Teobaldo Llosa, M.D., Ph.

HANDBOOK ON

ORAL COCAINE
IN ADDICTIONS

1
 Teobaldo Llosa, M.D., Ph.D.

Handbook on
Oral Cocaine
in Addictions
History, Botany, Coca Leaves, Coca Infusions, Coca
Powder, Chemistry, Pharmacology, Toxicology,
Toxicity, Cocaine Liability and Dependence,
Cocainization as Agonist Therapy, Clinical
Researches, Legal Status, References, Abstracts

with the colaboration of

J. Ernesto Chang-Fung, M.D.

To my son
Luis M. Llosa, M.D.

Lima, 2007

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Second Edition, review and up-to-date (June, 2007) (*)
Presented in the NIDA/CPDD 69th Annual Scientific Meeting,
Quebec City, Canada, June 16-21, 2007

Teobaldo Llosa, M..D.,Ph.D.

(*) Dr. Luis M. Llosa, M.D., was co-author of the first edition (Oral Cocaine as Agonist Therapy in Cocaine
Dependence, 2005), but no participate in the second edition, because at present is under Psychiatric
Residence training, in New York, USA

Handbook on
ORAL COCAINE IN ADDICTIONS

Teobaldo Llosa, MD, Ph.D., Psychiatrist

Graduated in the Medical School of the Universidade do Brasil, Río de Janeiro
Philosophical Degree (Doctorado), Universidad Nacional Mayor de San Marcos, Lima
Flight Surgeon, School of Aerospace Medicine, Brooks, AFB/USA, Texas
Air University, Maxwell, Alabama
Former Fellow of the Addiction Research Center of the National Institute on Drug Abuse, ARC/NIDA, Baltimore
Associated Member of the College on Problems of Drug Dependence/CPDD
ASAM/ISAM Associated Member
Member of the Peruvian Psychiatry Association/APP, and Addictionology Association, Lima
Member of the international Red de Neurociencias, Dominican Republic
Director of Psychiatry and Stress (Medical Office Tower), San Isidro, Lima, Peru
Director of COCA MEDICA
Author of several books and research-articles on cocaine addiction and stress

With de colaboration of

J. Ernesto Chang-Fung, M.D.

Pediatrician
Graduated in the Medical School of the Universidad Peruana Cayetano Heredia, Lima
Associated Member of Peruvian Pediatric Society
Torre de Consultorios Anglo Americana, Lima

With our thanks to Dr. Alejandro Colichon (Medlab), Mr. Esteban Flores, Coca products industrial,
Dra. Silverai Dongo (Enaco)

Picture: COCA: USES AND ABUSES, Raul Miranda (+), Artist, Lima, 1984

mail address:
Dr. Teobaldo Llosa, Editor
COCA MEDICA
Torre de Consultorios Anglo Americana
Alfredo Salazar 314, C-402, San Isidro, Lima 27, Perú

e-mail address: cocamedica@hotmail.com

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FOREWORD

Cocaine by oral route is an ancient form of use by farm and miner workers in South-
America without producing illness as is common when is used by other routes. For many years
investigators around the world have been searching in laboratory pharmacological solutions for
the inadequate use of cocaine which leads to addiction, but until now most of the studies have
identified mainly the substances that are not effective and very few that are (Llosa &
Llosa,2005). “Cocaine is a significant public health problem associated with serious medical,
psychiatric, social, and economic consequences. Although, many compounds have been
evaluated for the treatment of cocaine dependence, none has been approved by the Food and
Drug Administration (FDA) for this indication” (Vocci & Elkashef,2005). The latest
therapeutic hope is the agonist therapy proposed by Llosa in 1989 named
“cocalization”(cocainization): substitution type I therapy that uses a low but effective dose of
cocaine (range 50 mg to 500 mg daily), by oral route administered in two or three doses (Refill
process).

Treatment is based in: - the evidence of its innocuousness by millions of healthy people
that ingest it daily for years without the development of illnesses nor abnormal behaviors; - the
pharmacological and toxicological results from laboratory protocols and the lack of toxicity
signs in addicted volunteers that ingested daily two or three times the typical dose, as it is used
by the traditional consumers; - its positive effects that showed that as an agonist substance is
capable of reducing the appetence to cocaine when it is abused by different routes; - the low
cost and easy over the counter access in the Andean countries; - the high acceptance and
adherence to treatment; - the minimal adverse effects in short and long terms; - fits the
substitution criteria; - effects does not meet the ICD-10 y DSM-IV-TR criteria for cocaine
addiction.

It has been proved that the daily administration of oral cocaine in low and fractionated
doses does not disturb the physiology, behavior or biochemistry of users, even over long
periods. Its medical prescription has reduced the average of relapses and has increased the
abstinence period in cocaine-addicted patients. In the last years there has been an increase in
the interest to study the effects of oral cocaine as a substitution therapy, but the investigations
have been mainly pharmacological and toxicological. What all these studies have done is only
to “confirm what the Andean populations impregnated with cocaine chronically already knew
thousands of years ago.”

There are few studies on the therapeutic effects of oral cocaine as a substitution therapy
in humans; almost all of them were developed in Peru>USA>Bolivia. It is necessary to design
more international protocols to establish the therapeutic patterns and prescriptions for crack,
cocaine hydrochloride and coca paste-addicted patients. Here we present a second edition (the
first was in the NIDA/CPDD meeting, 2005, Orlando, under the title “Oral Cocaine as Agonist
Therapy in Cocaine Dependence, with L.M. Llosa as co-author), of the handbook aimed to
collaborate with researchers interested in the study of oral cocaine as a substitution therapy,
and to explain the theoretical basis of the cocainization (cocalization) therapy.

The Author

4
INTRODUCTION

The history of coca leaves is full of contradictions. When the Spanish arrived to South
America they noticed that the natives constantly chewed on a plant named coca to reduce their
fatigue while working or to get stimulated for their religious or social ceremonies. There are
not many scientific references about coca leaves and its uses before the discovery of America,
and few until the identification, extraction and use of the it’s alkaloid named cocaine. Valdizan
mentioned in 1913 that “truly, beside the study by Unanue in 1794 and the writings of some
important naturists like Muñiz in 1896, there is not much knowledge of the use of coca leaves
by the native Indians of Peru that can be used as scientific reference”. Many Hispanics and
Mestizos learned how to chew coca just like the natives. The extraction of cocaine from coca
leaves changed the history of the plant and society. Many would be surprised to know that
during the second half of the 1800´s there were many products and medicines that were
produced from coca leaves, and that were sold freely over the counter and drug stores.
Pharmaceutical companies like Merck and Co. and others in South America, North America
and Europe used coca leaves in the production of many citrates, bromates and hydrochlorate
formulas for diverse products. There were many alcoholic beverages that contained pure
cocaine such as the Mariani wine and many non alcoholic such as the original cocainized Coca
Cola. Although not the only ones, these later survived the strict controls that were imposed
after some reports showed that cocaine use by injection produced intoxication and obsessive
compulsive behavior similar to those produced by morphine addiction, as mentioned by Musto.
But in the early 1900´s things began to change and new international laws were passed to
control the industrial production and use of coca leaf products, and later even its own
cultivation.

What is interesting about the coca plant and cocaine is their historic bipolarity. It went
from being a praised and sacred plant to an evil and illegal one and as a consequence its
industrial production was reduced to only a fraction. Only in the last few years some countries
such as Peru and Colombia are increasing its legal industrial production mainly as coca tea. In
Bolivia there is a wider variety of products derived from coca leaves but the quality tends to be
more folkloric and it would hardly pass international quality controls. Coca Cola, the North
America and the most international product, survived due to the changes that were made to its
original formula, making it cocaine free but not coca free.

The alkaloid went through similar experiences, it passed from being a chemical
“wonder” to one of the most feared and controlled substances in the world. This led to a total
loss of interest in the 1930´s to 1960´s from psychiatrists to find a pharmaceutical treatment for
its addiction. With the rebirth of its use in the 1960´s, what Musto calls the “second epidemic”,
and the ways to use it such as coca paste in Peru and free basing in North America, studies
began to appear in the early 1970´s trying to find ways to control the addiction and prolong the
abstinence period. More than 30 years later we still have not found a specific and effective
therapy to this problem.

The introduction of “crack” and the drop of cocaine´s prices in Andean countries
favored the growth of the market and addiction with a negative outcome to the millions of
dollars that were being invested trying to control and treat the addiction. Many forms of
therapy were used including electric-convulsive, acupuncture, psychotherapy, brain surgery,
social, pharmacological and many others but none of them proved to be more than 50%

5
effective at long term. In the last decade due to advances in neurobiology there has been an
increase in ways to find different substances that would interact with cocaine receptors.

Some factors made this problem even worst, when in the 1980´s there were many
experts that would doubt the real malignancy of cocaine addiction. Many current texts consider
crack to be the most addictive form of using cocaine, but they are wrong. Due to its chemical
composition, the early addictive pattern and resistance to treatment, coca paste causes the
worst addiction. It is more toxic and more addictive than the other forms of cocaine due to the
double addiction that it develops because it is smoked with either tobacco or marihuana. This
double addiction makes it a lot harder to treat as many researchers found out in the 1980´s
during their first studies.

It calls to our attention that it has been 20 years since crack cocaine use was introduced,
since then no other modality of cocaine has been introduced. This shows that cocaine addicts
are not expecting greater benefits from this drug but instead they are trying new forms of
cocaine by mixing it with other type of drugs such as tobacco, marihuana, heroin and alcohol.
The first helps in the constant search to find a proper therapy but the second makes it a lot
more difficult.

Another factor that limited us in finding a useful therapy was not to consider the
differences in chemistry, pharmacology and toxicology of the different types of cocaine used
by aspiration, inhaled or injected compared to the alkaloid used by oral route. With the
appearance of crack the direction of research turned into this new form of smoked cocaine and
the studies on oral cocaine and coca paste were put aside except for interesting exceptions. Due
to that is that we lack modern research protocols about the effects that oral cocaine has in
people of Andean countries that have been using it a mean of six days a week for more than 30
years and do not show signs and symptoms that meet the criteria of the DSM-IV-TR or ICD-10
about drug dependence nor intoxication. Those populations represent an active and forgotten
laboratory of millions of people that have been taken out of the research budget. The first
studies about oral cocaine tried to find an addictive pattern and its pathology but instead it
proved the opposite, now it tries to prove that it is innocuousness and that is why research is
heading in ways to use it as an agonist therapy in the treatment of cocaine dependence. Even
with this in mind, the protocols are still misguided because the studies should not try to prove
that oral cocaine has no addictive effects but to prove the benefits that it can produce. Research
should try to prove that cocaine is capable to control it´s own addiction as an agonist therapy
when used orally but it should also go deeper into other properties that it has such as the
effective, save and prolonged stimulation that it causes in people needing an external stimulant
just as it happens with coffee and other legal stimulants.

In recent years researchers such as ElSholy, Jackson, Van Dyke, Llosa T, Cone,
Jenkins, Ferreira, Floren, Rush, Walsh, Bigelow, Filmore, Llosa LM, Grabowsky, Lopez
and Chang-Fung, have made interesting laboratory studies or comments about the
physiological, toxicological, psychological and behavioral effects of oral cocaine, using
similar, double and up doses of those ingested by traditional users in South America. The
results proved the innocuousness it had in volunteers. The first and the best description about
the effects of the coca tea (Peruvian) is the anecdotic use of it in a San Francisco clinic,
mentioned by Siegel et al. and published by JAMA in 1986, where he describes how it was
used as a “cocaine substitute” in cocaine dependents. What all these studies have done is only
to “confirm what the Andean populations impregnated with cocaine chronically already knew
thousands of years ago.”

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 After our experiences in the late 1980´s with the use of oral cocaine in the treatment of
coca paste and cocaine hydrochloride addiction using coca tea infusions and the lack of
chemical and toxicological data about these kind of therapy, we took to the National Institute
on Drug Addiction (NIDA) samples of Peruvian and Bolivian coca tea. These enabled us to
design new pharmacologic and toxicological protocols that yielded results that increased the
interest in oral cocaine due to many articles that we published after that. One of them, done by
our team led by Cone (in which was analyzed the pharmacology and toxicology of coca tea)
was published in the Journal of Forensic Science International (Jenkins et al, 1996). Others
that were published in the Journal of Substance Abuse (AMERSA) in 1994 and in the NIDA
Research Monograph N˚ 174 (CPDD) in 1996, informed about the results of three studies done
by our team with oral cocaine which was named as cocalization and cocainization therapy.

The lack of interest to study the use of oral cocaine in the Andean population is
probably the best evidence that cocaine by this route does not cause medical nor addictive
problems compared to the other routes and other forms of preparation. With this in mind it is
also important to mention that it has never been a necessity to find a treatment for chronic oral
cocaine use, but instead we have only found out its benefits. That is why it would not be absurd
to think that in a near future this form of cocaine use would be widely used to treat cocaine
addiction, as it has been prescribed for the last 15 years by our team in Peru. The ethic and
legal aspects should be managed by the scientists in their own countries, especially in those
where coca leaves are not cultivated nor its industrial derivatives are sold freely. The experts in
agonist therapies are the ones indicated to suggest and comment about the therapeutic guide
lines, just as it was the case with methadone and transdermal nicotine therapies.

In 1992 Sorer mentioned that the discovery and development of pharmacotherapies for
the dependence of cocaine is fairly new compared to that of opioids that were developed more
than 40 years ago. Ten years ago, the investigation programs did not consider the use of
cocaine as an alternate therapy for its own addiction, even though Llosa in 1989 and 1990
(Cocadi), 1992 (Amersa), 1993 (CPDD), Montoya et al. in 1992 (Amersa), and León et al. in
1993 (CPDD), had already informed about the use of coca tea infusions for the treatment of
addicts to coca paste in Peru. In June, 2005 (CPDD), Llosa & Llosa presented the Handbook of
Oral Cocaine in Addictions, and in May, 2006 in Barcelona, Spain, Pérez de los Cobos, and in
June, 2006, in the CPDD meeting in Arizone, Grabowsky, inform about the oral cocaine
schedule suggested by Llosa & Llosa in order to control appetence in cocaine-addicted
patients. With the current interest to study the effects of oral cocaine in humans, and because of
the new facilities that can be obtained to create new protocols with oral cocaine, it would be
convenient to develop research programs in countries like Argentina, Bolivia, Colombia and
Peru where millions of healthy people consume oral cocaine in a daily basis, when chew coca
leaves in traditionally patterns, drink coca tea or eat several meals prepared with coca powder,
a new form of consume oral cocaine in Andean regions. The history, low cost and legality as
either coca leaves, coca tea infusions, and coca powder make it a custom that many natives
have and that many tourists acquire when they visit these countries.

7
THE COCA PLANT

Varieties: chemical analysis

Coca plant is one of the ancient cultivated plants in South America. Possibly it was
discovered as a wild plant in the mountains of the Andes, east of Peru (Morris,1889) (Burck,
1890) (Rusby,1900) (Machado,1969) (Plowman,1979) and known by the Spanish when they
arrived to America, just as it was mentioned by Americo Vespucio in 1954, as he referred to it
as a “plant used by Indians in the Northern Coast of South America, which they chewed with a
white powder and was only used by the males” (Vespucio,1540) (Patiño,1967). Archeological
findings in Ecuador established that chewing coca was already a custom 3000 years BC,
although the older species of coca leaves consist of little fragments found in Ancon-Chillon
North of Lima, Peru, referred to be as old as 1950 years BC (Patterson,1971). Another
reference comes from the area known as Asia, 125 Km south of Lima, is thought to be from the
year 1314 BC which Engel suggested that was brought by people from the mountains
(Engel,1963) (Rostworoski,1973).

By “coca” we are referring to two different but related species of plants from the genus
Erythroxylum (erithroxylaceae): E. Coca known as Bolivian coca or coca Huanuco and E.
Novogranatense, known as Colombian coca and one of the varieties known as coca Truxillense
that grows in the northern part of Peru. There are about 250 different species and varieties of
the genus Erythroxylum; 200 are originally from American tropics. Those that grow in the

8
Andean regions of Peru and Bolivia are the ones that contain the highest quantity of cocaine.
There are four varieties of Erythroxylum Coca: Lambran, grown in Cusco (Peru), has the
highest content of cocaine (1.10%). Mollecoca, grown in Huanuco (Peru) which contains
0.86% of cocaine. Fusiform, also grows in Huanuco and it contains about 0.72% of cocaine.
Ovoide, also grown in Huanuco, contains 0.63% of cocaine. Coca from regions of Yungas and
Chapare (Bolivia) contain 0.6% y 0.5% of cocaine (Sauvain et al,1997).

