IMl llllllll Illillll lllll lllll lllllllllllllll llllllllllllllll ll~lllll Ill1 USOO5152994A United States Patent [I91 [II] Patent Number: 5,152,994 Lotsof 1451 Date of Patentz * Oct. 6, 1992

[54] RAPID METHOD FOR INTERRUPTING OR ATTENUATING POLY-DRUG OTHER PUBLICATIONS DEPENDENCY SYhmROMES “Effect of on -precipitated with- [76] Inventor: Howard S. Lotsof, 46 Oxford PI., drawal syndrome in chronic -dependent Staten Island, N.Y. 10301 rats”, Dzoljic et al, Arch. Int. Pharmacodyn Ther., 294, 64-70, 1988. [ l ] Notice: The portion of the term of this patent subsequent to Feb. 12,2002 has been Primaty Examiner-Thurman K. Page disclaimed. Assistant Examjner-Carlos Azpuru Attorney, Agent, or Firm-Howard C. Miskin [21] Appl. No.: S31,100 1571 ABSTRAtX [22] Filed: May 31,19!X! The administration to a poly-drug addict of ibogaine, [51] Int. Cl.5 ...... AOlN 43/W, A6lK 31/55; ibogaine, , in the family of A6lK 9/08; A6lK 9/48 apocynaceae, or their non-toxic salts have been discov- [52] U.S. Cl...... a...... 424/43% 424/451; ered to interrupt the physiological and psychological 424/463; 424/464; 514/214; 514/810; 514/811; aspectsof poly-drug dependency (, cocaine, alco- 514/812; 514/513 hol, nicotine, caffeine, amphetamine, desoxyephedrine [58] Field of Search ...... 514/810, 81 1, 812, 813, or in combinations thereof). A single treat- 514/214; 424/401, 436,451,463, 464 ment or series of treatments may be effective for one to References Cited eighteen months or longer. Treatment consists of the 1561 oral or rectal administration of ibogaine, , U.S. PATENT DOCUMENTS tabernanthine or their salts or derivatives in dosage 4.499096 2/198S Louoft- ...... s. 514/214 ranges of 1 mg/kg to 60 mg/kg. 4.587.243 VI986 Lotsoff ...... 514/214 4,85X523 E/l989 Lotsoff ...... 514/214 7 Claims, No Drawings ciare E. Rothlin. Raymond-Hamet published the “Ef- ‘RAPID METHOD FOR INTERRUPTING OR fects Gf lbogaine On The Isolated Rabbit Uterus*’ in AlTENUATING POLY-DRUG DEPENDENCY 1938 (Compt. rend. sot. biol. 127:592-4). Raymond- SYNDROMES Hamet continued to study the drug for a period of ,22 5 years. He singularly published 9 papers: Pharmacologi- BACKGROUND OF THE INVENTION cal Action Of Ibogaine (Arch. intern. phartnacodyna- The present invention relates generally to improve- mie, 63:27-39, 1939). Two Physiological Properties ments in the treatment of poly-drug dependency and Common To Ibogaine And Cocaine (Compt. rend. sot. and relates particularly to an improved biol. 133:426-g, 1940), Ibogaine and Ephedrine (Ibid. method for interrupting the physiological and psycho- lo 134:541-4, 194(J), Difference Between Physiological logical aspects of detoxification and withdrawal associ- Action of Ibogaine And That Of Cocaine ((Ibid. ated with combined in which heroin, metha- 211:285-S, 1940), Mediate And Intermediate Effects Of done, cocaine, amphetamine* caffeine, nicotine, - Ibogaine On The Intestine (Compt. rend. sot. biol. ephedrine and ethol may be used in various 135:176-79, 1941) Pharmacological Antagonism Of combinations, concurrently. 15 Ibogaine (Compt. rend. 212:768-771,1941), Some Color While previous patents have been granted for the Reactions Of Ibogaine (Bull. sot. chim. biol. 25205-10, treatment of dependency (U.S. Pat. No. 1943), Sympathicosthenic Action Of Ibogaine On The -4,449,096), - . - . - cocaine. and amphetamine abuse (U.S. Pat. Vessels Of The Dog’s Paw (Compt. rend. 233:757-58, No. 4,587,243) and alcohol dependency (U.S. Pat. No. 1946) and Interpretation Of The Ultraviolet Absorp- 4,857,523) there has heretofore been no general treat- 20 tton Curves Of Ibogaine And Tabemanthine (Ibid. ment for multiple addiction syndromes. The majority of 229:1359-61, 1949). drug users are now poly-drug addicted and researchers A good source of botanical, pharmacological and in the area of drug dependency treatment recognize the toxicological data coming our of this historical period pharmacological differences and behavioral uniqueness ~~ can be found in Jean Delourme-Houde’s Thesis (Etude of such dependencies. de l’Iboaa, Universitv of Paris. 