REVIEW OF ORAL COCAINE AS AN AGONIST THERAPY

IN COCAINE DEPENDENCE:
NEW APPROACHES
Teobaldo Llosa, M.D,, PhD (*)
Luis M Llosa, M.D.
IRP/NIDA, June 18, 2012, Baltimore , MD
(*) COCA MÉDICA, LIMA
 Biological treatments tested for cocaine
dependence in the last 100 years
• SUBSTANCES: After 100 years of use and test many pharmacological
treatments, from Veronal (1903), Scopolamine, Bromocriptine,
d-Amphetamine, Carbamazepine, to cocaine Vaccines, Topiramate,
etc., studies have Identified mainly the substances that are not
effective, and very few substances that are partially effective
(statistically significant). To date, the FDA nor neither any
international organization not approved treatment to control the
addiction to cocaine dependence.

• OTHER SOMATIC TREATMENTS: electric shock, acupuncture, psychosurgery,

deep electric stimulation.

1. Bumke O (1917) Über psychische Erkrankungen (On mental illness), Breslau, Germany
2. Gorelick DA (2009) Pharmacologic interventions for cocaine, methamphetamine, and other
stimulant addiction. in Ries RK,Fiellin DA, Miller SC, & Saitz R (Eds) Principles of
Addiction Medicine, 4th edition, (Philadelphia, PA: Lippincott Williams & Wilkins),
2009, chapter 51, pp. 707-721.
 Seminar Objective

To present evidence that oral

cocaine could be an alternative
to control craving and relapse
in cocaine dependence
 FACTS

• For thousands of years Andean people have used

oral cocaine contained in coca leaves (by chewing)
or coca infusions (coca tea) for its anti-fatigue
effects in physical work (farmers, miners, runners)
and for mood stimulation.
• According with Siegel et al, coca tea drinkers did not
satisfy the diagnostic criteria for either cocaine
intoxication or cocaine abuse (Siegel RK et al, 1986,
Cocaine in Herbal Tea, Letter, JAMA, Jan 3, 255, N° 1
HISTORY
Twenty years ago (1991), Dr. T. Llosa brought samples of coca leaves to
ARC/NIDA in the form of coca tea to be studied. In 1991-92, in the ARC/NIDA,
Jenkins A, Llosa T, Montoya I, Cone E, performed the most comprehensive
study of coca tea to date (Forensic Science International, 77:179-189, 1996).
 Background
Coca tea box, sold over the counter
without restrictions in Peru, contains
With the results of 100 coca tea bags. Each bag contains
research in Peru, we 1 g of crushed coca leaves with 5 mg of
cocaine alkaloid.
optimize trial designs in Cost: avg US/. 7 dollars
patients who did not
improve with other
biologic therapies,
including psychosurgery
that we applied in 33
coca paste addicted
patients(1981-1983).
 First Anecdotal References on Oral Cocaine Used to
Control Cocaine Dependence
COCA TEA CO was sold in the USA (San
After visiting Bolivia in 1975, Francisco) from 1983 to 1986.
Kantak KM suggested the use of In 1986, Siegel RK et al., cited the use of coca
chewing coca leaves to control tea infusions as a cocaine substitute
cocaine addiction. treatment in a hospital in San Francisco, CA.
First Studies with Oral Cocaine Used as Agonist Therapy
In 1994 Llosa T published the results of
At the end of the 1980s we began using first open study with oral cocaine as
coca tea to control craving in coca paste- agonist therapy.
addicted patients in Lima, Perú
Llosa T (1994) The Standard Low doses of Oral
Llosa T (1990) Uses and Abuses of Coca, Cocaine used for Treatment of Cocaine
Dependence. Substance Abuse, Vol 15, N 4,
Preliminary Report, COCADI, Lima Amersa
 Toxicological, Physiological and Psychometric Studies on
Chronic Oral Cocaine Use Among Traditional Farmers and
Miners in Perú
CASAPALCA STUDY (Andes, 2004). Miners.
QUILLABAMBA (Cusco, 1996) STUDY. Farmers, Compared groups that chewed an avg 40 g coca
avg use of chewed coca leaves: 30-50 g of leaves (150- leaves (urine 30236 BE ng/ml at 10 hours) versus
250 mg cocaine alkaloid) mixed with llipta (alkaline), control subjects that didn’t chew leaves over an 8-
chewed 6 days a week over 30 years. Toxicological hour period of work at 4000 m.o.s.l. Open trial. Coca
results showed urine BE avg 49394 ng/ml (range 140- users showed less Cortisol level (p0.01).
203000). No behavior or medical problems related to
chronic coca use.
 Old and Modern Forms of Ingesting Oral Cocaine
Since 2000, COCA FLOUR, containing
COCA COLA (1886) contained 2.5 mg/ml of pulverised coca leaves, has become a
cocaine alkaloid per 100 ml, until 1903, popular ingredient in meals and drinks
when it was removed from the formula. in Andean countries. Contains ± 5 mg of
cocaine alkaloide per gram, plus several
nutrients. It is also used for medical
purposes in the form of capsules.
ENACO, Technical report, 2005, Lima
 Use of Cocaine for Addiction
COCAINE HYDROCHLORIDE TAKEN BY FROM THE 1980s IN THE USA
SNORTING (LINES), INTRAMUSCULAR SMOKING CRACK IN A PIPE OR
AND INTRAVENOUS ROUTES WERE
THE FIRST ROUTES OF USING TUBE BECAME A POPULAR FORM
COCAINE FOR ADDICTIVE PURPOSES OF COCAINE USE
Andean Modality of Using Cocaine by Smoking since
the 1970s: Coca Paste, a double dependence
cocaine-nicotine/or THC
COCA PASTE: cocaine alkaloid
mixed with many impurities
such as sulphuric acid and
kerosene. Coca paste cigarettes
(CCPC) contain coca paste mixed
with tobacco (or marijuana),
smoked in comercial cigarettes.
Each CCPC contains avg 152 mg
coca paste (95 mg of cocaine) +
298 mg tobacco (4 mg of
nicotine). Avg 20 (6-50) CCPC a
day. CCP is the most toxic
cocaine drug.
Llosa T, Henningfield JB (1993), Tobacco
Control 2: 333-336
 To Consider