Coca tea infusions and coca powder are made of different types of coca leaves which
contain different chemical compositions depending on the region from where they are grown.
For the production of coca tea and coca powder each region uses their variety of coca leaves.
Peru uses mainly leaves from Cuzco and Huanuco, while Bolivia uses mainly leaves from the
genus Erythroxylum Coca from the region Chapare, and Colombia from the region Cauca.
There is a different form of E. Coca known as Ipadu that can be found in the lower part of the
Amazon and is grown in low scale by some indigenous tribes. Coca Truxillense has smaller
leaves and about 0.56% of cocaine but due to its high content of volatile fatty acids like
gualtheria oil, it is used as a source of flavor for different product such as Coca Cola. This was
the variety of coca used industrially but its production decreased, that is why nowadays the
coca that is exported to the USA for the preparation of Coca Cola is mainly from Cusco and
some regions of Bolivia (Plowman, 1979). Today the number of hectares cultivated in South
America (Colombia> Peru> Bolivia) are greater than 100,000. Between 10% and 20% are for
traditional uses (chewing) or legal industry (coca cola, coca wines, energetic beverages, coca
tea, cosmetic products). The remained of them are used for illegal activities (narcotic traffic
and/or addiction), as coca paste or cocaine hydrochloride form, but not as coca leaves.

Legal regulations: banned and exceptions

The history of coca leaves restrictions is a lot older than that of cocaine, because
already in the Incas Empire it was only allowed for royalty (Hernández de Ovidio y
Valdéz,1547) (Garcilaso de la Vega,1609). Cocaine restrictions appeared 40-50 years after its
discovery and extraction (1860) when it was proven that it could lead to intoxications and
addiction and when pharmaceutical companies such as Merck began to produce large amounts
of refined cocaine and there were more reports of intoxication (Bono,1998). Diverse medical
reports of that time were the main cause by which cocaine use dropped in many popular
preparations and combinations which contained high doses of cocaine, as it happened with
Coca Cola which replaced cocaine by caffeine in the beginning of the 20th century and the
Mariani wine lost its good name. One of the first laws passed to control the use of cocaine in
the United States was the Pure Food and Drug Act of 1906 and the Harrison Act of 1914
(Engel,1991) (Gold et al,1992). Later international regulations bases on the Act of the
Convention of 1961, New York, prohibited the cultivation of new coca plantations and its
eradication in a period of 25 years (García Sayán,1989) (Soberon,1994). Cocaine is a
Schedule I controlled substance. The wording in Title 21, part 1308.12 (b)(4) of the Code of
Federal Regulations estates: “coca leaves (9040) and any salt, compound, derivative or
preparation of coca leaves including cocaine (9041) and ecgonine (9180) and their salts,
isomers, derivatives and salts of isomers and derivatives, and any salt, compound, derivative,
or preparation there of which is chemically equivalent or identical with any of these
substances, except that the substances shall not include decocanized coca leaves, or extractions
of coca leaves, do not contain cocaine or ecgonine”. It is significant that the term “coca leaves”
is the focal point of that part of the regulation controlling cocaine (Bono,1998). The unique
natural cocaine enantiometer that exist in coca leaves is l-cocaine and in some countries
considerer that only l-cocaine is an illegal drug (ONU/ST/NAR/7,1986). If researchers were to

9
agree with the evidences of the agonist therapeutic effects, they should try to change
international laws in order to help millions of addicted-pattiens affected with this disease. At
present, legal cultivation and uses of the natural coca leaves (contained cocaine) are permit
only in comprobated traditional and historical areas, as Cusco, in Peru, and Yungas region, in
Bolivia (Roncken,1999) (Rivera,2003) (Argandoña,2006) (TNI,2006) (WHO/EB120/36,
Dec,2006). In these countries many coca derivates commercial products have legal licence for
sell it over the counter.

Derivatives: Chemical Analysis and Uses

1.- Natural

Coca leaf

Natural coca leaves from Cusco, Peru, contained alkaloids, vitamins and minerals

The oldest and most popular way to use cocaine alkaloid is by the oral route as chewing
(chacchado, accucllico, picchado) or as a drink. It is absorbed from the leaves chewed by the
Andean and Amazonic populations, drunk in the form of coca tea infusions or eaten pulverized
as some Brazilian or Colombian populations do. The fruits or stems are not used for tea
infusions nor for chewing. When the leaves are chewed, they are used mixed with a substance
known as llipta or troca (cal, lime) which is made from plants and slaked lime. This is done so
cocaine can be released from coca leaves (Carrol,1977) (Carter & Mamani, 1978)
(Machicao,1986). Until the 1990-92s the prevalence of coca leaf use was 90.1% (Bolivia),
<0.1% (Colombia), 5% (Ecuador), and 5.3-30.5% (Perú) (Negrete,1992) (WHO/UNICRI,
1995) (Montoya & Chilcoat,1996). Today (2007) Colombia is the main source of coca leaves,
most of them used for narcotic traffic, because the traditional and industrial uses are very few.

10
 The chemistry of coca leaves shows that it can contain from 0.25% to 2.25% alkaloids.
Fourteen alkaloids have been identified, one of them being cocaine (Martin et al,1970),
besides other substances (Duke et al. 1975), even though another publication refers that it
contains 19 alkaloids, including nicotine (Turner et al,1981) (Cabieses,1985). The chemical
findings will depend that were directed mainly for narcotic traffic or addictive purposes
appeared, such as coca paste (basuco), freebase and crack, which contain a high percentage of
residual toxic substances from their process of elaboration (Morales-Vaca,1984) (Arif 1987)
(Llosa,1994). Coca leaves contains several nutritional substances, mainly calcium (2000 mg
per 100 grams), iron, phosforus, tiamine, beta-carotene, nirtogenous, proteines, fiber (Collazos
et al,1964) (Duke et al,1975),, and many others as tanine and essential oils, that people ingest
when chew coca, drink the coca infusions or eat coca powder.

Coca infusions

Coca tea co (peruvian mate de coca), first exportation of coca tea bags to USA in 1983-85

The most popular infusions from coca leaves (immerse in hot water), are the traditional
infusion, which is drunk mainly in the regions were they are prepared (north od Argentina,
Cile, Bolivia, border of Brasil, Colombia and Peru), and the commercial (crushed coca leaves
contains in filterable bags), infusions known as mate de coca that are drunk mainly in the cities
and zones of Bolivia, Colombia and Peru that are visited by tourists (Carroll,1977) (Siegel et
al,1986) (Montoya and Chilcoat,1996). Traditional coca infusions are not usually mentioned
by journalists and researchers of coca leaves (Castro de la Mata & Noya, 1995) (WHO/PSA,
1995). Coca leaves release cocaine alkaloid and other substances (vitamins, minerals), during
the infusion process in hot water, and the extraction is more efficient when the coca leaves are
immerse during 5 minutes in the cup (Llosa & Chang-Fung,2006). There are other coca
infusions prepared in water or alcohol (wines, liquors, aguardients, macerates), that have been
produced since the XIX century (Mariani Vin), many of which are not produced anymore.
Later, many coca infusions products (refreshers, energizant drinks), in limited amounts yet,
was, and are elaborated (Andrews & Solomon,1975) (Peterson & Stillman,1977) (Coincoca
Products,1990) (Llosa,2002) (Kallpa Products,2005) (Home Power Products,2006).
Cocaine contained in coca leaves can be ingested as coca tea made from fresh whole coca
leaves immerse in hot water, traditionally referred as “coca infusions”. There are no

11
pharmacological or toxicological studies in blood or urine of users of this ancient modality
(Andrews and Solomon,1975).

Coca infusions are ingested without the alkali substance (llipta, lime), because heat
makes it possible for cocaine to be released in the infusion and then in digestive tract, including
the oral mucosa (Van Dyke et al.,1978) (Jenkins et al,1996). The chemical analysis of coca
infusions are similar to those of coca leaves, varying in the percentage of extracted alkaloids
depending on the type of coca leaf that is used, the boiling time and the procedure of extraction
(Jenkins et al,1996) (Llosa & Chang-Fung,2007).

The first study about the commercial infusion product known as Mate de Coca (coca
tea) made from crushed coca leaves reports a mean of 234.5 mg of cocaine in 100 grams of
leaves (Institutos Nacionales de Salud, Lima,1982). The first report about decocainized coca
tea bag (contained 1 gram of crushed coca leaves) was in 1998, it showed the absence of
cocaine or ecgonine (Hagelin and Co. Inc./ Industrial Testing Laboratories, New York, 1988),
even though no commercial decocainized tea are made or sold today in Andean countries.

Coca Powder (Flour, Harina de coca)

Coca powder is a new commercial modality of sold coca leaves over the counter in Peru
and Bolivia that is purchase mainly in order to use it in meals, nutritional or medical purposes.
It is a natural coca product obtained from crushed coca leaves to powder without any solvent.
People use coca powder adding it in meals or drink with juices or milk. A gram contains an avg
of 5 mg of cocaine alkaloid plus nutritional substances of the coca leaves, as calcium, vitamins,
proteins, carbohydrates, iron, and fibre. It´s pH is 4.5, and is sold in a packed of several
weights or contained in gelatin capsules of 1 g each. Likewise, is the new form of consume
cocaine by oral route, without addictive goals (Dongo,2006) (Llosa et al,2006)

12
Llipta, Troca, Cal, Lejia (Lime)

Llipta is not a coca product nor derivate, but it is the susbtance that is added to coca
when it is chew in order to release the cocaine contained in the leaves. Its chemical
composition is variable according the geografical place in that is prepare and consume it, but
ever have an alkaline pH. The most comun in Andean regions is the llipta made with
vegetables (seeds), as quinua, cacao, yuca, and in some places, as the coast regions is used the
“cal” (lime). After the study of Llosa & Chang-Fung, variable amounts of sodium bicarbonate
is added to coca powder when some meals are formulated. So when coca powder is use in
agonist therapy schedules (Vespucio,1540) (Patiño,1967) (Browman,2004) (Hurtado-
G,2005) (Henman,2006) (Llosa & Chang-Fung,2007).

Cocaine (cocaine alkaloid, cocaine base)

This is the name of one the alkaloids found in coca leaves. Chemically natural cocaine
is known as l-cocaine, beta cocaine, methylbenzoylecgonine o C1H21NO4, which is an
alcoholic base related to atropine. It can also be described as a benzoic acid ester and a
nitrogenous base with a molecular weight of 303.4, with a fusion point of 98˚ C and solubility
(1g/ml) of 1300 in water, 7 in ethanol, 4 in diethyl ether and 0.5 in chloroform. It has a pK of
8.6, reason why is extracted from biological fluids with organic solvents that have an alkaline
pH. Cocaine is hydrolyzed to benzoylecgonine when exposed to a very high pH (Stewart et
al,1979), so we have to be maintain a pH lower than 10 during the extraction. Cocaine is
hydrolyzed by the plasma and liver pseudocholineterases. In vitro its half life is about 60
minutes at 37°C. The main metabolites are benzoylecgonine and methylesterecgonine (Jatlow
et al,1980); other are norcocaine, cocaethylene (cocaine plus alcohol) and methylecgonidine
(by pirolysis when smoking) (Jenkins & Cone, 1998) (Karch,1998). Until 1923, the main
source of cocaine was from coca leaves. In that year, Willstatter was able to synthesize a
mixture of d-cocaine, l-cocaine, d-pseudococaine, and l-pseudococaine (Willstatter et al,1923)
(Bono,1998). Cocaine may also be chemically synthesized with cold aqueous succinaldehyde
and cold aqueous methylamine, methylamine hydrochloride, salt of acetone- and the potassium
dicarboxylic acid monomethyl ester (ONU ST/NAR/7,1986) (Saferstein,1988)

2. Manufacturing products

Commercial coca products from Bolivia, Colombia and Peru, sold over the counter

13
Oral cocaine sources, other than coca leaves for traditionally chew (chacchado)

Many (more than one hundred products prepared with coca leaves), were famous and
wildly used in the second half of the XIX century in Europe and America. Pharmaceutical
formulations, tonics, alcoholic (Mariani wine and simillars), and no alcoholic (Coca Cola and
similars) beverages, infusions, pastills, tablets and cordials, were elaborated with extracts,
concentrates, essences or elixirs made from coca leaves or with cocaine salts, before the coca
plant ande derivates control laws. Mariani´s wine contained between 35 and 75 mg of cocaine
per glass. Angelo Mariani, was a Corsican pharmacist working in Paris, who had been selling a
coca leaf-Bordeaux wine infusion since the early 1860s. Mariani´s product was the most
popular tonic of its time, and was used by celebrities, poets, popes, and presidents. In Britain a
popular “medicated wine” was sold: Hall´s wine. It contained 4 mg of cocaine in a 1½ ounce
wineglass (House of Commons,1914)(Mariani,1896) (Andrews & Solomon, 1975) (Musto,
1982) (Siegel, 1993). Today very few manufactured products are elaborated legally with coca
plant or its derivatives (coca leaves form traditional uses, coca infusions, coca powder, coca
extracts), almost all in Andean regions. It is not known if before the extraction of cocaine in
1860, there were any wines prepared with macerated coca leaves.

Coca Cola become the ancient and the best advertising of oral coca-leaf use until today

At present cocaine could be ingested by oral route in different preparations as follow:

a. Contained in infusions like the ancient Mariani wine (alcoholic beverage), and other
alcoholic or no alcoholic drinks to which infusion of coca leaves were added (cocachados.
Macerates, concentrates, aguardientes or extracts), or prepared mixed fresh crushed coca leaves
with hot water (traditionaly infusions) or contains in filterable bags known as “mate de coca”.
Today these products are manufactured in Bolivia (Coincoca), Colombia (Coca Seck), and
Peru (Chaska), only. For the last decade there has been a drink made from pisco (typical
aguardiente from Peru made from grapes) and coca known as Coca Sour (El

14
Comercio,13.2.1993, Lima). There are chemical studies of these drinks but no clinical nor
toxicological studies in humans (Andrews and Solomon,1975) (Musto,1992), excepted with
the industrial coca tea (mate de coca), which have some chemical studies and clinical and
toxicological reports on regular and sporadic human users (INS,1982)(Siegel et al,1986)
(Jackson et al.,1991) (Ferreira & Gentner,1991) (Floren & Small,1993) (Yon &
Davila,1994) (Jenkins et al,1996) (Llosa,1996) (Rerat et al,1997) (Llosa et al.,2004) (Home
Power,2006).

b. Contained in coca powder, that are used for nutritional or medical (agonist therapy) purposes
(Llosa & Llosa,2005) (Llosa et al,2006) (Enaco,2006) (Agroindustrias Chaska/Kallpa,
2006)

c. Contained in many new manufactured nutritional products and meals that are sold over the
counter, prepared with coca powder alone or mixed with other vegetables, milk, juices or ice
cream (Coincoca,1990) (Kuychiwasi,2000) (Mixtura Andina,2005) (Kallpa/Agroindustrias
Chaska,2005) (Señorio de Sulco,2005) (Barrio,2005) (Coca Sek,2005) (INCAA,2006)
(Mana,2006) (Ferias Regionales,2006) (Nasa,2006) (Food & Art,2007) (Coca
Médica,2007)

Popular meals prepared with integral coca leaves as flour or infusions: biscuits, bread, candies, wines, juices, chocolats

3. Oral cocaine for medical and energetic uses

Oral cocaine ingested in capsules (contained pulverized coca leaves), in the commercial
infusions or in leaves as traditional chew are advertised as a physiologic stimulant directed to
maintain physical and emotional well-being in healthy persons and as a stress modulator,
antidepressant and as a muscular activator and for its antifatigue effects in athletes. Some
users, specially athletes or workers must consider the fact that oral cocaine ingested even in

15
small amounts as one capsule or one coca tea cup, urine, saliva, blood or even hair
toxicological tests can produce positive results, which can carry on sanctions due to
competitive doping regulations (Palmer,1885) (Hanna,1970) (Baselt & Chang,1987)
(Jenkins et al,1996

In the second half of the 1800s were elaborated and sold “over-the-counter” many
remedies containing small amounts of pure cocaine or its salts as cocaine hydrochloride,
bromate or citrate, as syrups or “medicated wines”, some of them contained 300 mg de cocaine
per dose (Andrews & Solomon,1975) (Siegel et al,1993) (Musto,1992). As Petersen
commented, William Golden Mortimer, a New York physician, was an Editor of the
Pharmaceutical Journal and of the New York Journal of Medicine, and he published an
extensive History of Coca in 1901 (reprinted in 1974). This volume summarized the existing
knowledge about coca and cocaine (Mortimer,1901) (Petersen,1977). The first chemical
analysis of coca infusions is that of the Mariani tea bag, which contained 480 mg of cocaine
per cup and was used with therapeutic purposes (Mariani,1896) (Siegel, 1993). Products made
from coca concentrates or cocaine were mainly used to reduce fatigue or as an stimulant, and to
obtain and maintain the well being in healthy people, especially those that worked in the fields
or mines. Today they are used as stimulants to the respiratory and cardiovascular system when
people go to the mountains of the Andean regions (Arellano,1993). (Musto,1992). In the
1970s the “Bromptom´s Cocktail” formulated with heroin, cocaine hydrochloride, ethyl
alcohol, syrup and chloroform water was sold for cancer pain (Wesson & Smith,1977)
(David,1978), and in 1973 was included in the British Codex (Avron,1980).

