Abstract. A substance extracted from the Amazonianvine Banisteriopsis caapi was shown in the 1920s to alle-viate parkinsonism. These pioneering studies were crit-icized and forgotten for a number of reasons, includingquestions as to the identity of the active agent andfailure to conduct strictly controlled studies. We now re-port the first double-blind, randomized placebo-con-trolled trial of a Banisteriopsis caapi (BC) extract for treat-ment of Parkinson’s disease (PD). A single dose of BCadministered to de novo PD patients resulted in signifi-cant improvement in motor function evidenced by de-cline in the Unified Parkinson’s Disease Rating Scale(UPDRS) score. The beneficial effects were maximal bythe second hour and persisted until the last evaluation ofthe patients at 4 hours. However, tremor was not im-proved and in some patients tremor was exacerbated.All patients also experienced a degree of transientnausea or vomiting. We measured the concentrations ofthe putative active agents (harmine, harmaline, andtetrahydroharmaline), and hypothesize that the benefi-cial effects were primarily due to glutamate receptor an-tagonist actions of the harmalines.

Marcos Serrano-Dueñas, MD, is in the Neurology Service of Carlos AndradeMarín Hospital in Quito, Ecuador. Fernando Cardozo-Pelaez, PhD, and Juan R.Sánchez-Ramos, PhD, MD, are in the Department of Neurology at the Univer-sity of South Florida in Tampa, Florida. E-mail: jsramos@hsc.usf.edu.

Supported in part by the Helen Ellis Research Fund.

THE SCIENTIFIC REVIEW OF ALTERNATIVE MEDICINE Vol. 5, No. 3 (Summer 2001)

EFFECTS OF BANISTERIOPSIS CAAPI EXTRACTON PARKINSON’S DISEASE

Marcos Serrano-Dueñas, Fernando Cardozo-Pelaez,and Juan R. Sánchez-Ramos

129

INTRODUCTION

AYAHUASCA IS A BEVERAGE PREPARED FROM A

combination of two plants, the vine Banisteri-opsis caapi (BC) and the leaves of other plants, mostcommonly Psychotria viridis, which contains the hallu-cinogen dimethyltryptamine (DMT). Ayahuasca(known as hoasca in Brazil, Yage in Colombia, and Caapiin other parts of the Amazon basin), has a long historyof use in medico-magical-religious ceremonies by nativesof the Amazonian rain forests.1,2 More recently,ayahuasca has been used as a religious sacrament by twostate-approved churches in Brazil (Uniao do Vegetal andChurch of Santo Daime). The banisteriopsis vine con-tains contains b-carbolines such as harmine, harmaline,and tetrahydroharmine,3,4,5 which normally do not pro-duce the desired psychotropic effects unless they are usedwith the DMT-containing plant. When taken orally,DMT is metabolized by monoamine oxidase (MAO) andis inactive, but the combination of DMT and the MAOinhibitor banisterine results in psychotropic effects.

The active agent of the banisteriopsis vine was iden-tified by Louis Lewin, who named it banisterine. Based onthe subjective sensations experienced by Lewin followingself-adminstration, he recommended it for treatment ofrigid-akinetic syndromes in the late 1920s in Germany;4

all the reports mention improvement in rigidity, but con-flicting results regarding tremor. Rustige also noted im-provement in mood and affect. Later, Halpern studiedthe subjective effects on herself, and noted a sensation oflightness of body and a belligerent, aggressive mood.

Original Research

From the 1930s to the present, the use of banisterine intreatment of PD has been virtually forgotten.

One of us (MS-D) had previously evaluated 13 pa-tients who admitted use of ayahuasca occasionally (every5 or 6 months), and who felt it helped alleviate the signsand symptoms of PD. In 4 of these patients we were ableto directly observe the effects of consumption ofayahuasca. In one of these, extract of Banisteriopsis caapi(BC) was taken alone (no admixture of plants) and inthe other 3 patients, the admixture of plants was in-gested. Approximately 20 minutes after ingestion of thebeverage, there was an improvement in rigidity with ex-acerbation of tremor and appearance of abnormal invol-untary movements as well as the induction of a halluci-natory state. The motor effects and hallucinations weremuch less evident in the single patient who took onlythe BC extract.