After the onset of coca paste and

crack 20 years ago has not
developed any new form of cocaine
for purposes of abuse or
dependence, which should make us
think that the chances of a new use
have been exhausted.
 SUBSTITUTION THERAPY: definition
(World Health Organization, 2004)

SUBSTITUTION THERAPY (agonist pharmacotherapy, agonist

replacement therapy, agonist-assisted therapy):
is defined as the administration under medical supervision of a
prescribed psychoactive substance, pharmacologically related to
the one producing dependence, to people with substance
dependence, for achieving defined treatment aims. Substitution
therapy is widely used in the management of nicotine (nicotine
replacement therapy) and opioid dependence (methadone,
buprenorphine and LAAM).
 SUBSTITUTION THERAPY: criteria
(WHO, Drug Substitution Project, Geneva, May 1995)
The following criteria should be considered essential for a
drug to be appropriate for substitution therapy:
• It shows cross-tolerance and cross dependence with the
psychoactive substance causing dependence.
• It reduces craving and suppresses withdrawal symptoms.
• It facilitates psychosocial functioning and improved health.
• It has no short or long term toxic effects.
• Affordable and available.
• Does not grossly impair psychomotor functioning.
• Less attractive for diversion than the psychoactive substance
for dependence.
 SUBSTITUTION THERAPIES
classification proposed by Llosa T, Llosa LM, 2005

SUBSTITUTION TYPE I (Agonist): uses the same addictive substance (original) or

combination in which the same substance is present but through another modality
or route of administration, in order to change, reduce or control the addictive
behavior or its damages. At this time, transdermal nicotine and oral cocaine are the
unique substitute type I for agonist treatment.

|
SUBSTITUTION TYPE II (Agonist): uses a different substance (mainly synthetic) than
the addictive substance but it is similar in its chemistry to the original substance, it is
equivalent but with less pharmacological, psychological and behavioral negative
effects (methadone, buprenorphine, methylphenidate, amphetamine).

SUBSTITUTION TYPE III (non specific substances): uses different substances to the
above to control or attenuate the physiological and behavioral effects of the original
addictive substance. This may include a variety of agonist and antagonist substances,
antipsychotics, lithium, disulfiram, antidepressants, anti-parkinsonians, prophylactic
antibody or vaccines, topiramate, tiagabine, ibogaine, vigabatrin, or naltrexone.

Note: Substitute I and II must meet the criteria of an agonist substance in all cases.
At this time no non-pharmacological treatment fits the criteria for substitution
therapy.
 ORAL COCAINE USED AS A SUBSTITUTE
(Cocalization Schedule)
• Cocalization is the use of natural cocaine (alkaloid), which can be
extracted by chewing coca leaves, drinking coca infusions (teas) or
ingesting food products containing coca flour, as a substitution
therapy.