Oral cocaine for pre-clinic research purposes

Used in rats, rabbits, monkeys or dogs, with oral infusions, mainly as cocaine
hydrochloride formulas for pharmacological studies (Gutierrez Noriega & Zapata
Ortiz,1944) (Siegel et al,1976) (Siegel et al,1980) (Valentine et al,1988) (Falk et al,1990)
(Macenski and Meisch,1992) (Meisch & Stewart,1995). There is one study with Peruvian
coca tea in animals (Oyola de Bardales,1993), and one with Peruvian Andean Llamas
(Siegel,1989)

4. Coca derivatives for addictive and illegal uses.

Coca paste (pasta de coca, pasta, base, basuco)

Is the popular name given to coca leaves macerated and prepared with high toxic
substances that is smoke with addictive purposes, mixed with tobacco and sometimes with
marijuana (Nizama,1979) (Jerí,1984) (Cohen,1984) (Morales-Vaca,1984) (Arif,1987)
(Llosa, 1994). Llosa classifies coca paste in four types, being coca paste type IV or CCP-IV,
the coca paste that addicts use. It must be considered as an addictive drug different from the
other cocaine preparations. Coca paste that is smoked by addicts contains an average of 50% of
cocaine mixed with remains of sulfuric acid, cocaine sulfate, coca alkaloids, alkaline
compounds, kerosene, gasoline, many toxic substances, virus, bacteria’s, tobacco or marijuana
and several impurities used and mixed by the makers and sellers (Llosa,1994). Coca paste is
the most toxic drug obtained in the street. Its smoke produces by pyrolisis the metabolite called
methylecgonidine (anhydroecgonine methyl ester)(Novack & Salemin,1984) (Jacobs et al,
1990) (Murrelle et al,1990) (Murrelle et al,1991) (Zhang & Foltz,1990) (Aguilar et
al,1993) (Jenkins & Cone,1998) (Oliver,2004)

16
Cocaine hydrochloride

In many places cocaine is cut in lines of 25-50 mg, for facilitate sniff. Other using the fingers
Is the most popular chemical preparation of cocaine, used as an anesthetic or for
illegally goals as narcotic traffic and addiction. Their use as an anesthetic has been replaced by
synthetic anesthetics, which are non addictive. When coca paste is treated with hydrochloric
acid and the product is refined, cocaine hydrochloride of 98% or better purity is obtained; this
is called cocaine. It appears on the illicit market at 12-75% purity after being diluted with
sugar, local anesthetics, amphetamine, or caffeine. As much as 1% of cocaine hydrochloride
can survive heat combustion during smoking (Arif,1987). Smoked cocaine hydrochloride is
not a common practice. Its average fusion level is 157° C.. Its solubility in water is 0,5 (which
makes its absorption easier in water), 4.5 in ethanol, 18 in chloroform, and almost insoluble in
diethylic eter (ONU ST/NAR/7,1986).
Free-basing
Cocaine hydrochloride is converted to its alkaloid by treatment with an alkali. A variety
of methods are used. Some involve extraction with a solvent followed by evaporation, others
simply involve the addition of ammonia or other alkali. Free-basing (cocaine base, cocaine
alkaloid, base, freebase) contains some of the adulterants found in the illicit cocaine. It has a
lower vaporizing point than cocaine hydrochloride, and thus less is lost when heated and
inhaled (Arif,1987) (Gold,1992). Ether was frequently added to extract the cocaine base.
Because preparing and using cocaine freebase in this manner involved volatile chemicals such
as ether and the use of high heat (often from acetylene or butane torches), the process was quite
dangerous (Weiss et al,1994).

Crack
Is different to freebase only in the process used to obtain cocaine from adding sodium
bicarbonate (baking soda), and water to cocaine hydrochloride. The results are not pure cocaine
because the adulterants used in the conversion process. As with freebase, crack is smoked in a
water pipe, which is usually made of glass (Weiss et al,1994) (Gold,1992).

17
AVERAGE OF COCAINE USED BY THE CONSUMERS

Traditional and accustomed users

- traditional infusion users (coca tea): 1-2 grams of coca leaves (5-10 mg of cocaine
alkaloid)
- traditional farmer chewers (chacchadores) of coca leaves (oral route during 8 -12
hours job): ≥1year - ≥ 30 years of use of cocaine alkaloid (6 days a week): 150 mg to
250 mg daily (Llosa,1997).
- typicaly miner chewers (chacchadores) of coca leaves during the regular job period
(8- 12 hours): cocaine alkaloid: 184 mg to 257 mg (avg 202 mg) (López & Llosa,
2004)

Sporadic users (infusions)

- 4mg to 20 mg (1 to 4 grams of crushed coca leaves/ 1- 4 coca tea bags): national and
foreign tourists (Siegel et al,1986) (Siegel,1993)
- commercial drink (K Drink): 1- 3 bottles (12 mg - 36 mg of cocaine alkaloid daily)
(Llosa et al,2004)

New modality of use oral cocaine in Andeans regions (coca powder)

- 5 mg – 50 mg of cocaine alkaloid contained in coca powder added to meals or

juices (Llosa & Llosa,2005) (Llosa et al,2006) (Llosa & Chang-Fung,2007)

Volunteers under laboratory studies with oral cocaine

- 20 mg of cocaine alkaloid in coca tea infusion (Llosa,1990)

- 36 mg of cocaine alkaloid in infusion (Llosa et al,2004)
- 31 grams of coca leaves (± 150 mg of cocaine) under chewing (Sauvain et al,1997)
- 150 mg in one ingest. Cocaine hydrochloride in gelatin capsules (Filmore et al,2002)
- 300 mg in one ingest. Cocaine hydrochloride in gelatin capsules (Rush et al,1999).
- 400 mg daily (in four doses of 100 mg each in gelatin capsules contained cocaine
hydrochloride (Walsh et al,1998) (Walsh et al,2000).
- 10 – 50 grams of coca powder (± 50 – 250 mg of cocaine alkaloid) in drinks
(Llosa,2006) (Llosa et al,2006)

Addicted-patients under oral cocaine treatment as agonist therapy (coca infusions, coca tablets,
coca in capsules) (Reports and follow of abstinent patients) (Dr. Llosa)

- 17 mg divided in three daily doses. Cocaine alkaloid in coca tea (Llosa,1994)

- 60 mg divided in three daily doses. Cocaine alkaloid in coca tablets (Llosa,1997)
- 100 mg to 300 mg daily divided in three doses for three months to ≥ 1 year. Cocaine
alkaloid in coca tea or in pulverized coca leaves in capsules (Llosa,2002) (Llosa,2005).
- 500-750 mg (cocaine alkaloid) daily during 2 weeks, in coca tea (Llosa,2005)
- 10-30 mg divided in three daily doses (Llosa & Llosa,2005)
- 50 – 250 mg (cocaine alkaloid) daily contains in coca powder (ingested mixed with alkaline
supplement (llipta,lime), added to meals, milk or juices (Llosa & Chang-Fung,2007)
- some former patients used an average of 10 mg daily (2 coca tea bags) for ≥10 years as

18
 maintenance treatment (Llosa & Llosa,2005).
Cocaine-addicted patients (ICD-10 and DSM-IV-TR)

- nasal route (in a typical binge) cocaine hydrochloride: from 100-500 mg to 5000-15000
mg (5 to 15 grams) (Verebey & Gold, 1988) (Llosa,1994).
- pulmonary route-smoked as coca paste/basuca cigarettes (cocaine) in a typical binge:
1900 mg / 20 cigarettes (570 mg to 4750 mg) in 6 to 50 cigarettes (Nizama,1979)
(Jerí,1984) (Murrelle et al,1991) (Llosa,1994).
- pulmonary route-smoked as crack (cocaine base or free base) in a typical binge: 25 mg
per line or ≥ 1000 mg per binge, that may even reach ≥ 5000 mg (Siegel,1993).
- intravenous route: 25 mg, 50 mg or 100 mg (Majewska,1996).

PHARMACOLOGY OF ORAL COCAINE

Neurobiology

“Cocaine self-admintration appears to be dependent on the brain´s dopaminergic system,

which projects from the ventral tegmental area to the nucleus accumbens, which is now viewed as
the central feature of the cocaine and dopamine (DA) hypothesis and by implication the core of the
endogenous drug reward system” (Gold & Miller,1992). “Cocaine inhibits the presynaptic
reuptake of the neurotransmitters norepinephrine, serotonin, and dopamine at synapses junctions.
This results in increased concentrations in the synaptic cleft. Physiological effects of this
stimulation include tachycardia, vasoconstriction, mydriasis, and hyperthermia. Central nervous
system stimulation results in increased alertness, diminished appetite, and increased energy. The
euphoria or psychological stimulation produced by cocaine is thought to be related to the inhibition
of serotonin and dopamine re-uptake. Cocaine also acts as a local anesthetic due to its ability to
block sodium channels in neurons” (Warner,1993) (Jenkins & Cone,1998). “Several studies of
chronic cocaine abusers have demonstrated substantially elevated prolactin levels”. “Elevated
prolactin levels persist for at least 1 month after stopping cocaine”. “Positron emission tomography
(PET) studies found market decrese D2 receptor density persisting for at least 2 weeks after
stopping cocaine” (Gold,1997). At present there are not brain´s PET studies with traditional coca
chewers nor with coca tea drinkers and coca powder users.

In Animals

One of the first studies about the effects of cocaine in animals was done in Peru in 1885;
the description of the toxicity found in dogs and other laboratory animals has great historic value
(Bignon,1885). Gutierrez-Noriega and Zapata Ortiz studied the effects of cocaine in dogs and one
of their conclusion was that ”when cocaine is administered by the oral route the signs of habit are
less evident and less toxic than when administered parentally”. They also concluded that when
cocaine is administered in small and fractioned doses is less toxic than if administered in one large
dose” (Gutierrez-Noriega & Zapata Ortiz,1944). Woods measured the concentration of cocaine
in dogs plasma after the administration of 15 mg of cocaine per Kg and found the levels to be 1000
ng/ml after 2 hours (Woods et al,1951). There is a study done in monkeys after they chewed coca
leaves from Huanuco which contained 0.58% of cocaine. Coca leaves were administered in
packages of 0.9 gram of coca mixed with a small amount of Arabic gum and 0.1 sodium
bicarbonate. The amount of coca leaves used in each package was determined in such a way that
was similar to the amount of cocaine used in previous studies with oral cocaine in monkeys (Siegel
et al,1976) (Siegel et al,1980). In a later study that remains anecdotic, Llamas from the Andes

19
were given pellets with 0.58% cocaine, noticing no alteration in their conduct or eating habits
(Siegel,1989).

Decocainized coca leaves from coca Truxillense was administered in liquid form mixed
with honey to rats and rabbits to study their growth and weigh patterns (Valentine et al,1988). Self
administered oral cocaine as hydrochloride to study the pharmacokinetic and water deprivation
effects had been done with rats (Falk et al, 1989) (Falk et al,1991) (Bell et al,1992), and to study
monkeys behavior (Macenski & Meisch,1992) (Meisch & Stewart,1995). Even though the
preferred route to administer cocaine to animals have been intravenous, intraperitoneal and
intragastric (the last two being exclusive for animals research) there have been other routes such as
dermal, pulmonary and oral. The nasal route has been the less used in research with animals
(Jones,1984). The great majority of studies have used pure cocaine or cocaine hydrochloride (Lee
et al,2003). The only study done with mate de coca in animals was done in cobayos (Oyola,1993),
but it lacks some data that makes it hard to draw any conclusion from it, as said by Castro de la
Mata and Noya (Castro de la Mata & Noya,1995). The study of oral cocaine in animals has not
contributed much to what we already know about the pharmacology in humans. The similarities
between oral cocaine studies in animals and humans are a constant. The use of cocaine alkaloid
found in coca leaves by chewing is something that can be done only in humans due that it is almost
impossible to reproduce in animals.

In Humans

Ingestion of coca leaves and its infusions follow the principles of oral cocaine
pharmacology. Pharmacokinetic studies showed that the area under the concentration-time curves
after intranasal and oral doses were not significantly different, although both were smaller than that
reported for similar intravenous doses of cocaine (Wilkinson et al,1980). The fact that ancient
Andean and Amazon populations chewed coca leaves and drunk coca infusion is enough evidence
that it produced some kind of effect in their bodies, mainly to reduce fatigue, anesthesia and
stimulation. This was first noticed by the Spanish when they arrived. Monardes describes in his
writings (1569) the Indian practice of chewing a mixture composed of tobacco and coca leaves to
make themselves drunk and to induce “happiness”. During the 16 th and 17th centuries there was
also recognition of the role of coca as an Indian remedy for such diverse medical problems as skin
ulcerations, venereal diseases, headaches and muscular pains (Bayer,1776) (Mortimer,1901)
(Monardes,1580) (Mantegazza,1975) (Andrews & Solomon,1975) to fight fatigue on students
after a long day of studies (Christison,1868) (Palmer,1885) to treat morphine, opium, and alcohol
addiction (Bentley,1880)(Freud,1885) and for the treatment of chalices and diarrhea (Valdizán &
Maldonado,1922). Recent studies showed that “cocaine given by the oral route is at least as
effective as the same dose given by intranasal route. Cocaine is not detected in plasma until 30
minutes after oral administration and between 3 and 5 min after intranasal administration, but
peaks in plasma concentrations are similar for both routes. The subjective responses in man are
greater after oral than intranasal administration” (Van Dyke et al,1978). Reports we have about
the effects of infusions, extracts and wines made from cocaine in the XIX century
(Hammond,1887) are similar to those that described the chewing of coca leaves even before the
identification of cocaine, specially about their effects on reducing fatigue, appetite control, mood
stimulation and reducing the effects caused by high altitude such as hypothermia and hypoxia
(Andrews & Solomon,1975) (Musto,1992) (Collazos et al,1965) (Escobar,1994)
(Urrunaga,1992) (Villena & Sauvian,1997).

All of this led to the conclusion that the coca plant or some substances in its leaves were
responsible for these effects. With the extraction of the alkaloid cocaine in 1860 the studies about

20
the effects of coca leaves became much deeper with standardized measurements, toxicological
tests and went from observational to demonstrative studies in laboratory and clinics
(Grabowsky,1984) (Clouet et al,1988) (Sorer,1992) (Walsh et al,2000) (Filmore et al,2002).
Hernandez de Oviedo was the first journalist to describe the effects of coca as a substance that
“reduced thirst and fatigue” and referred to an Spanish that “got used” to its effects in Maracaibo,
Venezuela (Hernández de Oviedo, 1547). Monardes was the first to describe the mood and
conducts after the use of oral cocaine: “the Indians use it when there are tired, hungry and thirsty,
for their parties to get drunk and they smoke it with tobacco making them feel out of themselves
and with great happiness” (Monardes,1580).