L-dopa is the gold standard of PD treatment, but itsuse is limited by the development of motor complica-tions, including dyskinesias, in 30 to 80% of chronicallytreated patients.6 As a result, additional therapies havebeen developed that increase and stabilize synapticlevels of dopamine without augmenting the adminis-tered dosage of L-dopa, as for example by inhibitingdopamine metabolism with MAO inhibitors or with cat-echol-O-methyl transferase inhibitors.7,8

Based on the remarkable effects of banisterine re-ported in the late 1920s and the dramatic effects noted

in the few patients described above, we undertook adouble-blind, randomized, placebo-controlled study ofthe acute effects of a single dose of BC extract in a co-hort of 30 de novo PD patients.

PATIENTS AND METHODS

Thirty consecutive patients with newly diagnosed PDwere selected (using diagnostic criteria of Calne et al.9)from the Neurology Service of Carlos Andrade MarínHospital in Quito, Ecuador. The patients were randomlyassigned to receive either banisteriopsis extract orplacebo tea (Figure 1).

All patients underwent assessment of higher cor-tical functions with the Short Test of Mental Status(STMS);10 the Hamilton test for depression (HT);11 cra-nial CT; serum chemistry (urea, creatinine, and glucose);hepatic enzymes (GOT, GPT, GGT); and cardiac eval-uation including EKG.

Patients who scored more than 50% on the HT, whoscored less than 29 points on the STMS, or who exhib-ited anomalies on the serum tests or cardiac evaluationwere excluded from the study.

BC was prepared as a liquid extract 12 hours beforeadministration in a standard manner: 50 g (dry weight)of the vine was chopped into small fragments, and addedto 1500 mL of water, brought to boiling for four hours

130 THE SCIENTIFIC REVIEW OF ALTERNATIVE MEDICINE

Figure 1. Double-Blind, Placebo-Controlled Trial of a Single Dose ofBanisteriopsis caapi Extract for Treatment of Parkinson’s Disease

Consecutive de novo patients (n = 30)

Not Randomized (n = 0)

randomized

Single dose placebo tea (n = 15) Single dose banisteriopsis extract (n = 15)

Examined at 1, 2, and 4 hrs (n = 15) Examined at 1, 2, and 4 hrs (n = 15)

Withdrawn from study (n = 0) Withdrawn from study (n = 0)

until the volume was reduced to 200 mL. The solutionwas filtered and adminstered in that form.

All patients came to the clinic fasting and received200 mL of either the BC solution (BC) or placebo (P),which consisted of 200 mL of manzanilla tea. Patientswere not allowed to eat or drink anything but waterduring the course of the session.

Patients were evaluated using the motor componentof the Unified Parkinson’s Disease Rating Scale(UPDRS)12 before (baseline) and 60, 120, and 240 min-utes after ingesting the test infusions (questions 3, 4, 9,11, 14, 17, 32–39, and 41 of the UPDRS were not in-cluded). Analysis of variance (ANOVA) of the data fol-lowed by Bonferroni corrections for multiple compar-isons was performed. An value of 0.05 was chosen andp < 0.0125 was considered statistically significant.13

This protocol was approved by the Department ofDocencia and Research of the Andrade Marín Hospitalin Quito, Ecuador. All patients provided informed con-sent.

Measurement of harmala alkaloidsin Banisteriopsis caapi extract

Analysis of the levels of harmala alkaloids (harmine,harmaline, and tetrahydroharmine) present in the ban-isteriopsis extract was performed as described previously3

with certain modifications. HPLC system: The mobilephase was 100 mM ammonium acetate, pH 6.9, with20% methanol and 20% acetonitrile. Flow rate was keptat 1 mL/min using a BAS 200 series pump (BAS, W.Lafayette, Ind, USA). The mixture of harmala alkaloidswas separated using a reverse phase YMCbasic HPLCcolumn (4.6 × 150 mm) with a 3-micron particle size(YMC Inc., Wilmington, NC, USA). Harmine and har-maline were purchased from Sigma Chemical Co. (St.Louis, Mo, USA). Tetrahydroharmine was producedfrom the reduction of harmaline with sodium borohy-dride, as described previously.3 Harmine, harmaline, andtetrahydroharmine were detected using a LS-3B fluores-cent detector (Perkin Elmer, Norwalk, Conn, USA).Harmine was detected using a wavelength of 300 nm forexcitation and 360 nm for emission. Harmaline andtetrahydroharmine were detected with wavelengths of340 nm and 480 nm for excitation and emission, re-spectively. A calibration curve was constructed withknown amounts of the 3 compounds and the area of thepeaks was recorded and compared to the areas producedby the injection of the Banisteriopsis caapi extract. Levelsof harmala alkaloids were expressed as micrograms permilliliter of extract.

