Joumul of ~tnrlo~ilar-rrlucoiugy, 1 (1 Y79) 69 - 78 69

@ Elsevler &quoia S.A., Lausarrne - Prtnted in the Netheriands

COCAINE IN BLOUL) OF COCA CHEWEIM*

BO HULMS’l’EL)T, JAN-EkIK LlNIXHEN and LAUKENT RIVfEk**

~e~ur[rItent of Toxzcoitigy, Swetiish ~edl~a~ Reseurch Council, Karolinska Institutet,

S-l u4 01 Stockiioim (Sweden)

TlMO’l’HY PLOWMAN***
Botantcal Museum, Hat-mm University, Cantbridge, MA 02138 (U.S.A.)
(Recerved August 20,1978)

Coca leaves (Eryrnruxylurn coca Lamarck) and powder (5 - 10 g) were

taken orally by numan subjects in the same way as South American natives
do. The cocaine, as measurea by mass fra~entography, was immediately
detected in the blood, reached peak concentrations from 10 - 150 ng/ml
plasma at 0.38 - I .95 hours, and persisted in the plasma for more than 7 hours.
Half-lives of the elimmation of cocaine were calculated and ranged from 1.0
to 1.9 hours. The absorption half-lives ranged from 0.2 to 0.6 hours. The
shape of the curves fits with the subjective effects reported. There is no reason
to be&eve that the stimulating effect achieved by the use of either coca leaves
or powder is not due to cocaine.

Introuuction

Although the use of cocaine, either by sniffing or injection, is considered

harmful by some medical authorities, considerable controve~y exists as to
whether tile chewing of coca (Erythro;uyEum coca Lamarck), as practiced by
South America11 Indians, is detrimental or not. Coca chewing has been said
to be physioioglcally beneficial for Andean Indians in terms of their adapta-
tion to hunger, cold and fatigue at high altitudes (Hanna and Hornick, 1977).
Some authors have concluded that coca chewing does not seem to result in
obvious physical and men&al deterioration among the Indians {Murphy et al.,
1969: Grmspoun and Bakalar, 1976). Zapata-Ortiz, on the other hand, main-
tailIs tnar; chronic coca chewmg produces a progressive deterioration of intel-
ligrrlce, decrease m atLemion, torpidity, and deterioration of reaction time
(Zapara-Urtiz, 1970). He quotes earlier work using psychological and psycho-
ph~~siolo~i~al ?XSCSof dubious applicability to the Andean Indian.

*A summary of tnis paper appeared in Bot. Mus. Leafl. Harvard Univ., November 1978
**Permanent address: Institute of Plant Biology and Physiology of the University,
CH-1006 Lausanm, Swnzeriand.
***Presenr. adaress: Botany Department, Field Museum of Natural History, Chicago,
IL 60605, U.S.A.
70

Coca chewers exhibit a general stimulation for about an hour after

chewing. This stimulation has been equated by some investigators with that
produced by cocaine. As a result, coca leaf chewing and cocaine-sniffing have
been regarded as one and the same problem (Wolf, 1952). Some research
workers maintain that cocaine ingested during chewing is, in the greater part,
decomposed in the gastrointestinal canal before it is absorbed. They believe
that ecgonine and other alkaloids - but not cocaine - play the most impor-
tant role in the use of the drug by the “coquero”. These workers suggest that
coca chewing could be of importance in glucose metabolism at high eleva-
tions (Burchard, 1975; Nieschulz, 1971). Other studies have shown that coca
leaves contain appreciable amounts of vitamins and minerals, and may con-
tribute significantly to the nutritionally deficient diet of the Andean Indian
(Duke et al., 1975; Machado, 1972).
Coca chewing thus has both defenders and detractors, and as a conse-
quence vehement polemics have resulted. These observations are not cited to
obscure the potential danger of coca chewing nor to advocate coca use in the
high Andes, but rather to stress the need for a thorough awareness and under-
standing of the interlocking nature of the components of a people’s long-
standing adaptation to their environment.
The purpose of the present study, as a contribution to our knowledge
of coca use, is to determine the amount of cocaine in blood upon adminis-
tration of coca by the two distinct methods practiced by Indians of the Peru-
vian Andes and those of the Amazon region.
(1) A number of toasted coca leaves are placed, together with an alkaline
material called llipta, in the mouth and are “chewed” (actually only rolled
around with the tongue and wetted) into a wad or quid which is held in the
cheek and periodically “rechewed”. The juice is swallowed and some of the
leaf material may occasionally be ingested.
(2) The second method of use, consisting in taking coca leaves in pow-
dered form (as described below in detail), is restricted to the western Amazon
region in Brazil, Peru, Ecuador, and Colombia. This variation of coca use is
practiced by numerous tribes (Schultes, 1957).
During Phase VII of the Alpha Helix Amazon Expedition 1976 - 1977
we had occasion to study both methods of administration and to determine
the amount of cocaine in blood uersus time by an unequivocal method of
analysis*. Much of the controversy in the older literature seems to be attri-
butable to the lack of determinations of cocaine in blood from coca chewers
(Montesinos, 1965).