Absorption and metabolism

Pharmacological studies of oral cocaine have come a long way because of new laboratory
methods in biochemistry and toxicology. Not all cocaines have the same pharmacological profile,
its effects are going to vary according to how they enter the body, their chemical composition (if it
is an alkaloid, coca paste, cocaine hydrochloride, or mixed with other compounds such as alcohol,
tobacco, marihuana or heroin), the doses taken and the region of absorption in the digestive tract
(oral mucosa or intestine). The effects of oral cocaine have been known for hundreds of years but
until the 1980´s it was not known how oral cocaine was absorbed in the digestive tract or if it
suffered hydrolization mainly in the liver, and if the effects of the coca plant was due to cocaine or
to another metabolite that it contained. (Van Dyke et al,1978). In the 1880´s Freud made the most
complete description of self administered pure oral cocaine. He concluded that the stimulant
effects occurred about 10 to 20 min after ingestion and that they lasted 4-5 hours (Freud, 1885).
Later studies have proven the relation between the doses and the levels of plasmatic concentration,
showing that the stimulant and energetic effects are related to the concentration of cocaine in blood
(Holmstedt et al,1978). Few but consistent studies have been done to prove that cocaine is
absorbed by the oral mucosa and the intestines. Until 1978 there were no reports of cocaine
concentrations in plasma after the administration of oral cocaine, there was a report that year that
showed the effects of oral cocaine after the administration as hydrochloride (Van Dyke et al,
1978). The development of new analytical techniques as immuneassays and gas chromatography
improved the pharmacological studies of cocaine and its metabolites (Jatlow & Bailey,1975)
(Jatlow et al,1980) (Cone,2004). There are no bibliographic references to differentiate the
pharmacology of oral cocaine contained in coca leaves when they are chewed and when they are
drunk as infusions. There are no references about cocaine absorption when people do gargles.
Cocaine absorption is slower through the skin and the digestive tract than through other
routes. Cocaine alkaloid is absorbed by skin faster and in higher percentage that the cocaine
hydrochloride according the studies performed by Baselt et al. (Baselt et al.,1990) Cocaine is well
absorbed from the digestive tract (Van Dyke et al 1978). Cocaine is well absorbed during coca
chewing and provides a pharmacological basis for understanding the physiological and
psychological effects of chewing coca leaves (Paly et al,1979). The effects of cocaine alkaloid
when chewed appear in about 300-600 seconds and its highest peak lasts 45-90 minutes. The
effects of oral cocaine as hydrochloride appear in 600-1800 seconds. Oral bioavailability is 20% to
30%. After the digestive absorption of oral cocaine the concentrations in blood rise slowly in about
10 to 15 minutes. The slower and more sloped peak in blood levels is thought to be responsible for
the apparent low rate of addiction of the oral route (Verebey & Gold,1988) (Gold,1992).
According to Verebey and Gold cocaine hydrochloride is absorbed by the digestive tract slower
than cocaine alkaloid when it is ingested through coca leaves (Verebey & Gold,1988).
Chromatographic studies of coca tea infusions have shown that the percentage of cocaine released
from the leaves is 81% during elaboration and it rises according to the time of filtration (Jenkins
et al,1996). Oral cocaine pharmacokinetics is still the open compartment model. When we give
cocaine as infusions it can be absorbed in the oral mucosa. Cocaine (pKa 8.6) is ionized in acid

21
media like the stomach making its absorption more difficult in this region and easier in an alkaline
medium like the small intestine (Wilkinson et al,1980).
Initially it was though that the metabolism of cocaine was by the liver, but posterior studies
showed the presence of an enzyme known as pseudo cholinesterase that hydrolyses cocaine in
plasma and that the liver has only a secondary role (Van Dyke et al,1978) (Stewart et al,1979).
This could explain the similarities between the absorption of cocaine by the nasal and oral route
(Wilkinson et al,1980). There are studies that show that “cocaine addicts have normal activity of
butyrylcholinesterase” (Gorelick et al,1992) (Washington et al,1994). “In humans, cocaine is
metabolized mainly by hydrolysis of the ester linkages. Plasma and liver cholinesterases produce
the inactive metabolite ecgonine methyl ester (EME). The second major metabolite,
benzoylecgonine (BE), is formed spontaneously at physiological pH. N-demethylation of
benzoylecgonine produces benzoylnorecgonine”. “Cocaine may be demethylated by cytrochrom P-
450 system to produce an active metabolite, norcocaine” (Jenkins & Cone,1998). ). The
psychological and physiological effects of oral cocaine last twice as long as those when used by
aspiration, three times as those when used by the intravenous route and five to ten times longer
than those when smoked. This gives it many therapeutic advantages: a slow absorption avoiding its
accumulation and toxicity, low blood concentrations, low but sensible physiological and
psychological effects and it is easily dosable in blood, urine and hair, just as Cone et al. mention
(Cone et al,1995). Gorelick states that “when cocaine is smoked it leads to dependence and abuse
faster than when used by aspiration” (Gorelick,1992). During a recent treatment study Clapp et al.
found two cases who reported active cocaine use by sublingual route exclusively (Clapp et
al,2004). In 2006, Llosa et al., demonstrated that cocaine contained in coca powder in most
efficiente absorbed by digestive tract when is mixed with an alkaline supplement as sodium
bicarbonate or plant seeds called llipta (Llosa et al,2006) (Llosa & Chang-Fung,2007),
When cocaine alkaloid is consume contained in coca leaves or in coca tea, showed acid pH
reaction, and for this, Indians mixed with alkaline substance when chewing in order to facilitate the
release cocaine and up the pH reaction. Hot water release the alkaloid (pK 8.6) from the coca
leaves to the infusion, but the infusion is not alkaline, but acid pH (< 7). However, cocaine
behavior indicated that the alkaloid is no recombine with the infusion in the digestive tract,
because is well absorbed in the duodenal area, similar as when is consume with alkaline
supplement, but different as when is consume without alkaline supplement or prepared in cold
water. Llosa & Chang-Fung done the first study with oral cocaine alkaloid using or not alkaline
substance. Urine levels of benzoylecgonine were significatively different (p < 0.05) at the same
oral cocaine dose when was ingested with alkaline substance (higher), and without llipta
Physiological parameters differences were no significative (p ≥ 0.05) when oral cocaine was
ingested in the four preparations (Llosa & Chang-Fung,2006) (Llosa & Chang-Fung,2007).

TOXICOLOGY
Coca-leaf chewing
When cocaine was isolated in 1860 there were chemical methods to identify and quantify
the amount of cocaine in coca leaves and in its products. After, there were development
biochemical methods to identify its presence in organic fluids (Turner et al,1981). But the lack of
sensitive and specific laboratory methods at that time made it very difficult to detect cocaine and
its metabolites in blood, urine, saliva, hair and other fluids in amounts less than 1 ng/ml. All these
was solved by the introduction of new laboratory methods such as immunoassays and
chromatography (Jatlow et al,1980) which are used today and left behind the old methods that
could only detect cocaine and its metabolites if they were in concentrations greater than 300 or
1000 ng/ml (Verebey,1992). The levels of cocaine obtained from chewing coca and from drinking
its infusions are usually lower than its metabolites because it is degraded very fast in blood.

22
Because of this it is better to dose its metabolite benzoylecgonine in urine which can be detected
during 24-72 hours. In some rare occasions it can take longer than that, as two weeks (Cone &
Weddington,1989) (Burke et al,1990) (Kranzler et al,1992). The first toxicological studies with
cocaine in blood were done using cocaine hydrochloride in humans and animals. There are only a
few toxicological studies done in blood and urine from coca leaves chewing. The vast majority of
studies have been done analyzing benzoylecgonine from urine. The toxicology of coca leaves
chewing in its traditional form matches the absorption and elimination of cocaine and of its
metabolites benzoylecgonine and methylesterecgonine in laboratory (Van Dyke et al,1975). The
chewing of approximately 10 gm. of coca leaves produced plasma concentrations of cocaine that
ranged from 50 to 90 ng/ml. Fifty grams of coca leaves produced levels between 150 to 450
mg/ml. One subject, who ingested 50 gm of coca leaves, had a cocaine plasma concentration of
850 ng/ml (Paly et al,1979). Verebey and Gold found plasma peak levels in coca chewers to be
150 ng/ml compared to 200 ng/ml in those that take oral cocaine hydrochloride (Verebey &
Gold,1988). Levels of 98 ng/ml (range 28 to 289) after chewing 31grams of coca leaves during 1
hour were detected in Bolivian volunteers (Sauvain et al,1997). Two studies of cocaine and its
metabolites in hairs of 5 to 20 Bolivian coca chewers that consumed 100mg of coca leaves a day
showed a peak level of 28.9 ng/ml and 50.6 mg/ml of cocaine and 4.4 ng/ml and 17.7 ng/ml of
benzoylecgonine respectively (Henderson et al,1992) (Moller & Fey,1992). In chronic chewers
(>30 years of chewing, 6 days a week) Llosa found peak benzoylecgonine urine levels
(immunoassay Axym/TDx) of 203,000 ng/ml (Quillabamba´ Study,Llosa,1997). In the first
toxicological study done with Peruvian miners that chewed coca leaves, Lopez and Llosa found
benzoylecgonine levels (immunoassay Axym/TDx) of 30,236 ng/ml in urine (López &
Llosa,2004).
Coca infusions
There are no mentions in blood or urine toxicology on people that have taken traditional
coca infusions (three or four leaves immerse in hot water during several minutes); all the literature
refers to the modern and commercial presentation (coca tea) known as mate de coca (start up in the
1970s). The first toxicological study done with mate de coca was performed in an individual that
was given a single cup of peruvian mate de coca (Healthy Inca Tea) which contained 4.8 mg of
cocaine in a coca tea bag. The analysis of. the infusion was done with gas chromatography/mass
spectrometry which indicated that it contained 2.15 mg of cocaine and no free benzoilecgonine.
After 2 hours of ingestion the levels of benzoylecgonine reached a peak of 1274 ng/ml and after 29
hours the levels come down to 117 ng/ml (ElSohly et al.,1986). Later there were few but very
interesting studies about the toxicology of mate de coca (Jackson et al.,1991) (Ferreira &
Gentner,1991) (Floren & Small,1993) (Llosa et al,1994) (Jenkins et al,1996). There is only one
study that indicates the amount of cocaine (587 ng/ml) in urine of an individual after the ingestion
of mate de coca (Jenkins et al,1996) because all the other studies have centered in its metabolites,
mainly benzoylecgonine. Analysis of coca tea drinkers indicated levels of 1274 ng/ml (ElSohly
et al,1986), 2800 ng/ml (Jackson et al, 1991), 2608 ng/ml (Floren & Small, 1993), 4600 ng/ml
(Llosa et al.,1994), 4155 ng/ml (Jenkins et al,1996), 12000 ng/ml (Llosa et al,2004), 32000
ng/ml (Lopez & Llosa,2004). There is only one analysis of the metabolite metylesterecgonine in
coca tea drinker, that showed 2520 ng/ml (Jenkins et al,1996). Llosa et al. made an open study
comparing volunteers that where given mate de coca, alfalfa tea and Coca Cola from Bolivia,
Chile, Peru and USA. The results showed that the individuals that drunk mate de coca came out
positive in their urine tests (Abuscreen Ontrak ≥ 300/ml) and the quantitative analyses showed
2460 ng/ml of cocaine (TDx/Axym immunoassays). The control subjects that were given alfalfa
tea came out negative in their urine tests with Abuscreen/Ontrak. The four subjects that were given
Coca Cola also come out negative in their urine test both qualitative (Abuscreen/Ontrak) and
quantitative TDx/Axsym immunoassay (Llosa et al, 1994).

23
 There are no qualitative or quantitative cocaine blood studies done with mate de coca
drinkers. There are also no blood, urine or hair studies done in drinkers of traditional coca
infusions (no commercial coca tea as Mate de Coca), coca wines or liquors. Contrary to what some
reports suggest, the majority of research studies done with oral cocaine from coca leaves chewing,
coca infusions, or with capsules containing cocaine hydrochloride have proved that oral cocaine in
its traditional or experimental form does not produce any behavioral changes, addiction or diseases
(Carroll,1977) (Siegel et al,1986) (Llosa, 1994) (Llosa,1995) (Rush et al,1999) (Rush et
al,1999) (Walsh et al,2000). Therapeutic doses usually vary between 50 mg and 300 mg daily of
cocaine ingested by infusions indicated. Toxicological tests show the levels of benzoylecgonine to
be higher than 1000 ng/ml in urine but usually they are higher than 10,000 ng/ml and can even
reach 50,000 ng/ml. At those levels it can be mistaken with the levels obtained by the nasal,
smoked or injected route. Studies done in chronic coca chewers (>30 years) from Andean
populations indicate values higher than 200,000 ng/ml in urine, because of this we have to be very
careful when we analyze the results if we do not have a detailed medical history of the individual
(Quillabamba´Study,Llosa,1997).

Simple method for determine pH of coca powder with and without alkaline supplement

Urine toxicologycal tests become rutinary in people that ingest coca powder for agonist
therapy. The benzoylecgonine (BE) levels vary when coca powder is ingested with alkaline
substance or without the substance. Studies done with similar doses of coca powder (5 grams),
ingested with alkaline substance (1 gram of sodium bicarbonate), showed higher levels of urine
benzoylecgonine (Axsym immuneassay, Abbott Lab) than when coca powder is ingested without
the alkaline substance (BE avg 28000-35000 ng/ml, against 6000-7500 ng/ml). Coca powder
prepared in hot water during 5 minutes result in similar BE urine levels as when is ingest with
alkaline substance. Coca powder ingested without alkaline substance and ingested mixed with cool
water showed similar BE urine levels (Llosa & Chang-Fung,2007).

Cocaine hydrochloride by oral route

Used only for laboratory studies with volunteers. There are few blood toxicological studies
with oral cocaine hydrochloride administered in capsules to humans (Post et al,1974a) (Baselt &

24
Chang,1987) (Baselt et al,1990). Verebey and Gold found plasma peak levels of 200 ng/ml in
those that take oral cocaine hydrochloride in capsule (Verebey & Gold,1988). Analysis of cocaine
hydrochloride ingested in gelatin capsules detected in plasma showed average levels of 150 ng/ml,
and 1200 ng/ml of benzoylecgonine, 175 ng/ml of ecgonine methyl ester, and 6.5 ng/ml of
norcocaine (Walsh et al,2000).

TOXICITY

“Coca tea drinkers do not satisfy the diagnostic criteria for either cocaine intoxication or
cocaine abuse” (Siegel et al.,1986). There is only one anecdotic reference about mate de coca
intoxication in a subject that drunk 80 bags (aprox. 400 mg of cocaine). The subject showed severe
symptoms of agitation, tachycardia, perspiration and rise in blood pressure that lasted 2 hours
(Siegel et al.,1986). This same author refers that some people even combine concentrated mate de
coca with alcohol to intensify its effects. A combination of cocaine with alcohol produce a
metabolite known as cocaethylene, which is synthesized in the organism of users (Bailey,1993). Is
common practice that people sniff cocaine hydrochloride in order to diminish alcohol effects,
because of the “awake” effects. This combination could some times be very dangerous because the
synergic pharmacological toxicity of both substances and also because of the toxic effects of the
metabolite cocaethylene (Bailey,1993) (Harris et al,2003). It is also a custom for Andean workers
to chew coca leaves and to drink aguardiente in the weekends and holidays without any reports of
acute or chronic illnessess as a result of this combination.

Farmers from Cuzco (Peru) that chew an average of 40 grams of coca leaves during 8
work-hours a day (mean 200 mg of cocaine), six days a week (1400 mg of cocaine a week, 5600
mg a month," 75.6 gram in a year), during 33 years (mean of 2.500 Kg of cocaine alkaloid in that
period), did not show any variations in their vital signs, hepatic function or blood work except for a
high eosinophil count which can be explained because coca leaves are not cleaned before being
chewed (Quillabamba Study, Llosa,1997). Miners from Andean regions that ingested an average
of 202 mg of oral cocaine contained in coca leaves during they daily work, did no show any
abnormal physiological nor behavioral reactions, and its cortisol blood levels were normal and
fewer than cortisol level of the miners that no chew coca leaves during work (some Christian’s
people) (Lopez & Llosa,2004). Doses of 300mg (Rush et al,1999), 400 mg (Walsh et al,2000)
and 150 mg (Filmore et al,2002) by the oral route have been reported as save and non toxic: “The
results of this experiment proved that across a six-fold range of doses, oral cocaine HCL is well
tolerated by individuals with recent histories of cocaine use and can be safely administrated under
controlled laboratory and medical conditions (Rush et al,1999). As commented by Walsh et al,:
“Maintenance on low doses of oral cocaine produced limited direct pharmacodynamic effects and
no signs of toxicity. Administration of oral cocaine at doses up to 400 mg/day can be well tolerated
and suggests that restricting the dose schedule to preclude cocaine administration just prior to
bedtime enables normal sleep” (Walsh et al,2000).