• During the cocalization schedule, besides the cocaine alkaloid, the

patient receives the nutritional supplement contained in coca leaves.

• Currently its use is limited to Andean regions where coca products

for oral and dermal use are legal and sold over the counter without
age restriction.

• Under this schedule, the patient needs to take a large amount of coca
leaves (as tea or flour) to obtain the necessary dose of oral cocaine.
ORAL COCAINE USED AS A SUBSTITUTE TREATMENT
(Cocainization schedule)
• Cocainization schedule is the treatment of patients with
pure cocaine alkaloid or cocaine hydrochloride taken in
capsules.

• The capsules deliver a higher concentration of cocaine in

less volume, making it more suitable for treatment.

• The capsules do not contain the nutritional supplement

contained in coca infusion or flour.

• Cocaine hydrochloride has been used in the USA inside

gelatin capsules for research purposes, and potentially
could be used as an agonist therapy (cocainization)
outside the Andean regions.
 Simple Efficient Methods to Extract Cocaine From
Coca Leaves as Coca Flour for Oral Use:
Toxicological results in urine
Dose Dose Substance and Supplement pH BE level (1) t-Studen
CCP(2) CAlk (3) At 10 hours Avg(20 subjects)

5g 25 mg CCP mixed in cool water (200 mL)

during 5 minutes 6.0 6003 ng/mL (avg)
5g 25 mg CCP mixed in hot water (200 mL)
during 5 minutes at 100° C 5.5 31142 ng/mL (avg) p< 0.05
5g 25 mg CCP contained in gelatin capsules
drink with a cool water (200 mL) 5.5 7769 ng/mL (avg)
5g 25 mg CCP mixed with cool water (200 mL)
plus 1 g sodium bicarbonate (4) 7.5 27100 ng/mL (avg) p< 0.05

(1) Quantitative Urine Benzoylecgonine level (AxSym/IFA/Abbott)

(2) Coca flour
(3) Cocaine Alkaloid.
(4) NaHCO3 (pH 8.6) CCP plus NaHCO3 (5/1) (pH 7.5-8.0)

REF: Llosa T, Chang-Fung E (2007) Efficient Absorption of oral cocaine contained in coca powder: a new form of use oral
cocaine in Andean regions, NIDA/CPDD 69 th meeting, Quebec City, Canada, June 16-21
 TREATMENT SCHEDULE: Cocalization
Llosa T, Llosa LM (2005) Oral Cocaine as Agonist Therapy in Cocaine Dependence, CPDD 67 th meeting, June

• Substance: cocaine alkaloid.

• Goals: control craving , reduce relapses, increase abstinence days, reduce negative effects.
• Route: oral exclusively.
• Vehicle: coca tea, coca flour contained in gelatin capsules or tablets.
• Doses: according to the daily dose consumed by the patient in a binge, but usually starts
with 50 mg three times a day and after three days can be increased by 50 mg daily.
According to symptoms, doses can be adjusted up to 300 mg or more (400-500 mg) per day
divided in three doses.
• Consider the possibility of comorbidity. In such cases you must prescribe the appropriate
treatment to the other diagnosis.
• Having achieved control of the craving, withdrawal and relapses (usually accomplished
during the first month) it is recommended to continue treatment for at least 6 to 12 months,
according to the background.
• Assessment: psychosocial and psychometric control, patient, family and/or school or work
information. Urine toxicological tests are not useful for assessing abstinence because
patients under agonist therapy will always show positive urine to BE.

• Negative toxicological BE urine test during treatment indicates that the patient is not
following the treatment correctly. Crack and coca paste addicts must be forbidden to
smoke tobacco. Cotinine urine test must show negative results.
 MONITORING AND CONTROL: New Approaches

URINE TESTS CAN NOT BE USED TO ASSESS THE

EFFECTIVENESS OF ORAL COCAINE THERAPY AS A
POSITIVE RESULT COULD INDICATE THAT THE PATIENT
IS FOLLOWING THE THERAPY OR CONTIUNING TO
RELAPSE.