1943)., Still another re- In the treatment for poly-drug addiction syndromes, searche:Vincent, D.-began his work on ibogaine by a there are no known medical procedures for general collaboration with Sero, I.: Inhibiting Action Of Taber- application. Those treatments which are applied are nanthe Iboga on Serum Cholinesterase (Compt. rend.’ directed toward specific dependencies within the poly- sot. biol. 136:612-14, 1942). Vincent participated in the drug spectrum and have substantial associatedproblems 30 publication of Five other papers: The Ultraviolet Ab- in which the patient will be re-addicted to another nar- cotic and/or suffer substantial discomfort during the sorption Spectrum Of Ibogaine (Brustier, B., Vincent, detoxification treatment procedure or require daily D. & Sero, I., Compt rend. 216909-911, 1943), Detec- injections or administrations in a chronic modality of tion Of Cholinesterase Inhibiting Alkaloids (Vincent, other addicting or mood altering substances. 35 D. & Beaujard, P, Ann. pharm. franc. 3:22-26, 1945), The Cholinesterase Of The Pancreas: Its Behavior In HISTORICAL BACKGROUND The Presence Of Some Inhibitors In Comoarison With Ibogaine, ibogamine and tabernanthine are among at The Cholinesterases Of Serum And Brain’(Vincent, D. least 12 alkaloids found in the plant & Lagreau, P., Bull. sot. chim. biol. 31:1043-45. 1949); of West Africa. The Gabonese as well as, Africans in 40 and two paperswhich he and Ramond-Hamet worked other countries on that continent have used the iboga on together: Action Of Some Sympathicosthenic Alka- alkaloids in the Bwiti religion and Mbiri medical societ- loids On The Cholinesterases (Compt. rend. sot. biol. ies, principally, during the last century. Ethnographic 150~1384-86,1956) and On Some Pharmacological Ef- studies have been performed by two principal special- fects Of Three Alkaloids Of Tabernanthe Iboga, Bail- ists: Otto Gollnhofer and James W. Fernandez. Golln- 45 lon: Ibogaine, Iboluteine And Tabernathine (Compt. hofer’s works include “Rits of Passage in the Bwiti rend. sot. biol. 154:2223-27, 1960). Initiation Society among the Mitsogo: The chewing of Another of the French chemists to provide substan- Iboga, Doctoral Thesis, 3red cycle, Rene Descartes tial information on ibogaine has been Dr. Robert Gou- University, Paris V, 1974 as well as, “Iboga, an African tare], considered by two generations of French chemists Psychotropic Agenent; Psychotrope vol. 2, No. 3, 1985, SO to be the “father of ibogaine research”. Goutarel’s work Montreal, Que. and Ritual Uses of Iboga in Gabon, Ibid, includes, Structure of Ibogaine (Goutarel, R.; Janet, h4. Vol. 2, No. 3, 1985. Fernandez’s book, one of the few in & M.; Mathys, F and Prelog, V.: Compt. rend, ac. SC., English, “Bwiti-An Ethnography of Religious Imagi- 237:1718, 1953), “Research on Some Alkaloids and nation in Africa” (Princeton Press, 1982) offers an in Their Relations with the Metabolism of TrvotoohaneS‘ r ~~~-~- depth view of the Bwiti religion among the Fang pea- 5~ and Dihydroxyphenylalanine; (Thesis for doctorate of pies of Gabon. Science, Paris, 1954) nd U.S. Pat. No. 2,813,873 (Nov., One of the first European references to the drugs was 19, 1957) Derivatives of the ibogaine alkaloids. made by Professor Baillon at the Mar. 6th, 1889 session The structure of ibogaine was also investigated by of the Linnaen Society in Paris during which he de- Dickel et al (J.A.C.S. 80~123,1958). The first total syn- scribed samples obtained by Griffon de Bellay from 60 thesis was cited by Buchi et al. (J.A.C.S. 87:2073, 1965) Gabon and the French Congo. and (Ibid. 8B. 3099, 1966). Early isolation and identification of ibogaine was In 1956 Salmoiraghi and Page elucidated ibogaine’s accomplished by Dybowski and Landrin (Compt. rend. relations to serotonin (J. Pharm. & expt. ther. ac. ao. 133:748, 1901); Haller and Heckel (ibid. 133:850); 120(1):20-25, 1957.9). About the same time J. A. Lambert and Heckel (ibid. 133:1236and Landrin (Bull. 6S Schneider published three important papers. The tirst, sc. pharm. 