Many addicts take during their binges more than 5 to 20 times the amount of cocaine by the
nasal and pulmonary route than the highest consumers by oral route. There are no physiological
nor biochemical signs in most addicts to alert us of any imminent problem that they may presents
such as myocardial or pulmonary infarctation, arrhythmias or stroke, because of this many
consumers are even proud of their “perfect health”. Even though this may be true we have to
consider the hypertensive crisis, emotional liability and agitation that consumers present during or
right after consumption and some important signs as insomnia, rhinitis and midriasis among others.
The main problem about this is that most myocardial infarctions and other crisis occur right after
an acute and violent discharge of catecholamines produced by cocaine and does not give us much

25
time for proper care which most of the time leads to sudden death. Most of the time cocaine is
consumed with alcohol. The effects of cocaethylene are similar but longer than the effects of
cocaine, this is due to its longer half life which may lead to severe intoxications (Bailey,1993)
(McCance-Katz et al.1994). Walsh et al write: “…The present study provides empirical evidence
to support this hypothesis, and these data suggest that patients who have achieved abstinence may
be at increased risk for adverse cardiovascular events during relapse to use” (Walsh et al,2000).
As commented by Miller et al, “…using SPECT (CAT with photon emission) we have seen
the severe neurotoxicity produced by cocaine that in most cases is a product of the severe spasm
that it causes in brain vessels induced by the high release of catecholamines” (Miller et al,1992).
Cocaine consumption can lead to severe intoxication and death when used by any route, even oral.
The oral route has only been mentioned when an individual ingests packages containing pure
cocaine hydrochloride and these open in the digestive tract leading to coma, decerebration and
death. This has only been seen in “body packers or burrier” that use it as form of narcotic traffic
transporting cocaine in their stomach and bowels (Wetli & Mittleman,1981) (Clouet et al,1988)
(Sorer,1992) (Wetli,1992). The packages contain about 3 and 5 grams of cocaine hydrochloride
which can pass to the intestines through osmosis or when they break leading to an acute
intoxication and mesenteric ischemia, gastrointestinal perforation, hepatic failure and splenic
infarct that most of the time leads to death by intoxication and lack of immediate medical attention
(Goldfrank & Hoffman,1992). The levels of cocaine and benzoylecgonine dosed in these
individuals are higher than those found in chronic consumers. Levels of cocaine can reach 1000
ng/ml in plasma leading to organ dysfunctions and death (Rowbotham,1992).
Ambre has estimated that patients with benzoylecgonine levels between 100,000 and
200,000 ng/ml probably consumed about 500 mg of cocaine. He also found benzoylecgonine
levels of 1000 ng/ml after injecting 150 mg of cocaine to the vein. Using the same criteria an
individual showed levels of benzoylecgonine of 621,251 ng/ml probably after consuming 1000 mg
of cocaine (Ambre,1985) (Rowbotham,1992). This should not be considered a rule because we
have tested individuals that consume 5 grams or more in a single session and show levels below
100,000 ng/ml of benzoylecgonine in urine. There is a very big difference in toxicity between
traditional coca leaves chewers or coca tea drinkers and those carrying packages of cocaine in their
bowels mainly for narcotic traffic. The main difference is that cocaine hydrochloride is going to be
absorbed very fast by the digestive tract due to its high hydrosolubility compared to cocaine base
(alkaloid) which is not very hydrosoluble (Goldfrank & Hoffman,1992). This statement is
different that the Verebey & Gold commentary (Verebey & Gold,1988), although the last authors
talk about the cocaine alkaloid when is ingested contained in coca leaves.
There are no reports of any case that has lead to toxicity due to overdose of coca leave
chewing. The only case of toxicity that has been reported after drinking mate de coca was referred
by Siegel et al. (Siegel et al,1986). An anecdotic case of a 92 year old woman that chewed coca
leaves for 80 years with an average of 150 gram daily (that yields about 600 to 750 mg of cocaine)
divided in 6 to 10 doses was reported by Jeri and Perez (Jerí & Pérez,1990). This amount is much
higher than that used by traditional chewers that use about 250 mg of oral cocaine daily. With this
in mind our team suggested to some patients (2 adult men) that were taking 100 grams of coca
leaves from Cuzco daily, to increase the amount to 150 grams during two weeks. This yields about
750 mg of cocaine and about 225 mg of cocaine are absorbed by the digestive tract. In all cases
and after increasing the amount the physiological parameters stayed under normal range and there
was no significative variation (≥ 0.05) with those of the previous dose. Range of benzoylecgonine
in five urine dosages was under 50,000 ng/ml when urine was collected at 8 a.m. one day before,
during the two weeks of high ingest and one day after the last dose (Llosa,2004).
There are no reports in scientific literature of any illness or death because of the
administration of oral cocaine doses of that ingested in prescribed coca infusions, coca tablets or

26
coca capsules for therapeutic goals, although individuals with cardiovascular problems that travel
to high altitude Andean regions should consult their physician before taking high doses of oral
cocaine. People that ingest the new modality of use oral cocaine in Andeans regions (coca
powder), as volunteers for laboratory researchs, or as regular costumers that ingest coca powder
mixed with typically meals, milk or juices, do not report nor developtment physiological,
laboratory nor behavioral abnormalities after intake daily coca powder during one year or more
time. Cocaine addicted-patients under cocalization therapy do not report illnessess nor
abnormalities reactions related to coca powder under treatment during one year or more time of
daily use, in doses up to 50 mg of oral cocaine alkaloid (Llosa & Llosa,2005)
The unique common situation in which cocaine could development intoxication by oral
route, other than the “body packers”, is when subjects sniff cocaine hydrochloride and some drug
pass to the mouth and then is mix with the saliva and enter to the digestive tract. The same fact
occur when subjects smoke coca-paste in cigarettes by mouth (or to inhale crack). Cocaine of coca
paste and crack is take into the disgestive tract too.

ABUSE LIABILITY

The similarities between oral cocaine studies in animals and humans are a constant.
Gutierrez-Noriega and Zapata Ortiz studied the effects of cocaine in dogs and one of their
conclusion was that: ”When cocaine is administered by the oral route the signs of habit are less
evident and less toxic than when administered parentally”. They also concluded that: “When
cocaine is administered in small and fractioned doses is less toxic than if administered in one large
dose” (Gutierrez-Noriega & Zapata Ortiz,1944).

Use cocaine could development abuse and addictive behaviors in people that use it
repetively by nasal, intravenous and intrapulmonar routes. Althoug few years ago some
prominent professionals stated: “Used no more than two o three times a week, cocaine
creates no serious problems. In daily and fairly large amounts, it can produce minor
psychological disturbances. Chronic cocaine abuse usually does not appear as medical
problem” (Grinspoon & Bakalar,1980) (Gold,1992). Today this criterias are not more
accepted. According with ICD-10, and DSM-IV-TR criteria, continous use of cocaine, in any
chemical composition, by nasal, intravenous or smoke routes, development dependence,
produce abnormal behaviors (sociophatic), illnessess, and deats. However, cocaine by oral
route, as alkaloid or as hydrochloride do not show the same pharmacological behaviour
patterns as when is consumed by other ways. People that is accostumed to use cocaine by
oral route, as traditional chewers, coca infusion drinkers or people that eat rutinarily coca
products contained in food of Andean regions, do not fit with ICD-10 nor DSM-IV-TR
criteria for abuse, intoxication, nor dependence patterns, nor with Sthal criterias for those
diagnoses (Sthal,2005). “… Even when the Indians consume cocaine they do not become
addicts” (Kantak,1975). “Coca tea drinkers did not satisfy the diagnostic criteria for either
cocaine intoxication or cocaine abuse” (Siegel et al,1986). “The slow and more sloped peak
blood level is thought to be responsible for the apparent low rate of addiction of oral route
(Gold et al,1992). Several studies, observation and comments carry out since more than one
hundred years ago, support the criteria that cocaine effects by oral route in chronic
consumers are very different and do not carry out biological, psychological nor behavioral
abnormal reactions. (Mortimer,1901) (Monge,1952) (Martin,1970) (Weil,1978)
(Llosa,1989) (Gold,1992) (Llosa,1994) (WHO/UNICRI,1995) (WHO/PSA,1995)

27
(Argandoña,2006). Criteria about “addiction” meaning must be revised (Chassin et
al.,2007).

Rush et al, demonstrated that: “Across a six-fold range of doses oral cocaine hydrochloride
is well tolerated by individuals with recent history of cocaine use and can be safety administred
under controlled laboratory and medical conditions” (Rush et al,1999). Walsh et al., performed an
interesting study with oral cocaine as hydrochloride in chronic cocaine dependents volunteers, with
doses twice that doses used by coca-leaf chewers. In the summary they indicated: “Although
observer attenuation in this study was quite modest, this was accomplished with oral
psychostimulant doses that produced modest dynamic effects, were not associated with abuse
liability characteristics, and produce no signs of toxicity” (Walsh at al,2000). “The euphoria or
psychological stimulation produced by cocaine is thought to be related to the inhibition of
serotonin and dopamine re-uptake” (Jenkins & Cone,1998). Because the biochemical and
pharmacological effects of repetitive use, cocaine could development chemical addiction. By route
other than oral and dermal, cocaine use could produce dependence. “By dermal route could
produce intoxication according to the cocaine´s formula concentration” (Fleming et al,1990).
Several reports of chronic consume of cocaine by oral route demonstrated that could carry out
chemical addiction with the typical pharmacological effects (stimulation, increased alertness,
diminished appetite, increased energy, and antifatigue effects), but not developt abnormal
behaviors (sociophatic), illnessess nor deats as when is consumed by the other routes. The
physiolgical and psychological effects do not fit with Sthal criteria nor with ICD-10 and DSM-IV-
TR criteria for abuse nor dependence.

QUILLABAMBA´ STUDY (CHRONIC ORAL COCAINE USE)

Chronic time criteria, used when design protocols of laboratory investigations (weeks), do
not fit with chronic time criteria when oral cocaine is used by traditional coca-leaf chewers nor
coca drink as coca tea (years). Study with chronic users of oral cocaine was carry out by Llosa and
his team in Quillabamba city, in Peruvian Andean region, in 1995. Ten traditional coca-leaf
chewers, all urine positive at entry (Abuscreen Ontrak ≥ 300 ng/ml of benzoylecgonine),
volunteers (9 males, 1 woman), farmers, all bilinguals (quechua, spanish), no cocaine dependents
according with DSM-IV criteria, mean age 53.1 (33 - 80 years old), mean 37.1 (3 – 60) years of
living in Quillabamba area, Cusco (1200 meters over the sea level), mean 8 – 12 hours of work a
day, mean of active work 35.5 (18 – 50) years, mean years old when start-up chewing coca leaves
20 (8 – 40), mean 33.3 (18 – 45, SD 8.03) years of chewing coca leaves, mean 6.7 days/week of
coca leaves use, mean 40 grams of coca leaves daily (contained an average of 200 mg of cocaine
alkaloid), divided in average of 3.5 (2 – 4) times during the day. Conclusions of study (presented
in ASAM 28th Annual meeting, April,1997, San Diego, CA), were: Cocaine contained in coca
leaves was well absorbed by gastrointestinal mucous of the subjects (chewers). Benzoylecgonine
was detected in the urine of all subjects. The levels reached in urine varied between 410 ng/ml and
203,000 ng/ml, mean 48,915 ng/ml (TDxFLx, Abbott, cutoff 30 ng/ml). Physiological,
psychological/behavioural, and blood controls were normal except eosinophils, and one red cell
account (Quillabamba´ Study,Llosa,1996).

28
 Dr. T. Llosa and the traditional coca chewers (farmers), Quillabamba, Cusco, Peru, 1996

Many cocaine-dependent patients use oral cocaine daily (seven days a week), during
agonist therapy (cocainization therapy), in doses similar or twice the doses use by traditional coca-
leaf chewers (Quillabamba´ Study,Llosa,1996) (Llosa & Llosa,2005). Another important point
is the fact that cocaine used in laboratory studies is cocaine hydrochoride (elaborated by
Mallinckrodt Speciality Chemical Company, St. Louis, Mo., and other enterprises), administered
in gelatin capsules, while oral cocaine use by traditional users is a natural cocaine alkaloid ingested
when people chew or drink coca leaves. The different pH of cocaine hydrocloride (pH < 7), with
the cocaine alkaloid (pH > 7), is very important when cocaine is absorbed in the duodenal
environment, because cocaine is more efficient absorbed in alkaline environment, and when is
mixed with alkaline substance (lime, llipta), as is accostumed by traditional users in Andean
regions since more than thousand years (Acosta,1590) (Garcilaso de la Vega,1609) (Llosa &
Chang,2007).

CLINIC

- Chronic users (traditional farmers). There are few clinical studies done with protocols involve
chronic users of oral cocaine. The most important is the Quillabamba Study. Clinical evaluations
and blood laboratory screening included hepatic function performed in chronic coca chew users
(farmers) of oral cocaine (>30 years of use, >6 days a week), do not showed behavior,
physiological nor blood abnormalities, and no illnessess related to the oral cocaine use
(Quillabamba Study,Llosa,1997). These results agree with other previous clinical reports
(Unanue,1794) (Hammond,1887) (Valdizan & Maldonado,1922) (Monge,1952) (Andrews &
Solomon,1975) (Carroll,1977) (Caceres,1978) (Weil,1978) (Cabieses,1980) (Carter &
Mamani,1986) (Sauvain et al,1997) (Mamani,2007).

- Odontology. Since the firsts references of spanish chroniclers about coca chewing, ever
mentioned that chewers have black teeth (Vespucio,1540) (Acosta,1590) (Patiño,1967). Dentists
report that chewers have not caries (Llosa,E.,1993). When chewers lost a tooth, almost ever is by
bucal traumatism or bucal gum infection. Coca leaves have high calcium concentration, tanine, and
anti-bacterial effects and this could help that teeth do not development caries. Mixed coca leaves
(pH < 7), with alkaline substance (pH > 7) when is chewing could be an another explanation of

29
resistence to caries, because the pH enviroment. Coca-paste addicts, that smoke it in cigarettes by
mouth (oral coca paste residues), present higher levels of bucal infection and caries than normal
population (Llosa E,1993). Diaz & Espinoza informed that local coca concentrates reduce gum
coagulation time in dental surgery. Authors used desalcaloinized leaves, wherefore the coagulation
effects must be atribute to tanine that coca leaves contains (Diaz & Espinoza,2005). But when
whole coca laves are prepared as concentrates, the effects must be atribute to cocaine too, because
its vaso-constricting effects.

- Pregnancy. There are no references about the use of oral cocaine during pregnancy. Fetus, babies
and children of the chronic coca chew women that chew coca before become pregnacy, born and
development normal, and the children of the chronic coca chew fathers, born and development
normally, and if they have abnormalities there are not related to the coca chewing (Valdizan &
Maldonado,1922) (Carter & Mamani,1986) (Mamani,2007).

- Children. There are few references on the use of oral cocaine in children. Usually pregnant
women and children from the Andean regions do not use coca leaves as chewing. There are
references of twelve year old children who work as farmers that chew coca leaves during work
(WHO/UNICRI,1995). A new commercial drink made from coca tea sold in Colombia, advice
that kids, adults and old men can drink it without restriction (Nasa Esh´s,Coca Nsa,2004).

- Old people. There are several references of chronic coca leaves use by individuals older than 100
years old, mainly farmers in Andean regions. There are no medical reports on illnessess or
abnormal behavior attributable to chronic coca use (Jeri & Pérez,1990) (Llosa,1997).

- High blood pressure. There are evidences that progressive oral doses up to 400 mg do not lead to
significative effects in blood pressure in regular users of cocaine by nasal or intravenous routes
(Rush et al,1999) (Walsh et al,2000). The experience of millions of people (Andean chewers)
over the last hundreds years that use oral cocaine in the range of 100 mg to 200 mg of cocaine
daily is prove that it does not produce significative cardiovascular disturbances, and there are no
medical nor laboratory references that estate the contrary (Llosa,1997) (López & Llosa,2004)

- Sleep patterns. Reports of acute and chronic users inform that use of oral cocaine as coca tea or
as coca powder at bedtime do not produce sleep disruptions. Walsh et al informed: “…not was
there evidence of any mood or sleep disruptions (Walsh et al,2000). Post et al, informed that oral
cocaine administered to depressed patients significantly reduced total sleep and rapid eye
movement (REM) sleep (Post et al,1974)

- Physiological studies. In the second half of the 1900s, Bolivian and French researcher team
performed in La Paz, Bolivia, several interesting physiological, chemical, toxicological and
biochemical studies in volunteers during the coca leaves chewing (Villena & Sauvain,1997).
Before and after this date, some studies have been done in Peru (Llosa,1993) (Lopez &
Llosa,2004)

- Stress levels in high altitude mine´ work. Analysisl of blood cortisol obtained after regular miner
work in a high altitude mine (Casapalca, 4000 m.o.s.l.), in volunteers that are accostumed chew
coca leaves (30 g/150 mg cocaine alkaloid) during work period, showed normal levels (< 25), and
lower (p < 0.001) than a volunteers that are accostumed working without chew coca leaves (some
Christian´s people)(Lopez & Llosa,2004).

30
 Dr. T. Llosa with (Dr. L. Lopez) volunteers (miners), Casapalca mine, Andean region, 2004

- Medical illness. Ancient or traditional medicine is a common practice in South America. In

several illnessess local physician are accustomed use coca leaves or its derivatives (coca infusions,
extracts, macerates) for treat it. In the last times coca powder has raised it uses (mixed with milk,
water or juice or added to meals) for treat mainly osteoporosis, malnutrition, bulimia, arthritis,
cocaine dependence, poor memory, depression, chronic fatigue (Henman,2005), and other in
which no demonstrated yet efficacy (cancer, hair loss and others), and design protocols for use oral
cocaine in attention deficit and hyperactivity syndrome in children and adults (Llosa,2007)

-Attention deficit and hiperactivity disorder. In the last times is arise the interesting in the study of
the effects of oral cocaine in ADHD in children and adults. Use of coca leaves or its derivates is
not frequent in children, excepting when have stomach disorders. Many adults that ingest oral
cocaine as chew, infusions or powder indicated that they become relax or mild stimulate but no
hiperactive, and can sleep normal. Some protocols are under design for study the effects in ADHD
children and attention deficit in adults. Studies design for children must be to considerer that:
“Using SPECT (CAT with photon emission) we have seen the severe neurotoxicity is a produced
by cocaine that in most cases is a product of the severe spasm that it causes in brain vessels
induced by the high release of catecholamines” (Miller at al,1992). However, pharmacological
behavior of oral cocaine showed no severe spasm in animals, because the low rate of absorption
(Gutierrez-Noriega & Zapata Ortiz,1944). But in growing children these data should be taking
in consideration. SPECT studies in children under coca formulas for ADHD must be performed
during treatment, together with specific psychomteric tests.