RESULTS

The average age of the BC group was 67 ± 8.3 years andthe P group averaged 62.9 ± 7 years of age. Median du-ration of disease was 24.8 ± 12 months in the BC groupand 25 ± 7.7 months in the P group. Fifteen patientswere male and 15 female (Table 1).

At baseline, the mean UPDRS score in the BCgroup was 54.4, and 53.8 for the P group (p < 0.4). TheUPDRS scores at 60, 120, and 240 minutes were 41.4 inthe BC group compared to 46.4 in the P group; 22.4 inthe BC group compared to 52.5 in the P group; and 25.6in the BC group compared to 53 in the P group, respec-tively. These differences were statistically significant (p< 0.0004; p < 0.0001; p < 0.0001) (Table 2).

Side effects were noted only in the BC group.Nausea or vomiting was noted in 100% of the BC pa-tients, diarrhea in 53.3%, agitation in 26.6%, and 1 pa-tient experienced transient hallucinations. All of thepatients in the BC group experienced an exacerbation oftheir resting tremor and, in addition, postural and actiontremor. Abnormal involuntary movements, choreiformin nature, were also noted (Table 3).

Analysis of the Banisteriopsis caapi extract yieldedthe following levels of harmala alkaloids (mean ± sem):harmine 418.44 ± 11.78 m g/mL, harmaline 173.03 ±4.13 m g/mL, and tetrahydroharmine 382.40 ± 8.38

Serrano-Dueñas, Cardozo-Pelaez, and Sánchez-Ramos: Effects of Banisteriopsis caapi Extract on Parkinson’s Disease 131

Table 1. Patient Characteristics

BC P# of patients 15 15

Age mean 67 62.9(years) SD 8.3 7

range 49–81 53–76

Duration mean 24.8 25(months) SD 12.7 7.7

range 14–36 15–38

Depression mean 35.3 33HT SD 10.5 10.4(%) range 15–50 15–50

Dementia mean 34.2 33.9STMS SD 2.4 2.3(points) range 30–38 30–38

HT = Hamilton ScaleSTMS = Short Test of Mental StatusBC = Banisteriopsis caapi GroupP = Placebo Group

m g/mL. DISCUSSION

In this double-blind, randomized, placebo-controlledtrial, we demonstrated that a single dose of BC adminis-tered to de novo PD patients resulted in significant im-provement in motor function evidenced by decline inthe motor component of the UPDRS score. The benefi-cial effects were noted by 1 hour and motor functioncontinued to improve for the 4 hours during which thepatients were studied. However, all patients who re-ceived BC experienced a worsening of resting tremorand the development of action and postural tremors,with some abnormal choreiform movements. All pa-tients also experienced a degree of transient nausea orvomiting. With the exception of the single patient whoexperienced confusion and hallucinations, these side ef-fects were much less severe than those experienced byusers of the complete ayahuasca beverage.

The levels of harmaline in the banisteriopsis extractingested by the subjects in this study were almost iden-tical to those measured by Callaway and colleagues inthe preparations of ayahusaca used by members of theUniao de Vegetal in Brazil.3 However, the mean harmineand tetrahydroharmine levels were 25% and 35%, re-spectively, of the levels measured in their Brazilian sub-

132 THE SCIENTIFIC REVIEW OF ALTERNATIVE MEDICINE

Table 2. Analysis of Variance of UPDRS (Baseline versus 1st, 2nd and 3rd in BC compared to P)