*The RV Alpha Helix is a ship owned by the National Science Foundation (U.S.A.) and
administered by Scripps Institute of Oceanography. It accommodates twelve scientists
and has three air-conditioned laboratories. The scientific crew of Phase VII of the Alpha
Helix Amazon Expedition 1976 - 77 (March 15 - May 15, 1977) consisted of botanists,
zoologists, chemists, and medical men. We had at our disposal during the two-month
period a gas chromatograph-mass spectrometer for qualitative work on components of
toxic plants and animals. The instrument was also equipped with a multiple ion detector
for quantitative work and was used for the determination of cocaine in blood.
 71

Materials and methods

Chemicals
Cocaine hydrochloride was obtained from Karolinska Apoteket, Stock-
holm. Deuterated cocaine was synthesized as previously described (Holmstedt
et al., 1977).

Plant materials
Descriptions of the voucher specimens used in this study are given in
Table 1.
The RV Alpha Helix was anchored during the two-month period at the
small village of Pebas, where the Rio Ampiyacu flows into the Amazon. The

TABLE 1
Voucher specimens for chemical analyses and biological experiments

Plowman, Schultes Locality* Date Description* *

& Tovar No.

6663 A 5 April 1977 Erythroxylum coca, herbarium

specimens (USM, ECON)
6663A A 5 April 1977 Coca powder prepared from
dried leaves of Erythroxylum
coca (6663) and ashes of leaves
of Cecropia sciadophylla
(6664A) (ECON)
6664 A 5 April 1977 Cecropia sciadophylla, herba-
rium specimens (USM, US,
ECON)
6664A A 5 April 1977 Ashes of burned, dead leaves
of Cecropia sciadophylla
(ECON)
6750 A 12 April 1977 Erythroxylum coca, herbarium
specimens (USM, ECON)
7113 B 24 April 1977 Ery throxylum coca, dried
leaves purchased in market
(ECON)
7115 B 24 April 1977 Llipta, hardened ball of ash
prepared from stems of quinua
(Chenopodium quinoa Willd.)
(ECON)

*A = Peru: Dept. Loreto, Prov. Maynas, Rio Ampiyacu. B = Peru: Dept. Cuzco, Pisac.
**Voucher specimens are deposited in the herbaria cited: Economic Herbarium of Oakes
Ames (ECON), Botanical Museum, Harvard University, Cambridge, MA; Museo de Historia
Natural “Javier Prado”, Universidad National Mayor de San Marcos (USM), Lima, Peru;
U.S. National Herbarium (US), Smithsonian Institution, Washington, DC.
 surroundmg Indian tribes, Boras and Witotos, both cultivate coca in their
house gardens. The ingredients for the coca experiments were obtained from
the Indians in the upper Ampiyacu.
The use of coca leaves in powdered form is found in several areas of the
northwest Amazon m Colombia, Ecuador, Peru, and Brazil in a number of
unrelated tribes. The preparation of the powder is essentially the same
throughout the area. The fresh leaves of Erythroxylurn coca are gathered in
the late afternoon and carried to the main “maloca” (communal house). The
leaves are immediately toasted to dryness over a fire in a large hemispherical
ceramic bowl made especially for this purpose or on a flat ceramic “farina”
(Manihot-flour) plate. The leaves are constantly turned by hand to prevent
burning. When completely dried, they are placed in a large wooden mortar
(pildn) and thoroughly pounded to a fine powder with a pestle. At the same
time, fallen dead leaves of Cecropia sciadophylla Martius (or certain other
species of Cecropia or Pouruuma) are gathered into a large pile and burned
to ashes.
The coca powder is removed from the mortar and placed in a cloth bag
for sifting, a little at a time. The bag is shaken in a large bowl or tin can with
a cover to prevent loss of the powder. The powder, sifted through the cloth
to remove any fibrous material, is very fine and light green in color.
The clean grey ash is added to the coca powder little by little until the
right proportions are reached. The ratio of coca powder to ash varies from
1 :l to 2:l. The powder is often chewed after the evening meal by the men.
The greater part is stored in a bamboo tube or tin can for use during work
the following day. As the powder does not keep well, it is usually prepared
each day.
The prepared powder is taken in tablespoonful doses. It is held
between the cheek and the gum for a few minutes until it absorbs sufficient
quantity of saliva to become pasty in consistency. It is then worked with the
tongue into the recesses of the cheeks and gums, where it is allowed to remain
for one to several hours. By the time most of the juices are sucked from the
quid, very little coca powder remains, and the greater part is swallowed gradually.
Indians working in the forest may take coca powder numerous times during a
day. It is often used after the evening meal during discussions and story telling.