- Cocaine-dependent patients. Medical, laboratory, and psychological evaluation in patients that

ingested oral cocaine as coca infusions, tablets or coca powder during one year or more (some

31
during more than ten years in coca infusions schedule), for treatment purposes, do not showed
medical illnessess nor laboratory and behavioral abnormalities (Llosa & Llosa,2005).

- Spiritual science. The pay to the land (pago a la tierra) is an ancient traditional ritual in Andean
regions in order to give the thanks to the earth and the Inkas’ God before chewing coca leaves, eat,
working or participate in a local parties. Emotional and physical benefits have been demonstrated
with this ancient ritual, that is considerer as spiritual medicine by people (Carter &
Mamani,1978) (Mayer,1978) (Morales,1990) (Seminario,2005) (Trigo,2006) (Hurtado,2006)
(Eddowess M.A.,2007) (Yachau,2007).

The Kintu, coca leaves ritual, Andean Regions (M.Molina, Artist, Peru)

SUBSTITUTION THERAPIES

The meeting participants to the World Health Organization, Drug Substitution Project
agreed to the following definitions of substitution: “for people dependent on a psychoactive drug,
pharmacologically related to that substance, to achieve defined treatment aims, usually improved
health and well-being. The preferred route of administration for the drug prescribed for
substitution is oral, because this is the safest route with the fewest complications. However,
substitution should not be restricted to the oral route, because other routes of administration may
make it possible to reach some, otherwise unreachable populations. The following criteria should
be considered essential for a drug to be appropriate for substitute prescribing, namely, that: - it

32
shows cross-tolerance and cross-dependence with the psychoactive substance causing dependence;
- it reduces craving and suppression of withdrawal; - clients can be stabilized on the drug (stabilize
consumption within a therapeutic range); - it facilitates psychosocial functioning and improved
health; - acceptable to clients; - it has no long-term toxic (i.e. organ destroying) effects; and, it is
affordable and available. It is also desirable that the drugs chosen for substitution prescribing: do
not grossly impair psychomotor functioning; are less attractive for diversion than the psychoactive
substance causing dependence; and, do not have gross short-term toxic effects. Clients maybe wish
to stop substitution treatment (and should be supported in doing so) but it should also be possible
for treatment to be indefinite” (WHO Drug Substitution Project,Geneva,15-19 May, 1995).
“Agonist therapies, also known as substitution therapies, have proven to be most effective in the
treatment of other substance dependence disorders, including opioid dependence (e.g., methadone,
LAAM and buprenorphine), and nicotine dependence (e.g. nicotine patch, gum, spray)” (Walsh et
al,2000).

Similitaries in chemical formulas do not assure the total or partial agonist effects. This is
the case with l-cocaine compared to the effects of its enantiometer d-cocaine or some cocaine
analogs such as (+)-4β -(4-chlorophenyl)-1-methylpiperidine-3 ᾳ- carboxylate, piperidine-based
analog of cocaine or [(+)-CPCA], because their effects are lower and have no therapeutic guaranty.
We suggest that to administer a substance with addictive power as substitution therapy can change
a “pathologic chemical addiction into a non pathologic chemical addiction” according to the
criteria of ICD-10 and the DSM-IV-TR. There are some scientific, social and legal boundaries
when we use agonist therapies, especially when we use the same substance. As it happened with
transdermal nicotine we have to consider that we are using the same substance we are “fighting
against and its use may even be prohibited”. The answer to this should be a scientific one. These
aspects cannot be avoided in protocols specially when we use the same drug as the original
(Leshner,1997).

Substitute I, Substitute II and Substitute III

Based on the positive results obtained from the administration of substitution therapies with
agonist substances as methadone for heroin and transdermal nicotine for nicotine addictions is that
some protocols were designed to use oral cocaine as a substitute therapy for the treatment of
cocaine addiction, and later supported in the WHO/Drug Substitutuion Project, criterias.
Even though substitution therapies are being used today as an effective treatment for some
addictions there is no standard classification of the different substitution substances. We classify
the different substitution treatments according to the substance that acting over the addictive
behavior, knowing that there may be many classifications according to their pharmacological
effect, biochemistry or mechanism of action. We suggested the following classification:

1- Substitute type I: uses the same addictive substance (original) or a combination in which
the original substance is present but through another modality or route of administration, in
order to change, reduce or control the addictive behavior or its damages as is the case of
transdermal nicotine (for smoking tobacco addiction) and cocaine alkaloid or hydrochloride
by oral route (for injecting or snorting cocaine hydrochloride, smoking coca paste or
inhaled crack). At this time, transdermal nicotine and oral cocaine are the unique substitute
type I agonist treatments.
2- Substitute type II: uses a different substance (mainly synthetic) than the addict but similar
in its chemistry to the original substance, with an equivalent but with less pharmacological,

33
 psychological and behavioral effects, as is the case of methadone, buprenorphine, LAAM
for opioid addiction, and amphetamine, methylphenidate or similars for cocaine addiction.
3- Substitute type III: uses different substances to the above to control or attenuate the
physiological and behavioral effects of the original addictive substance. This may includes
a variety of agonists and antagonist substances, antipsychotics, anticonvulsants, lithium,
disulfiram, antidepressants, antiparkinsonians, prophylactic antibody or “vaccines”,
tiagabine, ibogaine, neurotransmitter precursors (for cocaine and alcohol dependence) and
naltrexone for cocaine and alcohol addiction.

Substitute I and Substitute II must meet the criteria of an agonist substance in all cases.
There are substances that may act as a Substitute I for specific addictive substance but as a
Substitute II or Substitute III to another addictive substance, as when cocaine was used in
morphine and alcohol addicted patients (Huse,1880) (Bentley,1880) (Freud, 1884) and disulfiran
and naltrexone for alcohol and cocaine addictions (Lima et al,2002) (Grabowsky et al,2004).

We differentiate two steps in the substitution process

1- Substitution- Includes the substitute substance, the route to be used and the initial dose to
control appetence. In this stage we analyze the reduction of frequency of relapses and the
drug effects, in order to the therapist could determine the effective dose of oral cocaine.
2- Maintenance- Continues with an established dose as long as needed.

One of the most important advantages of substitution therapy is that the patient does not
react pathologically in either a conductive or physiological manner to the effects of the drug that
used to affect him. The experience of more than 30 years with methadone for the treatment of
heroin addiction has proven that “normalization can be obtained with an adequate and constant,
daily, oral dose under supervision of trained professionals and with the social help required”
(Dole,1997) (Payte,1997). The most studied substances and approved as an effective therapy are
the synthetic opioid agonists such as methadone (D,L-4,4-diphenil-6-dimethylamino-3-hepatone),
LAAM (1-a- acethylmetadol) and buprenorphine (partial agonist mu), used by the oral route for
the addiction of opioid derivates. Another is the use of nicotine patches (transdermal nicotine) used
for the treatment of nicotine addiction (Henningfield,1995) (Fudala et al,1997) (Walsh et
al.,2000). Novick et al define the treatment with methadone as “the treatment by a primary care
physician or by patients under methadone maintenance that are working, do not abuse drugs and
do not need another therapeutic support”, finding that 82% of patients were stabilized when
studied between 12 and 55 months (Novick et al,1988) (Senay et al,1992). There is no
substitution therapy for alcohol dependence (Solhkhan & Wilens,1998).

“There are no evidences that guarantee the clinical success of substances such as
dopamininergic agonists, carbamazepine, antidepressants, disulfiram, mazindol, phenitoin,
nimodipine, lithium and neurecover-sa or neurotransmitter precursors in the treatment of cocaine
dependence” (Lima et al, 2002). Studies with carbamazepine associated with transdermal nicotine
showed significative reduction of relapses in coca paste-addicted patients with abnormal EEG
(Llosa et al,1992) (Llosa & Montoya,1992)(Llosa, 1995). In 1993 Halikas et al. showed the
effectiveness of different pharmacological therapies and their effects, not finding significative
differences between them to control the abstinence syndrome (Halikas et al,1993), even though
there was a previous study by Halikas in which it was informed that carbamazepine showed
positive results in the control of appetence and in the maintenance of abstinence (Halikas et
al,1991). In 1992 there were some studies in animals to develop possible “vaccines” as
prophylactic antibodies for cocaine abuse (Bagastra et al,1992), but it is anticipated that it will

34
suffer the same outcome as disulfiram did in the treatment of alcoholics. The opioid
agonist/antagonist buprenorphine was also used with different results, showing that its use in
higher doses (12-16 mg/day) can have positive results (Kosten et al,1989) (Schottenfeld et
al,1993). Gomez Sanchez has used the anxiolytic effects of Valerian (Valeriana officinalis)
infusions plus self-help in cocaine dependence (Gómez Sánchez,2001). Studies with Tiagabine
(8mg), a GABA reuptake inhibitor, showed no effects in the use of cocaine, suggesting that it was
not useful in preventing the effects of cocaine (Lile et al,2004). Studies in cocaine-heroin addicts
using d-amphetamine/placebo (30/60mg) as an agonist substance showed a significative reduction
in the use of cocaine, compared to a dose of 15/30 mg of d-amphetmine/placebo, mean while a
parallel study with the agonist risperidone (2/4) did not show any significant effects (Grabowski
et al,2004). Although, many compounds have been evaluated for the treatment of cocaine
dependence, none has been approved by Food and Drug Administration (FDA) for this indication
(Vocci & Elkashef,2005).

“For many years investigators around the world have been searching in laboratory
pharmacological solutions for the cocaine dependence, but until now most of the studies have
indentified mainly the substances that are not effective and very few that are” (Llosa &
Llosa,2005)

During the NIDA/CPDD meeting held in Arizona, June 2006 (Agonist therapies for cocaine
dependence symposium), Grabowsky showed the results of the methylphenidate use in the control
of cocaine addiction (Grabowsky et al,2006), and talk about the investigations of Walsh (Walsh
et al,1999), and Rush (Rush,2000), with oral cocaine in humans, and the Llosa & Llosa´s
treatment schedules using oral cocaine as agoniste therapy with cocaine-addicted patients in Peru
(cocalization/cocainization therapy). He mentioned that Llosa & Llosa recommend: Dosing based
on use in the last 30 days, starting dose 50 mg daily, stable dose 100-500 mg daily divided to two
or three doses per day for 6 to 12 months (Grabowsky,NIDA/CPDD meeting,2006).

During the Grabowsky’s presentation, the substances list that are, and were, under investigation
protocols in the last decades in the NIDA directed to cocaine dependence treatment, were showed
through the table that was actualizated by Ivan Montoya (NIDA/CPDD meeting,2006)

NIDA Tested Medications for Cocaine Dependence Treatment

❑ Amantadine ❑ Aripriprazole ❑ Atomoxetine ❑ Baclofen ❑ Buprenorphine

❑ Bup/naloxone ❑ Bupropion ❑ Clonidine ❑ Cocaine Vaccine ❑ Naltrexone
❑ Naltrexone depot ❑ Progesterone ❑ Propanolol ❑ Selegiline ❑ Sertraline
❑ Tiagabine ❑ Topiramate ❑ Venlafaxine ❑ Yohimbine ❑ Desipramine
❑ d-Amphetamine ❑ Dextrometorphan ❑ Disulfiram ❑ Divalproex ❑ Dronabinol
❑ Fluoxetine ❑ Gabapentin ❑ GBR12909 ❑ GCP44352 ❑ Hydromorphone ❑ LAAM
❑ L- Dopa/Carbi ❑ Lofexidine ❑ LY544344 ❑ Mecamylamine ❑ Memantine
❑ Methamphetamine ❑ Methylphenidate ❑ Methadone ❑ Modafinil
❑ N-acetyl- aspartate.
The list include many substances that were investigate in the 1900s decade, as Amantadine,
Bromocriptine, Buprenorphine, Naltrexone, Neuroleptics, Carbamazapine, Desipramine, L-
Tryptophan, Tropamine-Plus, Phenobarbital, Diazepan, Clonidine, Mazindol, Imipramine,
Nortriptalyne, Fluoxetine, Wellbutrin, Trazodone (Halikas et al.,1991)(Halikas et al.,1993)

New substances are under investigation, as the N-acetylcysteine (Mardikian et al,2005),

Cabergoline (Shoptaw,2005), Ondansetron (Roache,2005), pyrolidiniltolil pentanone analoges
(pirovalerone)(Meltzer et al.,2005), Diltiazen (Anderson & Pierce,2005), other for double
dependence (Pettinati,2005), or co-morbilidity (Oliveto,2005), or associated symptoms

35
(Kampman,2005). Somoza demonstrated another time the inefficace of the old reserpine in
control of cocaine craving (Somoza,2005). Study with Selegiline transdermal system (STS)
showed no effective results in treatment cocaine dependence (Elkashef et al.,2006), and
Kampman et al., informed that trial with amantadine, propranolol and their combination, none of
the three active treatments was significantly more effective than placebo in promoting abstinence
from cocaine (Kampman et al,2006). Gabapentin versus tiagabine for reducin cocaine use among
cocaine dependent methadone-treated patients was study. Gabapentin showed poor treatment
retention and ineffectiveness in reducing cocaine use (Gonzales et al,2007)

In May, 2006, Pérez de los Cobos in a meeting carry out in Barcelona, Spain, informed
about the new hypothesis and maintenance schedules for cocaine dependence, that include
methylphenidate, amphetamines, pemolide and oral cocaine (p.o 400 mg/daily instead of the 25-50
mg/daily ingested by the traditional uses in andean regions when chew coca leaves)(Pérez de los
Cobos,2006)

From the 1980s, investigators are immmerse in developt and test a new therapy for cocaine
dependence, denominated vaccines (anti-body vaccines), as the “KLH-cocaíne-complex” (cocaíne-
keyhole limpet hemocyanin complex), and other researchers (Bagastra et al.,1991) (Lerner &
Tramontano,1988) (Landry et al.,1993) (Carrera et al.,1995) (Yang et al.,1996)
(Landry,1997) (Kosten et al,2002) (Vocci & Elkashef, 2005). The most important advantages of
the anti-cocaine vaccines are the facts that they no act over the brain, but over the cocaine, and
produce minimal secundary effects, and the main disadvantages are that between 25% to 30% of
the patients do not development enough levels of antibodies, and the lack of antibodies during the
first 6 to 10 weeks (Kosten et al,2002) (Sofuoglu et al,2005) (Perez de los Cobos,2006).

Sundry Episodes in the History of Cocaine as Substitution Therapy

The history of coca leave use to alter the physiology and mood reactions in humans goes
back thousands of years to the Andean and Amazonic populations of South America
(Martín,1970) (Andrews & Solomon,1975) (Grinspoon & Bakalar,1981) (Holmstedt &
Fredga,1981). There are no references of the Incas traditions or the first Spanish observers about
any illness or abnormal behavior produced by coca leaves as there are after the discovery of
cocaine in 1860. It was used by different routes by the end of the XIX and especially in the end of
the XX century. The addiction to cocaine forced the development of new therapies to control it but
as Walsh et al. stated, “despite widespread efforts to develop a pharmacotherapy for the treatment
of cocaine dependence, none of the multitudinous agents that have undergone evaluation have
proven efficacious” (Walsh et al,2000). The history of cocaine addiction treatment is fairly new,
mainly because 25 years ago there was no clear opinion if the use of cocaine led to addiction or
abstinence syndrome. In 1980 Grinspoon and Bakalar commented that “used no more than two or
three times a week cocaine creates no serious problem. In daily and fairly large amounts, it can
produce minor psychological disturbances. Chronic cocaine abuse usually does not appear as a
medical problem” (Grinspoon & Bakalar,1980) (Gold,1992). In the late 1970´s when coca paste
appeared in Peru and later freebase and crack in the USA the view of researchers and users
changed and both groups agreed that the use of cocaine by sniff or smoke may develop
uncontrollable addictive behaviors and increase street delinquency (Nizama,1979) (Jerí,1980)
(Gold,1982) (Jerí,1984). In the early 1980´s Llosa et al. performed the first protocol with brain
surgery (anterior bilateral cingulotomy) in “unrecoverable” coca paste addicts and obtained long
abstinence results in ≥45% of the patients followed for 20 years (Llosa,1983) (Cohen,1984)
(Nahas,1989) (Llosa,1997) (Llosa,2004). In the end of the 1980s Llosa began the use of coca tea
for treat coca paste dependents (Llosa,1990)

36
 The idea to use cocaine as an agonist substance to treat a number of illnessess and
addictions is not recent. In 1880 Bentley (Bentley,1880) and Huse (Huse,1880) informed about
the use of cocaine to treat opium and alcohol habit. Four years later Freud suggested cocaine use to
treat headaches, melancholy, neurasthenia, and opium and alcohol addictions (Freud,1884). In
1896 Snow informed about of use of cocaine and opium for the treatment of cancer (Snow,1896).
In 1978 Weil suggested the use of coca gum or infusions to control amphetamine and coffee
addictions (Weil,1978).