11:1905). Potentiation Action Of Ibogaine On Morphine Analge- Interest in the drugs seemed to lie fallow until re- sia was done in collaboration with Marie McArthur search was picked up by Raymond-Hamet and his asso- (Experiential 12:323-24, 1956).The second was Neuro- 3 4 pharmacological Studies Of lbogaine: An lndole Alka- description which sets forth preferred embodiments loid With Central Stimulant Properties (Schneider, J. thereof. A. & Sigg, E. B.. Ann. of NT acad. of sciences. A feature of the present invention is based on the 66:765-76, 1957) and third was An Analysis Of The discovery that alkaloids of the family Apocynaceae and Cardiovascular Action Of Ibogaine HCl (Schneider, J. 5 their therapeutically active derivatives and salts, partic- A. & Rinehard. R. K., Arch. int. pharmacodyn. ularly for example, ibogaine, ibogamine and tabeman- 110:92-102, 19S7). thine hydrochloride, tannate, tartrate and other non- Ibogaine’s stimulant properties were further investi- toxic salts of those alkaloids, possess the unexpected gated by Chen and Bohner in A Study Of Central Ner- unique ability to interrupt poly-drug dependency. vous System Stimulants (J. Pharm & expt ther. IO For the puqose of definition, the poly-drug depen- 123(3):212-215, 1958). Gershon and Lang published A dency and abuse syndrome consists of the pharmacol- Psychological Study Of Some Indole Alkaloids (Arch. ogy imposed by such use and all of the symptomology intern. pharmacodynamie, 135:31-56, 1962). demonstrated by a drug abuser concurrently addicted R. D. Bunag evaluated certain aspects of the relation- to, or using, alcohol, heroin, methadone, cocaine, caf- ship between ibogaine and Substance P (Bunag, R. D., 15 feine, amphetamine, desoxyephedrine or nicotine in one Walaszek, E. J., The Cardiovascular Effects Of Sub- or more combinations thereof. stance P In The Chicken, Ann. NY Acad. sci. A single treatment or series of treatments of ibogaine, 104(1):437-48, 1963). ibogamine, tabernanthine or their salts or derivatives in Claudia Naranjo reported on the effects of ibogaine doses ranging from 1 mgikg to 60 mg/kg, administered on human subjects in his paper, Psychotherapeutic Pas- 20 orally or rectally interrupted the use heroin, cocaine, sibilities Of New Fantasy-Enhancing Drugs (Clinical alcohol, nicotine, methadone, caffeine, amphetamines Toxicology 2(2):209-224, June 1969). or desoxyephedrine in various combinations for one to Dhahir. H. I. nublished a good review of the oharma- eighteen months or longer. cology aid toxiiology of ib&aine in his Doctoial The- In the administration of acceptable dosage forms, any sis, A Comparative Study Of The Toxicity Of lbogaine 25 of a variety of preparations may be compounded, for And Serotonin (University Microfilms International example: capsules, tablets, pills, powder, solutions, ini 71-25-341,Ann Arbor, Mich.). The paper iives an over- jections or suppositories, Ftc. In addition to the active view of much of the work accomplished with ibogaine. agent, there may be present additional substances used Additional studies of interest include: The Effects Of in the manufacture of pharmaceutical preparations such Some On Aggressiveness Of Mice And 30 as binders, fillers