
These data arc from 5 cows, 2 of which (# 3782 & 3325) weregavapd E. viridiscollection 81-25 and 3 of which (# 3753.3754 B 38251were gavascd E. tdddfs~~Uection 82-23.

the animals were gavaged. Neither were there any trends in birth on that detection limit, neither plant could have had more than
weight (Table 1) nor thriftiness in experimental offspring. 1X 10” percent of any of the 4 compounds.
A comparison of the “tannic acid equivalent” values for E.
nevaahsis and E. viridis showed marked differences, although Discussion
both were very high. E. nevadensis and E. viridis averaged 7.77% The Ephedra spp. of the Great Basin are generally considered by
and 28.5% “‘tannic acid equivalents,” respectively, on a plant dry ranchers as suitable forage, particularly, for sheep. E. vitidis, E.
weight basis. GC analysis of plant samples for ephedrine, pseu- nevademis and other species found in the region generally show
doephedrine, norephedrine, and norpseudoephedrine revealed evidence of having been grazed. In fact, E. nevadensis is usually
that neither species had measurable levels of these components grazed heavily. These rancher observations are supported by the
literature. For example, Welsh et al. (1987) report that E. nevadensis

JOURNAL OF RANGE MANAGEMENT42(l), January 1989

 H
. . . . is consistently hedged back by sheep, to whom it is a valuable plants. This despite severe toxicity from E. viridis in cows and
source of browse,” while E. viridis “. . . . . is not so severely hedged ewes. Further experiments at lower dosages for extended gesta-
by browsing animals as some of the other species, but is still of tional periods with additional animals seem unwarranted, unless
considerable importance.” field reports at some future time suggest otherwise.
Teas brewed from branchlets of several of the E@hedru species On the basis of these experiments, &he&a nevadknsb seems to
including E. nevadensis and E. viridis have been popular for medic- be perfectly safe for grazing livestock since it induces neither
inal and recreational purposes for centuries (Dobelis 1986, Har- toxicity in ewes or cows gavaged the plant, nor congenital deformi-
rington 1967). These teas were utilized by early white settlers in the ties in lambs. E. viridis, on the other hand, has obvious potential to
Great Basin and were called by a variety of names including cause toxicosis in grazing sheep or cattle but not birth defects in
Brigham or Mormon tea. American Indians of the region, even offspring. Ranchers and land management personnel should be
earlier, used such teas or ground seed or plant material for colds, aware that toxicosis masquerading superficially as oak brush poi-
fever, or diuretics, as decongestants and for several other purposes soning may actually be due to @hedra viridk Amounts used by
(Dobelis 1986). But unlike some of the l@hedrus from other parts humans for brewing tea are orders of magnitude lower than the
of the world, the compound ephedrine and other B-phenethylamines levels gavaged these experimental animals. It seems unlikely that
were not found in E. viridis or E. nevaaksis by investigators 50-60 serious short-term toxicoses would result therefrom.
years ago (Terry 1927, Read and Feng 1927, Nielsen and McCaus- References
land 1928, and Nielsen et al. 1927). This is somewhat surprising in
view of the described medicinal uses. These uses suggest the pres- Brossf, A., rad B. Pecherer. 1970. Alkaloids containing a simple aromatic
I ence of one or more of the group even if at lower concentration. moiety. p. 24. In: S.W. Pelleticr (Ed.). Chemistry of the Alkaloids. Van
Nostrand Reinhold, New York.
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guajillo wobbles from the N-methyl-/3-phenethylamine from Acu- associated with administration of epinephrinc in chick embryos. Tera-
cia berlandieri Benth. (Kingsbury 1964). There was no cardiovas- tology 9203-210.
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man. Even if /3-phenethylamine compounds were resent in the mined by the br gene and those induced by adrenalin injection in the
plants at the detection limit of the methods (1X10 t o), the resul- rabbit fetus. p. 187-199. In: Swinyard, C.A. (Ed.). Limb Development
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sheep gavaged high dosages of E. nevadensk suggests a degree of flora(@hedru Family). Great Basin Natur. Memoirs. 928-29.
safety exists for concepti of pregnant animals ingesting these

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