Referring to the how complicated the treatment of cocaine addicts can be Roache et al.,
comment: “cocaine abuse and dependence have proven refractory to treatment and no single
medication has been shown to be particularly effective”. Because of the success of substitution
therapy with other drug dependencies, stimulant drugs including dopamine agonists and uptake
inhibitors must be examined as potential treatment agents. Pre-clinical animal models of cocaine
reinforcement have suggested the efficacy of such agents to decrease drug intake in humans.
However, the substitution approach for cocaine has been controversial. The concerns are multiple
and involve a determination of the extent to which stimulant medication: 1) can safely or
adequately “substitute” for cocaine; 2) will increase cocaine craving and drug use through
“priming”; 3) will itself have too high of an abuse potential; and/or 4) will potentiate cocaine’s
abuse liability or cardiovascular toxicity. While several studies have taken specific neurochemical/
neuropharmacological approaches to the treatment of cocaine dependence, we accept a broader
conceptualization of stimulant dependence which includes possible behavioral mechanisms for
medication efficacy. This concept includes the idea that stimulants may substitute for cocaine
sufficiently to reinforce treatment participation and facilitate cocaine abstinence. A compromise is
sought between the risks, benefits, and effects of therapeutic regimen compared to the abused
drug” (Roache et al,1998).

One approach that has received surprisingly little attention is the potential utility of using a
cocaine “agonist” or a compound whose effects mimic those of cocaine (Waslh et al,2000). That
is half true, because for many decades now several investigators have proved and stated the
innocuousness of oral cocaine in animals and humans (Gutierrez-Noriega & Zapata Ortiz,1944)
(Carroll,1977) (Siegel et al,1986) and have promoted the use of oral cocaine as substitution
therapy (Llosa,1990) (Llosa,1996) (5th Europad Conference,2002) (ISAM/APSA meeting,
2005). Up to 1988 there were few published studies about self-administration of cocaine agonists
(Winger,1988). Herling et al studied the effects of cocaine, amphetamines and pentobarbital on
the behavior originated by cocaine in monkeys (Herling et al,1979). In 1986 Robinson and Becker
stated that “even though is to soon to know if dopaminergic agonists can be useful in the treatment
of cocaine abuse, it is difficult to find a solution to their toxic effects” (Robinson & Becker,1986).
Many of the different pharmacotherapies for cocaine addiction have their base in some kind of
substitution theory, as is the hypothesis that dopamine is depleted with chronic use of cocaine and
that treatment replacing dopamine could block appetence just as methadone is used in the
treatment of heroin addicts (Self,1997). With that idea several drugs were used such as
amantadine, mazindol, methylphenidate, pergolide, and bromocriptine (Johanson &
Schuster,1995). Grabowsky used methylphenidate in many dependant patients and even though he
found that the benefit was not very significative it did not show an increase in the use of cocaine or
the appetence in patients treated with methylphenidate (Grabowsky et al,1997). Naltrexone has
been used for the treatment of cocaine dependence showing variable results (Hersh et al,1998)
(Schimitz et al,2004). In drug self-administration studies, ibogaine and related ibogaine alkaloids
reduce intravenous self-administration of cocaine 1 hour after treatment (Glick et al,1994).
Ibogaine reduces the preference for cocaine consumption in mice (Sershen et al,1994). Because

37
ibogaine displays lower affinity for the DA transporter as compared to cocaine, it met some of the
criteria for the “ideal cocaine antagonist” (Stanley,1998). Kozikowski et al, comment that “like
cocaine, the cocaine analog namely (+)-4β -(4-chlorophenyl)-1-methylpiperidine-3 ᾳ- carboxylate,
piperidine-based analog of cocaine or [(+)-CPCA] is a locomotor stimulant although it was less
potent and efficacious than cocaine. These results collectively suggest that [(+)-CPCA] it has an
atypical pharmacological profile having both cocaine-like “agonist” and some cocaine
“antagonist” properties that suggest that it may have utility in the treatment of cocaine craving and
dependence” (Kozikowski et al,2003) .

ORAL COCAINE AS SUBSTITUTION THERAPY FOR COCAINE DEPENDENCE

New criteria’s

Cocainization therapy has changed the concept of cocaine abstinence because the addict is
going to consume cocaine daily. As with transdermal nicotine in this kind of treatment we have to
put aside the idea of “abstinence”, mainly because the patient is not going to be in chemical
abstinence. In this case there would be no abstinence and the usual appetence is going to be under
control.

Theoretical support: the “refill process”

Substitution therapy type I (Llosa & Llosa,2005) with oral cocaine named “cocainization”
method (Llosa,1990) (Llosa,1997) is based on the administration of cocaine to consumers that
frequently use it by other routes in amounts that lead to behavioral changes or may cause illnesses
or sudden death. In these individuals the enzymes plasmatic and hepatic pseudocholinesterase
break down cocaine and briskly lower its blood level unfolding a new and demanding appetence.
The quantitative dosage of benzoylecgonine has been described as a reliable marker of cocaine
abuse and relapse (Batki et al,1994) (Reid et al,1994). This agrees with the observation by Moll
and Tennant: “When levels of benzoylecgonine are lower than 1000 ng/ml usually leads to
relapse” (Moll & Tennant,1995). We stated that the “substitution therapy replacing cocaine with
cocaine” is only comprehensible in the idea as “refill”. Because of this is advisable to maintain
certain minimum range of cocaine in the body to avoid its drop lower than critical levels and avoid
appetence effects. The refill step includes the administration of cocaine by oral route in low but
effective doses, in order to maintains neurotransmitters (norepinephrine, serotonine and dopamine)
in the synaptic cleft, in levels that could produce controlled stimulation but no uncontrolled
euphoria. Yet, the most important chemical substance in the substitution (agonist) process is
cocaine, and no the previous neurotransmitter mentioned. The effective control of appetence with
reduction in the relapse average during the “refill process” with oral cocaine (cocainization as
substitution therapy) support the design of our hypothesis (1). Then, the key words in substitution
therapy are: control craving, control relapse, and maintenance.

(1). In 1998 we suggest (no demonstrated) the synthesis of cocaine by the organism of addicts
which we named endococaine to explain the mechanism of relapse and refill (CPDD meeting,
1997/Llosa,1998).

“Because of the success of substitution therapies in treating other drug dependence

disorders and the lack of promising treatments for cocaine dependence, there has been a
developing interest in examining the potential utility of agonist agents (i.e., psychomotor stimulant
substitutes) for the treatment of cocaine dependence” (Grabowski at al.1997). At the present time

38
Llosa et al., there are use a new coca infusions and coca capsules brands (Agro-industrias Kallpa)
for substitution therapy in cocaine-addicted patients, and naltrexone plus oral cocaine for alcohol-
cocaine-addicted patients, plus counseling (Llosa & Llosa,2004).

Anecdotic and research steps

In 1975 the pharmacologist Kantak stated that “… even when the Indians consume cocaine
they do not become addicts” suggesting its use as a substitute therapy just as methadone is used for
heroin-addiction (Kantak,1975). The first mention about oral cocaine as a substitution therapy for
cocaine dependence is an anecdotic reference by Siegel et al. in The Journal of the American
Medical Association, JAMA, in January of 1986, in which he writer ...“Coca tea (mate de coca) is
promoted as a natural stimulant without caffeine”....“.and at least one cocaine treatment center
(in San Francisco,CA) supplies patients with the tea as a diuretic and cocaine substitute” (Siegel
et al.,1986) (Siegel,1993). In 1990 Llosa presented the first provisional study of the use of oral
cocaine to treat cocaine addiction using coca tea infusions known as mate de coca (Llosa,1990)
(Llosa,1991) and later designed and presented (Llosa,1992/Amersa) and published the first
protocol about oral cocaine as an agonist therapy which he named cocalization therapy
(Llosa,1994), that also presented in the meeting organized by the World Health Organization
(WHO) about substitution therapies, Geneva 1995 (Llosa,1995) (WHO Report,1995), later in the
58º annual scientific meeting of the College on Problems of Drug Dependence, CPDD
(Llosa,1996). In 1993 and 1995 there were reports of the anecdotic use of coca concentrate and
mate de coca as therapy in patients that smoked coca paste with some positive effects (Noya,1993)
(Argandoña, 1995). Hurtado, from Bolivia, inform about the first study given natural coca leaves
as chew (ackullico, chacchado, picchado), to coca paste dependents volunteers, in order to control
appetence. The study was done on the basis of clinic reports, but no toxicological nor statistical
datas (Hurtado-G,2000). In the last years there has been a number of pharmacological studies
done with oral cocaine out of Andean regions, that has given us important complementary
informations about its effects in the human organism and behavior, done with doses of 150 mg,
300 mg, 400 mg and 2000 mg (Walsh et al,1998) (Jufer et al,1998) (Rush et al,1999) (Walsh et
al,2000) (Jufer et al,2000) (Filmore et al,2002).

Therapy schedules

Modalities

Substitution (agonist) therapy type I, in which the therapeutic agent is always the substance
cocaine (cocainization), as alkaloid or as hydrochloride by oral route. There are two modalities of
cocaine administration: as cocalization and as cocainization method, but both methods are based in
the cocainization procedure or refill process.

Cocalization method

Agonist therapy that uses natural cocaine (alkaloid) contained in whole coca leaves,
crushed, grinded or pulverized (powder, flour), and used by the oral route by either chewing,
infusions, tablets or in capsules plus counseling. In this modality cocaine is absorbed directly from
the coca leaves or its natural products. It is used in Peru legally and can be found and bought freely
in stores as fresh coca leaves or packed as coca tea or powder, or powder contained in gelatin
capsules, at a very low cost. For medical purposes (substitution therapy in cocaine dependence), it
must be prescribed by physicians, in order to regulate the substitution doses. When people use coca
leaves or its natural derivates (coca infusions or coca powder), ingest not only the cocaine, but

39
other chemically substances contained in coca leaves, as other alkaloids, minerals, fibre, proteins,
carbohidrates, and vitamins. Andean coca is the plant that contains the highest concentratiom of
calcium in their leaf (average 2000 mg in 100 grams of coca leaves). For obtains more efficient
absorption of cocaine by oral route coca leaves or coca powder must be ingested with an alkaline
substance (lime, llipta), or prepared with hot water.

Cocainization method

Agonist therapy with cocaine as pure cocaine alkaloid or cocaine hydrochloride contained
in capsules, used by the oral route plus counseling. This modality is suggested in countries were
coca leaves or its products are not available or is not sold freely. This modality would be the most
recommended because of the exact dose of cocaine that can be administered; on the other side
there is the risk that addicts could open the capsules and use it by other routes. This could be
solved by mixing cocaine with a substance that could only be liberated in the digestive tract.
Similar to cocalization, uses cocainization method for therapy goals must be prescribed by a
physician. Because the international commerce of coca leaves or its derivatives is banned, new
legal regulations and policies are necessary to prescribe the therapy out of Bolivia and Peru, just
marihuana and some synthetic opioids are currently approved in some countries to control surgical
or cancer pain or nauseas, oral cocaine would have to be an exception for medical purposes,
mainly for cocaine-dependence, and mood, and stress regulation.

Sources

Capsules contained coca powder, used in agonist therapy

40
1. Coca tea bags: each bag contains 1 g. of crushed coca leaves and ± 5 mg of natural
cocaine alkaloid (Siegel et al,1986) (Jenkins et al,1996). Sold over the counter in
boxes containing 25 or 100 bags each. The cost is ± USD 2.00 per box (two dollars, 100 coca
tea bags) (Enaco, 2000) (Coincoca,2000) (Llosa,2007)
2. Commercial coca tea infusions (mate de coca): a regular cup (180 ml) contains ± 4 mg of
cocaine alkaloid (Jenkins et al,1996)
3. Coca tea infusions (natural coca leaves): a regular jar (10 grams in 1000 ml) contains
± 40 mg of cocaine alkaloid.
4. Coca tablets (only for research purposes): 2.5 mg of cocaine in 500 mg of coca leaves
pulverized and compacted (Llosa et al,1993) (Llosa,1996)
5. Coca capsules: each capsule contains ± 600 mg of micro pulverized coca leaves and
± 3 mg of natural cocaine alkaloid. Are sold over the counter in bottles containing 100
capsules. The cost is ± USD 10 per bottle (Flores Chumbe,2005) (Llosa & Llosa,2005)
6. Cocaine hydrochloride in capsules: (for researches purposes only). Amount of hydrochloride
cocaine according the protocol design.
7. Coca Powder (flour): 1 g (± 5 mg of cocaine alkaloid). One kilogram of coca powder cost USD
$ ±7 (seven dollars), sold over the counter in several weights by Peruvian Coca Enterprice,
Enaco (Enaco,2007).

Prescription

- For chronic cocaine hydrochloride, crack, and coca paste/basuco users.

- For sporadic users that develop intoxication or intolerance to the drug.

Routes of administration

Oral exclusively

Modalities of administration

Chew coca leaves, drink infusions, ingest capsules with coca powder, or coca tablets, and eat coca
powder mixed with meals, water, milk or juices.

Suggested doses. When to begin?

Substitution therapy with oral cocaine use a low dose of cocaine that could reach to 500 mg
daily. The doses to be administered will depend on the amount used on the last months (mainly the
last 30 days). Also the dose will depend on the bioavailability. We have to consider that oral
cocaine is absorbed by the digestive tract in about 20% or 30% of the ingested amount (Van Dyke
et al,1978) (Paly et al.,1979) (Verebey & Gold,1988) (Verebey,1992) (Wilkinson et al,1980). At
the beginning of treatment 30-50 mg of cocaine will be administered daily, and later the amount
varies between 100 mg and 300 mg daily under medical supervision. This mean that the effective
therapeutic range will be between ±30 mg and ±90 mg of absorbed cocaine. The active therapeutic
range for maintenance treatment (preventive) in an unlimited period of time will vary between 10
mg and 30 mg of absorbed cocaine. The patient can begin using the substitution therapy as early as
six hours after the last relapse, after cocaine levels in blood (its metabolized almost 100% after 2
hours) and its physiological and psychological effects have dropped (lasts few hours after
consumption), but at the same time we have to avoid appetence symptoms and relapse due to very

41
low levels of cocaine. Treatment should last at least 6 months but it’s desirable that is under
therapeutic range for a year or more.

¿Less doses or less frequency?

Investigation protocols estate that “laboratory studies conclude that a drug is better than
placebo when the drug reduces the number of relapses per week or month”, and not when it drops
the amount of drug used in each binge. Usually with cocaine addicts the indication that they must
consume less drug in each session does not work but instead we encourage them to consume less
times a week. This is going to give the addict more drug free days and a better chance to give them
adequate psychotherapy. Taking cocaine hydrochloride, crack or coca paste less times a month
even in the same amount by relapse is taking less total drug a month. This is a form of reduction in
a certain period of time in which the addict was used to take more drug.

Therapeutic range

After more than ten years or prescription, daily doses of oral cocaine for control appetence
in cocaine-addicted patients, showed that doses between 50 mg to 500 mg of cocaine are effective
in control appetence and relapses, with an average of 100 to 150 mg daily in most of the cases.

There is no blood level analysis of cocaine concentrations in patients under cocaine

treatment. The dosage of benzoylecgonine is not a reliable indicator of cocaine levels in blood.
References of cocaine levels in plasma after coca chewing or coca tea drinking must be taken as
reference only. The amount in grams of coca leaves intake indicate only the approximately amount
of cocaine absorbed according with the previous references. Clinical parameters will be taken as
referential indicator also.

a- In the method of cocalization with mate de coca it is recommended to begin treatment with 6 or
10 coca tea bags (6 gm or 10 gm of crushed coca leaves) daily, that contains an average of 30 mg
or 50 mg of cocaine (delivered in the infusion ± 24 to ± 40 mg), divided in four intakes at day.
With capsules (3 mg of cocaine each) the patients start with ± 20 mg every 8 hours (± 60 mg a
day) (Llosa & Llosa,2005). With coca leaves (± 5 coca leaves per gram) it is recommended to
begin treatment with 10 grams daily. If some patients choose the method of chewing coca leaves
(as the traditional chewers) they must split this amount in three daily doses. As Paly et al.
informed, the chewing of approximately 10 gram of coca leaves produce plasma concentrations of
cocaine in a range of 50 to 90 ng/ml (Paly et al,1979). If the cocaine is administered contained in
coca powder, must be mixed with an alkaline substance (llipta or sodium bicarbonate), in order to
facilitate the cocaine release and intestinal absorption. If the cocaine is contained in the coca
infusion, after prepared in hot water during three minutes at least, you do not need use alkaline
substances.

b- In the method of cocainization the dose of cocaine (as alkaloid or as cocaine hydrochloride) can
be delivery in tablets or capsules. With this we avoid the absorption of cocaine by the oral mucosa
and instead the absorption will take place in the intestine. In this case is not necessary to use an
alkaline substance or llipta because the tablets or capsules are going to release the cocaine in the
alkaline media of the small intestine. There are several evidences of intestine absorption of cocaine
hydrochloride when is delivered in gelatin capsules (Walsh et al,2000) (Filmore et al,2002), and
the cocaine alkaloid in tablets or capsules contained in pulverized coca leaves (Llosa,1997) (Llosa
& Llosa,2005).