BC PG

Evaluations EvaluationsB 1st 2nd 3rd B 1st 2nd 3rd

Mean 54.4 41.4 22.4 25.6 53.8 46.4 52.5 53DS 3.8 2.9 3.6 0.7 2.8 2.8 4.2 1.4Range 47–61 37–46 16–28 19–33 49–57 40–52 46–57 47–57Variance 14.6 8.6 13.4 13.9 4.6 14.5 8.9 7.1

B vs. 1st B vs. 2nd B vs. 3rd B vs. 1st B vs. 2nd B vs. 3rd

F statistic 109.2 548.5 436.5 6.5 1.8 0.8p < 0.001 0.0001 0.0001 0.01 0.1 0.3

BC vs. PB vs. B 1st vs. 1st 2nd vs. 2nd 3rd vs. 3rd

F statistic 0.5 15.5 609 536.2p < 0.4 0.0004 0.0001 0.0001

UPDRS (items excluded: 3, 4, 9, 11, 13, 14, 17, 32, 33, 34, 35, 36, 37, 38, 39, and 41)p < 0.01 is statistically significantBC = Banisteriopsis caapi groupP = Placebo groupB = baseline

Table 3. Adverse Effects

Nausea or vomiting m 8 of 15s 7 of 15total 15 of 15 = 100%

Dizziness m 6 of 15s 6 of 15total 12 of 15 = 80%

Diarrhea m 3 of 15s 5 of 15total 8 of 15 = 53.3 %

Pyschomotor agitation m 2 of 15s 2 of 15total 4 of 15 = 26.6%

Confusion 1 of 15 = 6.6%

Hallucinations 1 of 15 = 6.6%

AIMs m 8 of 15

Exacerb. Tremor s 7 of 15

m= moderate, s= severeAIMS = abnormal involuntary movements

jects, who ingested the complete brew prepared from acombination of plants.3 The proportion of banisteriopsisvine to Psychtria viridis leaves and the exact methods forpreparation of the brew were not noted in the Callawaypaper.

In the shamanic use of ayahuasca for religious, mag-ical, or healing purposes, the infusion is prepared from amixture of plants. A critical component of the shamanicbeverage is the presence of the DMT-containing Psy-chotria viridis.1,2,3 DMT is a potent hallucinogen whengiven systemically or when smoked; when taken orally,it is inactive due to its metabolism by gut and liverMAO. BC is an inhibitor of MAO and, when ingestedorally with DMT-containing plants, allows the DMT toproduce a range of psychotropic effects, with prominentvisions, hallucinations, and illusions.1,2,5

The dramatic improvement in signs and symptomsof PD produced by the extract of BC may be due to acombination of two known mechanisms of action of theharmalines, the putative active agents. Harmaline, a b-carboline compound with a structural resemblance toserotonin, is a known nonselective inhibitor of MAO.14

MAO inhibitors can potentiate the actions of endoge-nous dopamine, but the symptomatic benefits in PD arevery mild, as evidenced by the study of deprenyl in denovo patients.15 It is difficult to conceive that the dra-matic improvement produced by BC can be due solely toMAO inhibition. It is possible that the interaction ofharmaline at glutamatergic receptors plays a significantrole in restoring motor function in PD. Harmaline hasbeen shown to be an NMDA receptor antagonist.16 Har-maline displaces [3H]MK-801, which binds to the cationchannel of the NMDA receptor, from membranes pre-pared from rabbit brain tissue.16

Glutamate is an excitatory amino acid that plays arole in the symptomatic expression of PD17 and that hasalso been implicated in the process of neurodegenerationof dopaminergic neurons of the substantia nigra.18 Whendopamine deficiency develops, the adaptive changes inthe striatal outflow pathways result in disinhibition ofthe subthalamic nucleus. In turn, the hyperactive sub-thalamic-pallidal glutamate projection results in de-creased outflow from globus pallidus internal segment(GP-int) to thalamus, to produce the clinical manifes-tations of slowness and rigidity.19 Blockage of gluta-matergic receptors corrects the imbalance that resultsfrom dopamine deficiency and helps restore normalmotor function.20 In the rat, local infusion of NMDA re-ceptor antagonists to the GP-int/SNr has been shown toreverse the signs of parkinsonism.21 In both rats and pri-mates, the NMDA receptor antagonist LY235959 has