Gas chromatography-mass spectrometry

The mass spectrometric analyses were carried out on an LKB 2091 gas
chromatograph-mass spectrometer (GC-MS) equipped with a multiple ion
detector. The glass column (150 cm X 2 mm i.d.) was packed with 3% SE-30
Ultraphase on Gas Chrom Q (100 - 120 mesh) and maintained at a temper-
ature of 200 “C. Helium was used as carrier gas at a flow rate of 30 ml/min.
The temperature of the injection port was 240 “C and the ion source was
kept at 250 “C. The ionizing energy and trap current were 50 eV and 50 PA,
respectively.
During the mass fragmentographic (MF) analyses, the instrument was
adjusted to record the ions m/e 303 and 306 (M’) for cocaine and cocaine-ds.
 73

In some experiments, the mass spectromet,er was set to det.ect m/e 182 and
185 (base peak) for cocaine and cocaine-da in order to check the accuracy.
Standard curves for the determination of cocaine in plasma were obtained
by treating, in the same way as described below, a series of blood-blank plasma
specimens to which known amounts of cocaine (1 - 200 ng/ml) had been
added. The ratio of the peak heights of cocaine and cocaine-da was calculated
and plotted against the known concentration of cocaine in the standard
samples. The m/e 303 and 306 were chosen because a better signal-to-noise
ratio was obtained than with the m/e 182 and 185. Nevertheless, concentra-
tions of cocaine were almost identical with both systems.

Cocaine determination in the plant material

The cocaine content in plants was measured following the procedure
already published (Holmstedt et al., 1977), with slight modifications. 0.02 g
of coca material - either coca powder, commercially obtained dried leaves,
or air-dried fresh leaves - was ground up and mixed with EtOH (5 ml) con-
taining 50 ,ug of deuterated cocaine as internal standard and 0.1 g NaHC03.
The mixture was heated for 2 min at 75 “C and allowed to stand at room
temperature for over 5 hours. The sample was centrifuged (2OOOg, 1 min)
and 1 - 3 ~1 of the clear supernatant were injected directly in the GC-MS for
MF determinations.

Biological experiments
All experiments were performed on Eurasians or Jndians. Mnst sampling
took place on board the Alpha Helix and occasionally in the “malocas” or
communal houses of the Indians. It should be pointed out that the use of
coca leaves and preparations thereof, except for cocaine, is legal in Peru.
Weighed amounts of freshly prepared coca powder (voucher specimen
6663A) mixed with Cecropia leaf ashes (voucher specimen 6664A) or sun-dried
leaves of E. coca (voucher specimen 7113) purchased in the market at Pisac
(Dept. Cuzco, Peru) mixed with Quinua ash (llipta, voucher specimen 7115)
were given orally (time zero) and kept for various times in the cheek. as indi-
cated in Fig. 1. Blood samples were taken by venous puncture at regular
intervals with heparinized green stoppered 10 ml evacuated blood collecting
tubes fitted to a syringe (Venoject, Teruma, Tokyo, Japan).* Physostigmine
(eserine) was added immediately to a final concentration of lo-* M. and the
tube was shaken for 0.5 min. After centrjfugation (5OOOg, 20 min) the plasma
was kept cold (-40 “C, dark) until analysed the next day.

*This commercial brand of collwAion tuhe does not alter the plasma concentmtinn
of drugs as compared with the value ohtnined from the all-glass system (R. H. Cot.ham
and D. Shand, Spuriously low plasma proprannlol concentrations resulting from blond
collect,ion methods, Clin. Pharmacol. Ther., 18 (1975) 535 - 538).
Ex traction
To 1.0 ml of plasma in a 15 ml glass-stoppered tube 50 ~1 of the internal
standard (400 ng cocaineds/ml in ethanol), 0.1 g sodium bicarbonate, and
2.5 ml of anhydrous diethyl ether were added. The tube was shaken by hand
for 1 min and then centrifuged at 5000g for 10 min. The organic phase, dried
with anhydrous sodium sulphate, was transferred to a 3 ml methanol-washed
glass tube and evaporated to dryness at room temperature under a stream of
nitrogen. The residue was dissolved in 50 ~1 of toluene and 2 - 4 ~1 of this
solution was analysed by mass fragmentography .