42
c-The mixed method can be used at the beginning of treatment (although in some patients we can
use it as a long term maintenance treatment) in those patients that refer that they can not stop
inhaling, smoking or injecting cocaine. The idea is to administer oral cocaine along with their
regular route of consumption, getting them used to oral cocaine and increasing its amount while
progressively lowering the amounts used by other (addicitve) routes. This is no the most used
method at the beginning of the substitution therapy. Dependent subjects with these characterisitics,
should start-up treatment under hospitalization system and remain as inpatients during one to three
months. Most patients refer that after taking oral cocaine the urge to consume by other routes
diminishes greatly in few weeks.

GUIDELINES FOR START-UP, EVALUATE AND FOLLOWING COCA THERAPY

1. Verify that the patient is cocaine (hydrochloride, crack or coca paste) dependant. This may be
determined by the patient’s own declaration or through toxicological urine screens.

2. The initial evaluation and treatment should preferably be performed by a Psychiatrist, who
should request the following before treatment starts: clinical evaluation, EKG, CBC, LST, lipid
profile, glucose, amylase, lipase, cortisol, prolactin, ELISA test, chest X-Ray, brain imaging (when
justified) and quantitative toxicological profile (cocaine or benzoylecgonine) in urine. Find out if
the patient is a multiple dependant or abuser (i.e. user of other drugs, gambling/ludopathy, etc.),
dual (other concurrent psychiatric diseases), alcoholic, if he/she has legal problems due to drug
consumption, or if he/she is currently undergoing other medical treatment for a specific disease.

3. We should not forget that dependence is a disease that not only demands certain specific
diagnostic tests, like repetitive cocaine positive exams or its metabolite benzoylecgonine; but it is
also requires the history of behavior, typical signs and symptoms of a cocaine dependence. One
should be aware that every diagnosis of cocaine use requires at least one blood, urine or hair
positive cocaine or benzoylecgonine test. In addition, one should keep in mind that the detection
of cocaine or benzoylecgonine in urine is not enough evidence of cocaine abuse nor dependence,
since all coca chewers, coca infusion drinkers and coca powder consumers show positive cocaine
(benzoylecgonine) urine tests.

4. Sometimes it is necessary to start treatment by means of hospitalization in order to detoxify the

patient when he/she has symptoms of massive consumption or when it has been mixed with
alcohol, or when the patient’s behavior (paranoid, suicidal, aggressive, pessimistic) forces him/her
to be admitted in order to begin therapy.

5. Six hours after the last consumption, oral cocaine treatment may be started, with doses of no
less than 10mg. (three times a day/30mg), and regulating the doses in accordance to the level of
desire and the number of relapses per week, trying to rapidly reach 50mg. in as few days as
possible.

6. Periodically, we must use short and self-administrative psychometric tests (weekly or

monthly), as “Cocaine Craving Scale” (Halikas,1989), “Craving Questionnaire” (Llosa,1994),
and/or “Cocaine Craving Questionnaire-Brief” (Sussner et al.,2006).

7. Once the urge is under control, a psychological evaluation of personality and of any other
areas related to his/her addictive conduct (anxiety, mood depression, compulsion, aggression),
shall be performed.

43
8. Control parameters (past versus present) have to be established based on the interview and
behavior of each patient, which will force the caregiver to work according to his/hers observational
experience and rely on information given by those who have had close contact with the patient
(family, friends, teacher, boss, legal tutor).

9. Psychotropic use parallel to coca therapy must be determined, such as anxiolytics and anti-
convulsants, mood stabilizers, anti-depressants, anti-psychotics, naltrexone to control the
consumption of alcohol, vitamin complexes or maca, based on individual need and on that
determined by the therapeutic team.

10. Therapy should be performed for a minimum of six months, although it is recommended for
no less than a year.

11. Once the patient is stable and abstinence is proven, Psycotherapy treatment should follow and
be performed by Psychologists specialized in addictive behavior/cognitive-conductual therapy, its
causes and past history.

12. Once a maintenance dose and continuous abstinence have been established, a regular visit
with the Psychiatrist should be made (at least every month), in order to control the adequate
compliance of oral cocaine doses, as well as the use of other complementary psychotropics that
he/she might be taking. Likewise, the patient should agree with the therapist on a periodic
telephone control system in order not to fall out of touch.

13. Toxicological tests results must be interpreted by the therapist. Under oral cocaine
treatment, toxicological urine tests must indicate positive results always. We also have to avoid
screening for negative toxicological urine tests (<300ng/ml), because if the patient ingests oral
cocaine daily, urine levels are going to be positive(≥ 300mg/ml). So, positive results are not
evidence of relapse. Negative toxicological tests are proof that the individual is not consuming
oral cocaine, and even though this can be considered abstinence, there is no proof that relapses will
not occur in the event the patient were not following treatment guidelines, because the subject is
not fulfil the treatment. After treatment with oral cocaine for a period of time, we can determine a
toxicological urine benzoylecgonine average. Even though this result may vary depending on
various factors, a rise of benzoylecgonine over the usual average limit will indicate a possible
relapse. Should this happen, we should immediately order another quantitative analysis.

14. Legal problems derived from positive urine tests should be taken into account in sport
competitions and for medical insurance purposes, as well as for tourist trips. However, one should
remember that in the Andean region millions people have cocaine in their organisms and their
urine tests come out positive. Also, there exist informal sales of products which contain coca
(infusions, powder and others manufactured with coca sold over the counter) by different people
regardless of age, including children, in the Andean street markets as well as in supermarkets of
the large city capitals. This situation should be considered, not in order to reduce the sale of
industrial coca based products, but in order to acknowledge the regional reality (status quo) and to
emphasize that the use of oral cocaine in recommended or traditional doses, not only has no toxic
reactions, diseassess or sociophatic behavior, but contrarily, has proven to be the antidote to
control cocaine addiction and improve the well-being of the users of traditional and popular doses.

44
RESULTS
The first study with coca tea infusions (mate de coca) as therapy was presented in
1990 as a provisional report, but was not considered in the report of 51 patients presented in CPDD
meeting in 1996. Twenty volunteers, men, coca paste addicts, ingested each 4 coca tea bags (Enaco
Enterprise) daily (mean of ± 20 mg of cocaine alkaloid) for a period of three months. About 85%
of patients completed the treatment and had a significative reduction (<0.01) on their amount of
usage and better control of their behavior (Llosa,1990) (Llosa,1991). Until 1996 the results of
three studies on cocainization therapy under cocalization method were presented, with a total of 51
subjects taking oral cocaine as coca infusions (mate de coca) or coca tablets. The first study was
open trial, with 23 subjects, men, their relapse time lowered from a mean of 4.35 month to a mean
of 1.22 during the study and the number of abstinence days went from 32 to 217 during the 12
months the study lasted, ingesting a mean of 17.68 mg of oral cocaine as infusions (mate de
coca).The second study was a double blind, 5 weeks long study with 8 subjects that ingested coca
tablets with a maximum of 60 mg daily, lowering their relapse from a mean of 4.3 weekly to a
mean of 0.7 weekly. The third study was an open trial, 3 months long with 20 subjects that reduced
their mean relapse from 4.3 weekly to a mean of 0.3 weekly, ingesting 60 mg of oral cocaine daily
as coca tablets (Llosa,1997). The amount of oral cocaine administered was calculated
approximately taking as reference the only six studies done with coca tea bags at this time
(Institutos de Salud,Lima,1982) (Siegel et al,1986) (ElSohly et al,1986) (Jackson et al,1991)
(Floren & Small, 1993) (Jenkins et al,1996).

In the last 15 years more than 200 patients have used coca tea infusions in a systematic
manner, with the observation that the amounts were raised consistently in some patients over this
period of time due to the inefficacy of the initial doses (≤10 mg). The gathered knowledge and
proved harmless led to an increase of oral cocaine doses at the beginning of treatment and
maintenance doses of 100, 200, 300 mg and in some cases even 400 or 500 mg which help us
control the appetence and abstinence symptoms better than with initial doses lower than 100 mg.
We have determined the mean effective amount for the first phase of the substitution therapy
between 50 and 300 mg of oral cocaine daily which is about 15 mg to 90 mg of the absorbed
(active) cocaine divided in three or four ingests, noticing changes in the control of appetence from
the first and second week of treatment. Some initial but infrequent complaints are hyperactivity,
restlessness, herbs smell, increase urination, mouth dryness, tachycardia (rarely > 120 beats per
min), slight increase in blood pressure but always in the normal range and flashbacks which are
solved easily with the administration of short acting anxiolytic. Frequently is not necessary another
kind of psychopharmacs unless that co-morbidity exists. The use of substances as nimodipine that
increase the brain metabolism (Nahas et al.,1998), were suggested after the SPECT studies in
order to reduce the vessels spam (Miller et al,1992)

There are no SPECT studies in chronic oral cocaine consumers without addictive behavior
(traditional chewers, coca tea drinkers, coca capsules eaters). We should consider that SPECT
studies have only been done in individuals that consume cocaine by faster routes (nasal, smoked or
intravenous), because of this it is possible that the vasospasm and utilization of glucose differ from
that of oral consumers. Adherence to treatment is high, except in the cases were patients do not
like to drink high amount of liquids (coca tea therapy) but this is solved by changing to treatment
with capsules. A frequent concern of patients is that they may develop insomnia which we have
not seen in practice and is even less probable in those that are used to 10 or up to 100 times more
cocaine than the therapeutic doses. There is laboratory prove that fractioned ingestion of oral
cocaine does not produce any changes in sleep patterns (Post et al,1974) (Walsh et al,2000).

45
 One double blind, out-patient study (20 coca paste consumers, during 4 weeks)
(Llosa,2002) and two open out-patient studies that followed 28 (18 and 10 subjects each) regular
patients treated for 6 and 12 months are in review at this moment for a future publication (Llosa &
Llosa,2005). In these studies the percentages of success are similar to those obtained previously
with a drop in relapse that is higher than 80% in patients that follow treatment for more than three
months, even though many cases reach this level of success even in the first weeks of treatment.
Most cases that fail are mainly because of co-morbidity, incomplete diagnosis or lack of adherence
to treatment. The protocol for the maintenance treatment should be designed by our observations in
the medical appointments, patient information and that of someone in close contact with the
patient. It is advisable that an effective therapy schedule for each patient be followed at least for
the first three months. From there we can adjust the therapy in each case for as long as is
convenient. We should always remind the patient that cocaine addiction is a chronic and refractory
disease which needs long periods of treatment. It has been demonstrated with cerebral PET Scan
that cocaine consumers lower their number of D2 receptors and that this is related to the reduction
in frontal metabolism. PET Scan also shows significative changes in glucose metabolism in the
frontal cortical region. The period of time it takes for the brain to recover its basal metabolism can
easily take more than a year after sustained abstinence (London et al,1996) (Volkow,1997). There
are no studies with PET Scan in chronic consumers of oral cocaine but from our clinical,
psychological and behavioral analysis we can deduce that the neurobiological adaptation and the
dopaminergic path differ from those who take cocaine by other routes and in much higher doses
and faster routes (Koob,1997) (Self,1997) (Volkow,1997). In the experience we have with patients
in long maintenance therapy (between 1 and 10 years under oral cocaine), there are no reports of
significative intoxications, liver disturbances, illnessess, behavioral changes or deaths that can be
attributed to oral cocaine.

RESULTS OF 127 PATIENTS UNDER SUBSTITUTION THERAPY (COCALIZATION)(Llosa & Llosa)

No.Sub sex drug trial oral coc dose vehicle time r-avg(E) r-avg(e) year Status
daily
20 m CCP Open 20 mg CCT 3 mo 12 .8 mo 4.8 mo (1989) Report

23 m CCP Open 17.7 mg CCT 12 mo 4.35 mo 1.22 mo (1994) Published

8 m CCP Blind 60 mg CCT-CT 5 wks 4.3 wk 0.7 wk (1996) Published

20 m CCP Open 60 mg CT 3 mo 4.3 wk 0.3 wk (1996) No published

20 m CCP Blind 20 mg CT 4 wk 4.7 wk 1.18 wk (2002) Published

18 m HCC Open 100-300 mg CCT 6 to 12 mo 3.0 wk 0.4 wk (2003-05) Under published

10 m HCC Open 100-500 mg CCT 6 to 12 mo 2.7 wk 0.6 wk (2004-05) In review

8 m/w HCC Open 50-200 mg CP 3 to 6 mo 3.3 wk 0.8 wk (2006) In review

CCP: coca paste HCC: hydrochloride cocaine CCT: coca tea CP: coca powder CT: coca tablets r-avg(E): relapse
at entry (per week/month) r-avg(e): relapse at end (per week/month) mo: month wk: week m: men w: women

46
CONCLUSIONS

The agonist therapy by using oral cocaine (cocainization) has demonstrated to be an

effective therapeutic pharmacological tool for controlling the craving and reducing the number of
relapses in cocaine addicted patients, either in the form of hydrocloride used by nasal route
(snnifers), or smokers of coca paste. There are no studies performed on crack users.

There are two agonist schedules: cocalization (using natural coca leaves or its derivates as
coca infusions, tablets or coca powder in capsules), and cocainization (using hydrochloride cocaine
or isolate cocaine alkaloide) contained in gelatin capsules.

Considering that currently no specific pharmacological treatments exist for the disease
called cocaine dependence, and that pharmaco-clinic research has fundamentally demonstrated that
the majority of investigated medication is inefficient as long and medium terms, the agonist
therapy called cocalization or cocainization should be part of the more effective alternatives for the
treatment, since together with supportive psychotherapy have proved a high percentage of success
on a medium and long term basis, a fast start-up and no secondary effects. In addition, it is a
natural therapy, easily accessible and with no evidence of toxicity, low cost compared to other non
specific pharmacological therapies. The cost/benefit demonstrates that the benefit greatly justifies
its use, since it not only provides oral cocaine but also a series of nutritious substances used to
replace those lost through weak diets to which addicted patients are generally exposed.

To deny the opportunity of its use, especially in cases of intense or chronic consumption, is
to be blindfolded to a therapy that has demonstrated its effectiveness over other treatments. The
applicable norms of inadequate use for addiction purposes should not be applied discriminatingly
or erroneously in the use of oral cocaine for medical purposes, since the nicotine trans-dermal
patches are not forbidden, but on the contrary promoted during the anti-tobacco campaigns. Also,
this is the case of the coca paste-dependent smokers, who must use oral cocaine together with
nicotine patches and antidepressant medicine such as Bupropion.

This is very important remember that many investigators around the world have done
studies with oral cocaine in the last years, and that the focus in oral cocaine for legal, medicinal,
and nutritional uses is increased not only in Andean areas, but in countries out of this regions.

47
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 Dr. Teobaldo Llosa, M.D., and Dr. J. Ernesto Chang-Fung

Cocaine dependence is an uncontrolable health and behavioural problem. Since

many decades ago until now, millions of dollars had been used in researches, directed
mainly to demonstrated the prejudicial effects of use cocaine by nasal, pulmonar and
intravenous routes, and very few to study why in the Andeans regions millions of
people use oral cocaine in daily schedule (coca chewers, coca tea drinkers, coca
powder eaters), without show behavioral disorders or illnessess that fit with DSM-IV-
TR or ICD-10 criteria for cocaine dependence. In this book the author demonstrated
the advantages that investigators can obtain when interview or evaluate to the
traditional chronic oral cocaine users, most of which are physicaly and mental normal
people. These facts contradict to the WHO conclussions of the New York Convention
in 1961, when they indicated that el uso de cocaina oral llevaba al deterioro
mental y conductual de sus usuarios, conceptos desmentidos en modernos estudios
multicentricos diseñados por la misma WHO (Cocaine Project/UNICRI, 1995)
(Consultation on Drug Substitution Project/PSA,1995), pero que nunca autorizo sus
publicaciones. “What all these studies have done is only to “confirm what the Andean
populations impregnated with cocaine chronically already knew thousands of years
ago”. El autor y sus colaboradores enfatizan que el mal uso de la cocaina debe ser
controlado con el maximo rigor internacional, y tambien opina que los estudios sobre
cocaina oral deben ser desligados de cualquier aspecto prejuicioso politico y policial y
centrarse en el analisis cientifico y social de los usuarios. Asimismo, show the benefits
del uso de la terapia agonista con cocaina oral para reducir los efectos de la
dependencia a la cocaina en forma simple, economica e inocua (Llosa, 2005), and the
studies about the toxicological and pshysiopsychological effects of the ingest of coca
powder, a new madality, over the counter, of use cocaine by oral route (Llosa &
Chang-Fung, 2007).

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