DURING THE TREATMENT SCHEDULE, A NEGATIVE

COCAINE URINE TEST INDICATES THAT THE PATIENT IS
NOT FOLLOWING THE TREATMENT.
AFTER ONE OR TWO WEEKS OF ORAL COCAINE
INGESTION, WE CAN OBTAIN AN AVERAGE OF URINE
BENZOYLECGONINE. A HIGHER THAN AVERAGE LEVEL
IN FUTURE TESTS COULD INDICATE A RELAPSE.
MORE RELIABLE TOOLS FOR MONITORING PATIENTS
ARE CRAVING SCALES AND PERIODICAL PATIENT AND
FAMILY INTERVIEWS.
 Monitoring and Control

• FOR PATIENTS WHO SMOKE COCA PASTE CIGARETTES, THE BEST

METHOD FOR ASSESSING THE EFFECTIVENESS OF THE TREATMENT
IS TO FIRST INQUIRE HOW MANY CIGARETTES THEY SMOKE DAILY
OR DURING A BING. FROM THIS WE CAN CALCULATE THE AMOUNT
OF COCA PASTE, COCAINE, TOBACCO AND NICOTINE USED. THIS IS
MORE ACCURATE THAN COUNTING THE NUMBER OF RELAPSES.

• HOWEVER FOR PATIENTS WHO SMOKE CRACK, IT IS NOT POSSIBLE

TO CALCULATE THE AMOUNT OF COCAINE USED IN THIS WAY. FOR
THESE PATIENTS WE MUST REPORT THE NUMBER OF RELAPSES IN A
WEEK OR MONTH. THIS IS THE STANDARD TOOL USED IN STUDIES
AS TOXICOLOGICAL RESULTS ARE NOT RELIABLE IN AGONIST
THERAPY.
 Results of 147 Patients Under Cocalization Therapy (*)
(Llosa T. & Llosa LM., 2012)

No.Sub sex drug trial oral coc dose vehicle time r-avg(E) r-avg(e) year Pub.

• 20 m CCP Open 20 mg CCT 3 mo 12 .8 mo 4.8 mo (1989) Pub

• 23 m CCP Open 17.7 mg CCT 12 mo 4.35 mo 1.22 mo (1994) Pub
• 8 m CCP Blind 60 mg CCT-CT 5 wks 4.3 wk 0.7 wk (1996) Pre
• 20 m CCP Open 60 mg CT 3 mo 4.3 wk 0.3 wk (1996) Pre
• 20 m CCP Blind 20 mg CT 4 wk 4.7 wk 1.18 wk (2002) Pub
• 18 m HCC Open 100-300 mg CCT 6 to 12 mo 3.0 wk 0.4 wk (2003-05) Pre
• 10 m HCC Open 100-500 mg CCT 6 to 12 mo 2.7 wk 0.6 wk (2004-05) Pre
• 8 m/f HCC Open 50-200 mg CF 3 to 6 mo 3.3 wk 0.8 wk (2006) Pre

• 20 m CPP Open 100 mg CCT 8w 14 CCPC/d 4/7 CCPC/d (2009-12) n/p

• (*) During 20 years we have more patients in cocalization schedule, but not all under control studies.

• CCP: coca paste CCPC: coca paste cigarettes HCC: hydrochloride cocaine CCT: coca tea CF: coca flour
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 d:day m: men f: female , Pub: published Pre: presented in
meeting n/p non published nor presented in meeting
 Coca Paste (CCP) dependence: oral cocaine
treatment schedules
• Coca Paste is a smokable double addiction: cocaine plus nicotine (or THC)
• It has been shown that when coca paste addicts relapse, first they relapse in smoking tobacco.
• It has been shown that many patients stop coca paste smoking, but continue smoking tobacco.
• Therefore Coca Paste must be treated as a double addiction, that is, for cocaine and nicotine simultaneously.
• Coca paste use should not be considered primarily as an addiction to cocaine but as an addiction to both
substances, so it is valid qualify them as addiction to cocaine plus nicotine or nicotine plus cocaine smoked.

Our schedules
• oral cocaine + nicotine transdermal/oral nicotine (double agonist therapy)
• oral cocaine + bupropion + nicotine (mixed double agonist therapy)
• other substitute therapy (topiramate, disulfiran, antidepressants, etc) + nicotine (mixed
simple agonist therapy).
• in all cases must be accompanied by counseling

Comments:
• When crack appeared in the USA, researchers decreased their interest in studying coca paste.
REF: 1- Llosa T, Henningfield JE, Analysis of coca paste cigarettes. Tobacco Control, 2:333, 1993
2- Llosa T, Crack and Coca Paste must be Treat as Double Dependence, Substance Abuse, 30:81, 2009, AMERSA
 Provisional Results of 20 Coca Paste-addicted Patients Under
Simple, Double or Mixed Schedule Treatment with Oral Cocaine
with or without Anti-Nicotine Treatment
Aim: study of variation of number of CCP cigarettes (CCPC) smoked under oral cocaine
treatment.
20 Coca Paste addicted-patients (CCPA) male, average 14 (range 8-22) CCPC a day during the
last month, non tobacco cigarette smokers, avg 32 y.o. (16-38), urban citizens, volunteers,
entered an 8-week open/control study with oral cocaine treatment, with or without anti-
nicotine treatment between 2009 and 2012, in a private organization (Coca Médica), Lima, Perú.