been shown to potentiate the antiparkinson effects ofL-dopa, to stabilize the motor fluctuations and to alle-viate choreiform dyskinesias. However, MK-801, a glu-tamate NMDA receptor antagonist with hallucinogenicside effects (similar to phencyclidine and ketamine) hasbeen reported to induce dystonia when used with L-dopain a primate model of parkinsonism.21 In naive rats, MK-801 increases locomotor activity and potentiates themotor effects of L-dopa.23 The AMPA antagonist NBZX(2,3- dihydroxy-6-intro-7-sulfamoil-benzo-9[f ]quinoxa -line) im proved tremor, posture, and manual dexterity inparkinsonian monkeys.24 When glutamate antagonistsare given together with L-dopa, the dosage of L-dopa canbe greatly reduced without lessening motor function.20,24

To conclude, we suggest that the antiglutamate actionsof harmaline are most likely responsible for the anti -parkinson effects observed in the BC group of patients.

The transient worsening of tremor and induction ofpostural and action tremor by banisterine has been beennoted before by early investigators and, in fact, harma-line was used in the 1960s to study the mechanism of ac-tion tremor that could be induced by harmaline in pri-mates.25

Interestingly, L-dopa-induced dyskinesias are associ-ated with a decrease in the activity of the glutamatergicprojection to the GP-int. Paradoxically, glutamatergicreceptors are apparently involved in these dyskinesias,since adminstration of glutamate antagonists (of theNMDA receptor subtype) have been shown to be usefulin controlling L-dopa-induced dyskinesias.20

There is little concern for the possibility that theharmalines in the ayahuasca tea are cytotoxic at con-centrations found in the tea. Harmaline and a related b-carboline, ibogaine, are cytotoxic in rats only followingextremely high doses of 100 mg/kg or 100 mg/kg × 3.Two recent studies clearly demonstrated that even lowerdoses (25 and 40 mg/kg) given to rats did not producePurkinje cell degeneration.25,26

To summarize, extracts of BC were shown to haveremarkable symptomatic benefit in drug-naive de novopatients. This was the first double-blind, randomized,placebo-controlled trial of a BC extract for treatment ofPD. Studies with banisterine done in the late 1920s werecriticized because the benefits were believed by many tobe psychological. We measured the concentrations ofthe putative active agents, and hypothesize that the ben-eficial effects were primarily due to glutamate receptorantagonist actions of the harmalines. The most commonside effect was transient nausea/vomiting, which could inthe future be prevented by pretreatment with domperi-done. Hallucinations in a single case may reflect a higher

Serrano-Dueñas, Cardozo-Pelaez, and Sánchez-Ramos: Effects of Banisteriopsis caapi Extract on Parkinson’s Disease 133

sensitivity in that patient to the NMDA receptor an-tagonists. A complete dose-response study needs to bedone in human volunteers in order to determine the op-timal concentrations of b-carbolines to produce max-imal symptomatic relief and minimal side effects.

REFERENCES

11. Ayala Flores F, Lewis WH. Drinking the SouthAmerican hallucinogenic ayahuasca. Econ Botany. 1978;32:154–156.

12. Bennett BC. Hallucinogenic plants of the Shuar andrelated indigenous groups in Amazonian Ecuador and Peru.Brittonia. 1992;44:483–493.

13. Callaway JC, Raymon LP, Hearn WL, et al. Quanti-tation of N,N-dimethyltryptamine and Harmala Alkaloids inHuman Plasma after Oral Dosing with Ayahuasca. J Anal Tox-icol. 1996,20:492–498.

14. Sanchez-Ramos JR. Banisterine and Parkinson’s dis-ease. Clin Neuropharmacol. 1991;14:391–402.

15. McKenna DJ, Towers GH, Abbott F. Monoamine ox-idase inhibitors in South American hallucinogenic plants:tryptamine and beta-carboline constituents of ayahuasca. JEthnopharmacol. 1984:10;195–223.

16. Bédard PJ, Blanchet PJ, Lévesque D, et al. Patho-physiology of L-dopa-induced dyskinesias. Mov Disord. 1999;14(Suppl 1):s4–s8.