Calculations
Plasma concentrations were used to calculate rate constants for elimi-
nation and absorption by linear regression analysis and the method of resi-
duals (cf. Gibaldi and Perrier, 1975). Absorption was assumed to be more
rapid than elimination, and a simple one-compartment pharmacokinetic
model was used even though the possibility of a second, slower elimination
phase could not be totally excluded.

Results and discussion

Alkaloids in plant materials

Analyses by GC-MS have shown that the cocaine content of the various
plant materials used represents more than 95% of the basic chloroform
soluble fraction of the ethanolic extracts. Furthermore, no ecgonine nor
benzoylecgonine trimethylsilyl derivatives were detected by MF in the silyl-
ated ethanolic extract of those materials. This shows that we were dealing
with plant materials containing almost exclusively cocaine. The amount of
this alkaloid in freshly harvested leaves (voucher specimen 6750) immediately
air-dried and analysed was 0.39%, dry weight. The powder, as prepared by
the Indians (voucher specimen 6663A), showed a cocaine concentration of
0.24%, dry weight; the Pisac leaves (voucher specimen 7113), 0.48%, dry
weight.

A bsorp tion
Measurable cocaine levels in plasma found 5 min after chewing started
indicated rapid absorption (see Fig. 1). Some researchers have pointed out that
there may be differences between the use of coca leaves and cocaine. They
refer to the fact that cocaine in the leaves may be destroyed in the gastroin-
testinal tract (Montesinos, 1965; Nieschulz, 1971; Nieschulz and Schmersahl,
1969). Undoubtedly, some cocaine and perhaps even some metabolites are
swallowed and may ultimately be hydrolysed in the gut, but this does not
imply that a certain amount could not be absorbed in the stomach. It is also
conceivable that a certain amount of cocaine in the blood is locally absorbed.
No positive evidence for this exists at the moment but appreciable amounts of
cocaine in solution are known to be absorbed when the substance is used for
 75

SUBJECT TP
COCA P(IbKlER209
z2000
:,,ooo
5 500

Fig. 1. Cocaine concentration, as determined by mass fragmentography, in the plasma of a

volunteer chewing 20 g of coca powder (voucher specimen 6663A) corresponding to 48 mg
of cocaine. The arrow indicates time of disappearance of the quid in the mouth. The curve
was generated by use of the parameters derived for the pharmacokinetic model (see text).

topical application (Jatlow and Bailey, 1975; Van Dyke et al., 1976; Dvorchik
et al., 1977), and synthetic cocaine hydrochloride in a gelatine capsule is not
absorbed from the gastrointestinal tract until 30 min after oral administration
(Van Dyke et al., 1978).

Doses
The cocaine doses ranged from 15 - 50 mg total in the administered
amount. This dose must be considered low, when compared with the quan-
tities used in topical anaesthesia (Van Dyke et al., 1976), or intravenously
injected (Kogan et al., 1977). Much higher doses are known to be illegally
used: cocaine addicts may use up to 10 g in a day (Jaffe, 1975).

Means of administration
In both preparations studied by us, alkali is typically added. In the
better known method of use (the highland method employed in the Andes),
llipta is taken with the leaves. With the powder (the Amazon method), ash of
Cecropia leaves is used. This contributes to the extraction of the alkaloids
when the material is wetted (unpublished results). The effectiveness of the
addition of alkali to crude drugs has been discovered by widely different
ethnic groups. It occurs among the South American Indians, who mix ashes
with their several intoxicating snuffs (Schultes, 1967) and in the East Indies
when betel is chewed (Hartwich, 1911). It is also reported among the Aus-
tralian aborigines when they chew pituri (Barnard, 1952).

Peak levels
Cocaine was determined in plasma by MF, after addition of physostig-
mine at the earliest step of the extraction procedure (1O-4 M solution final
concentration) in order to inhibit all e&erase activities in vitro (Stewart et al.,
1977). The peak levels obtained amount to a maximum 150 ng/ml for 4.4 g
76

of leaves and 140 ng/ml for 20 g of powder (see Fimlrej. From t.he limit4
data available, it would appear that whole leaves and ll@tn provide a more
efficient means of administration than the powder-ash mixture. Of more
import,ance are the shape of the curve and the half-lives as reIat,ed to t,he
subjective effects. The volunt.eers were a&cd in a non-prnvocative way how
they felt; in all cases, they reported local anaesthesia in t.he mnllth and a
stimulating effect (“amphetamine-like”, “I feel fine”. “feel much more
awake”, “feel great”, “full of enera”, “feel vi?ornIls”. “fepl stim\llntpd”)
during the rising phase of the blood curve. Durine the falling phase. when
the quid was still in the mouth, less expressive stat.ements could he extracted
from the subjects, but all reported “nn more st.imulat.ion”.