Group A- 10 CCPA : 100 mg oral cocaine daily (coca tea) + transdermal nicotine (8 week
schedule), plus counseling

Group B- 10 CCPA control group: 100 mg oral cocaine daily (coca tea) + clonazepan (2-4 mg)
daily, plus counseling

Provisional results:
Group A: avg CCPC 4 (0-8) daily at end of 8 weeks . All subjects completed the study.
Group B: avg CCPC 7 (0-16) daily at end of 8 weeks. All subjects completed the study.

Statistical analysis and conclusions under review

Comments
• The review of the use of cocaine
by oral route as agonist therapy
has demonstrated its
effectiveness in controlling
cocaine use (craving, relapse,
time of abstinence, number of
coca paste cigarettes or amount
of cocaine), with no behavioral
or physical consequences.

• The doses that have

demonstrated effectiveness
have varied since our first trials,
but most recently doses equal
to or greater than 100 mg of
oral cocaine have proven to be
the most effective.
 Comments

• Coca tea and coca flour only contain a small

amount of cocaine per ml or per mg. Therefore
cocalization therapy requires large amounts of
these products to be consumed, which in some
cases may limit its use (edema, hypertension,
gastritis; taste of flour, etc).

• Cocaine could be administered in gelatin capsules

or tablets (cocainization therapy) mixed with a
substance that prevents its use in other ways and
for other purposes.
 Conclusions
• Like nicotine (transdermal/oral) the
use of oral cocaine as agonist therapy
fits the criteria for substitution therapy
(type I), and should be seen as a safe,
low cost, easy to obtain legally, and
effective alternative. Further studies
should be conducted inside and
outside the Andean region.

• As there is no treatment approved by

the FDA or any other international
health organization to treat cocaine
dependence, agonist therapy with oral
cocaine (cocalization/cocainization
schedules) should be an alternative for
further studies.
 Conclusions
• Crack and coca paste
dependence must be treated as
a double-addiction (cocaine-
nicotine or cocaine-THC).

• Treatment with oral cocaine

should be considered within the
criteria of regional treatment
modalities, which takes
advantage of the geographic
and economic resources of each
region.

• Use of cocaine by oral (and

dermal) routes does not meet
the criteria of DSM-IV-TR nor
ICD-10 for cocaine dependence.
 GOING FORWARD Lima, almost 10 millions people

• Future studies with more rigorous methodologies including large,

double-blind randomized controlled trials are needed in order to
substantiate our promising results.
• As a private organization Coca Médica does not have the resources
to conduct such trials. We hope than in the future larger
organizations will be able to build on our research and expand
access to oral cocaine as an agonist therapy for cocaine addiction.
 Studies performed in USA with Oral Cocaine
In 1998, Walsh SL, Jufer R, Cone E, Bigelow GE, demonstrated that oral consumption
of cocaine in doses similar or higher to those of the Andean users (≤ 400 mg daily,
divided in 3 or 4 doses), does not produce abnormal physiological nor behavioral
side effects. CPDD 59th meeting, NIDA Res Mong Series 178: 218

In 1999, Rush CR Baker R, Wright K, concluded that oral cocaine could be safely administered
under controlled laboratory and clinical conditions. Drug and Alcohol Dependence, 55: 1-12

In 2000, Walsh SL, Haberny KA, Bigelow GE, published the results of the effects of the
modulation of intravenous cocaine by chronic oral cocaine in humans. Psychopharmacology
150: 361-373

In 2002, Filmore MT, Rush CR, Hays L study the Acute effects of oral cocaine on inhibitory
control of behavior in humans. Drug and Alcohol Dependence, 67: 157-167

In 2009, Walsh SL, Stoops WW, Moody DE, Lin S.N, Bigelow GE, indicate that exposure to
controlled high doses of cocaine hydrochloride (875 mg(day) produces modest symptoms
consistent with cocaine withdrawal within hours of cessation of dosing but provide no
evidence of symptoms persisting beyond 24 hours. Exp Clin Psychopharmacology, August,
17(4): 205-216