17. Lang AE, Lozano AM. Parkinson’s disease. First oftwo parts. N Engl J Med. 1998;339:1044–1053.

18. Lang AE, Lozano AM. Parkinson’s disease. Second oftwo parts. N Engl J Med. 1998;339:1130–1143

19. Calne DB, Snow DB, Lee C. Criteria for diagnosis inParkinson’s disease. Ann Neurol. 1992;32:125–127.

10. Kokmen E, Naessens JM, Offord KP. A Short test ofmental status: description and preliminary results. Mayo ClinProc. 1987;62:281–288.

11. Hamilton M. A rating scale for depression. J NeurolNeurosurg Psychiatry. 1960;23:56–62.

12. Fahn S, Elton RL, and members of The UPDRS de-velopment committee. Unified Parkinson’s disease ratingscale. In: Fahn S, Marsden CD, Goldstein M, Calne DB, eds.Recent Development in Parkinson’s Disease. Vol. 2. FlorhamPark, NJ: MacMillan; 1987:153–163.

13. Dawson-Saunders B, Trapp RG. Bioestadística Médica.México DF: Editorial El Manual Moderno, 1993 [Basic andClinical Biostatics. Trans. Carsolio M. New York, NY: Appleton& Lange; 1990].

14. Udenfriend S, Witkop B, Redfield BG, Weissbach

H. Studies with reversible inhibitors of monoamine oxidase:harmaline and related compounds. Biochem Pharmacol.1958;1:160–165

15. Parkinson Study Group Effects of tocopherol and de-prenyl on the progression of disability in early Parkinson’s dis-ease. N Engl J Med. 1993;328:176–183.

16. Du W, Aloyo VJ, Harvey JA. Harmaline competi-tively inhibits [3H]MK-801 binding to the NMDA receptor inrabbit brain. Brain Res. 1997;770(1–2):26–29.

17. Ciliax BJ, Greenamyre T, Levey AI. Functional, bio-chemistry and molecular neuropharmacology of the basal gan-glia and motor systems. In: Watts RL, Koller WC. MovementDisorders. Neurologic Principles and Practice. New York, NY:McGraw-Hill; 1997:99–116.

18. Olanow CW, Jenner P, Tatton NA, Tatton WG.Neurodegeneration and Parkinson’s disease. In: Jankovic J,Tolosa E. Parkinson’s Disease and Movement Disorders. 3d ed.Baltimore, Md: Williams & Kilkins; 1998:67–103.

19. Young AB, Penney JB Jr. Biochemical and functionalorganization of the basal ganglia. In: Jankovic J, Tolosa E.Parkinson’s Disease and Movement Disorders. 3rd ed. Baltimore,Md: Williams & Kilkins; 1998:1–13.

20. Blandini F, Greenamyre JT. Prospects of glutamateantagonists in the therapy of Parkinson’s disease. Fundam ClinPharmacol. 1998;12:4–12.

21. Ossowska K, Lorenc-Koci E, Konieczny J, Wolfarth S.The role of striatal glutamate receptors in models of Parkin -son’s disease. Amino Acids. 1998;14:11–15.

22. Starr MS. Antagonists of glutamate in the treatmentof Parkinson’s disease: from laboratory to the clinic. AminoAcids. 1998;14:41–42.

23. Liljequist S, Ossowska K, Grabowska-Anden M,Anden NE. Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism ofdopamine in various brain areas of mice. Eur J Pharmacol.1991;195:55–61.

24. Lange KW, Reiderer P. Glutamatergic drugs inParkinson’s disease. Life Sciences. 1994;55:2067–2075.

25. Poirier LJ. The development of animal models forstudies in Parkinson’s disease. In: McDowell FH, MarkhamCH, eds. Recent Advances in Parkinson’s Disease. Philadelphia,Pa: F. A. Davis Co; 1971:83–118.

26. Molinari HH, Maisonneuve IM, Glick SD. Ibogaineneurotoxicity: a re-evaluation. Brain Res. 1996;737(1–2):255–262.

27. Xu Z, Chang LW, Slikker W Jr, Ali SF, Rountree RL,Scallet AC. A dose-response study of ibogaine-induced neu-ropathology in the rat cerebellum. Toxicol Sci. 2000;57(1):95–101.

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