Pharmacokinetic half-lives
This study was not designed as a nharmacokinptic invpstiration. but
some comments can be made on the disnosition nat,tern of oral cocaine in
man. Most of the plasma concentratio&time cur& obtained can he inter-
preted according to a one-compartment model. xsluninrr fir+orrier rate
constants for absorption and elimination. Tt has also to he assumed that the
absorption is more rapid than the elimination. smce the mndel cannot differ-
entiate between these two parameters. These rates have hren approximately
estimated yielding half-lives for the elimination from 1 .O 10 1.9 hours. The
absorption half-life ranged from 0.2 to 0.6 hours. The peak nlnsma cnnren-
tration occurred between 0.4 and 2.0 hours after thr cocaine dc;sa~c was
inserted (Table 2).

TABLE 2
Pharmacokinetic data on coca chewin
_. _..~ -- ._ -- _ -. ..-
Subject* Plant material Cocdl~r I:.. &! :‘ ’ ill... i: I?,, t’ l/Z
weight (kg)/ (g) (mg) I!\ :; ,!I’ ! lk~~!~ll , :;l) (h-‘1 (hj
we (w)
__._._.___~ __. __._.__~ ~~__ -.

BH, 841.58 (powder) n.d. n.d. I /_ .I _

/ I
: r; ;:,‘1 Ii.40 1 .i .2

OT, 62155 (powder) 10 24 j :: ,, -~>. ,.;, : ;:, ,I.,;.3 1 62

JEL, 78146 (powder) 7 16.P I/ :I :;:< 119
; ;; ! :_‘i ! _:;; 1 1;;: f, ;.i 0.95
TP, 75133 (powder) 20 48
OT, 62/55 (leaves) 4.4 21 1 ;- :, ;j:, : i!. -1 f, Cl.60 , 07
_:.

TP, 75133 (leaves) 6.4 30.7 ‘, i, F , :I 5f / :i :-.

J 37 I .s!!
_ -__. ~- -.-
*BH, JEL and TP are Eurasians. OT is ll:iliat; ‘P:. /$,, “>,i! \“‘1,.1, : ,Cill! -L’ ,5 tt,o .LIl\,+Ttb
correspond to the time of the experimr-;,tx i: :: ,. , :
h, = absorption rate constant. k,, = riimin,;f~~:n v IP ~--tn<~nnt. 1, ‘: = :l!,!~c;~-;~l!l,r! !l,dI’-lii*~.
t’1,2 = elimination half-life. C,, = rnnslnl\:i- c-+ .’ ‘:I’* , .:‘., f.!ii:)iTl :,t !.I :h: I:;:;..In;>. f!, :
time at which maximum concentration of (nc.,lrr ) ,- -,*,.:v+ 111 rl:n :>I:.QTI I; t! - r:ot
determined.
 77

Conclusions
Experimental evidence on coca chewing gathered scientifically in the
field has not previously been substantiated by measurements of blood levels
of cocaine. We have carried out such experiments and the stimulating effect
obtained seems to be well correlated with the rising concentrations of cocaine
in the blood. The differences in stimulation between using whole coca leaves
or the powder and taking cocaine by local application in the nose or by intra-
venous injection seem to lie essentially in means of administration and dosage
(Van Dyke et al., 1978). There is certainly no need to invoke as an explana-
tion the differences in the formation of metabolites known to be inactive as
euphorics and reaching peak concentrations later than cocaine (Kogan et al.,
1977).
There is, consequently, no reason to believe that the stimulating effect
achieved by the use of either coca leaves or powder is not due to cocaine.
As always in pharmacology, effect is dependent upon dose and means of
administration.

Acknowledgements
The Alpha Helix Expedition Phase VII was supported by the National
Science Foundation (Grant No. GB-37130). Support was also obtained from
the Swedish Medical Research Council, the National Institute of Health, the
Bank of Sweden Tercentenary Fund, the Wallenberg Foundation, and by
funds from the Karolinska Institute. We wish to thank the Swiss National
Research Foundation for a post-doctoral grant. We are grateful to the Katharine
W. Atkins fund at Harvard University for post-doctoral support (T.P.). We also
express our gratitude to Mr. Fred Schaub and associates of LKB America for
making possible the use of GC-MS equipment on board the RV Alpha Helix.
The help of Peruvian doctors, nurses and sanitarios is gratefully acknowledged.

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