and other inerl ingredients. Rats (Kostowski et al., Pharmacology 7:259-63, 1972), The advantage of this invention is that it allows for Cerebral Pharmacokinetics Of -Producing Har- the raeid interruption of physical withdrawal symptoms mala And Iboga Alkaloids (Zetler et al., Pharmacology associated with poly-drug dependency as well as, re- 7(4):237-248, 1972), High Affinity 3H-Serotonin Bind- moving the patient’s craving to continue poly-drug USC. ing To Caudate: Inhibition By Hallucinogenic And 35 The patients status, after treatment, if craving is noI Serotonergic Drugs (Whitaker, P. & Seeman, P., Psy- totally interrupted, allows successful reversal or mod% chopharmacology 59:1-5, 1978), Selective Labeling Of cation of drug seeking behavior via various adjunct Serotonin Receptors by d-(3H) Lysergic Acid Diethyl- techniques in the majority of cases, as the underlying amide In Calf Caudate (Proc. natl. acad. sci., USA psycopathology is usually unmasked with the acute 75(12):5783-87, Dec. 1978) and A Common Mechanism 40 interruption of drug dependency by the primary admin- Of Lysergic Acid, Indolealkylamine And Phenethyl- istration. amine Hallucinogens: Serotonergic Mediation Of Be- The following examples are given by way of illustra- havioral Effects In Rats (Sloviter, R. et al., J. Pharm. & tion of the present and improved method of treating expt, ther. 214(2):231-38, 1980).The most current work polydrug abuse or dependency and are not intended to has been performed by Dzoljic, M. R.; Dzoljic E. D. 45 limit the scope of the present invention. The examples and Kaplan, C. D. (Effect of Ibogaine on Naloxone- are part of a study of nine subjects, seven of whom Precipitated Withdrawal Syndrome in Chronic Mor- where successfully treated. phine dependent Rats, Arch. Im. Pharmacodyn., 29464-70, 1988.) EXAMPLE 1 50 Subject, age 43, was treated for cocaine dependency. SUMMARY OF THE INVENTION Subject was additionally smoking two or more packs of II is the principal object of the present invention to filter cigarettes per day, Subject was administered a provide an improved method for the treatment of poly- single dose of 15 mg/kg of ibogaine. Subject suffered no drug dependency. nicotine withdrawal and has not smoked cigarettes or Another object of the present invention is to provide 55 used cocaine for more than 24 months, at which time an improved method for lessening the physiological and tracking ceased. psychological aspects of poly-drug deprivation and withdrawal in the addict/abuser. EXAMPLE 2 Still another object of the present invention is to Subject, age 34, female was treated for heroin depen- provide a method of the above nature characterized by UJ dency. The subject was smoking Ii grams of heroin per its high degree of success,the absenceof the great pain day for three months, had been addicted without inter- and discomfort accompanying earlier treatme.nts, the ruption for over a year and had a fourteen year history ease and convenience of application, the absence of of heroin use. Subject was concurrently smoking one undesirable or persistent side effects, the long term and a half packs of filter cigarettes per day. Acute inter- effectiveness of the treatment and its acceptance to the 65 ruption of heroin addictiorrwas successfully completed addict population. with the administration of 15 mg/kg of ibogaine. Ciga- The above and other objects of the present invention rette smoking continued, but diminished over a thirty will become apparent from a rea$ng of the following day period at which time the subject ceased to smoke 5 6 cigarettes and maintained this state for sixty days, at usedheroin an averageof twenty-five daysa month and which time tracking was discontinued. cocaine base twenty days a month. Lifetime history of heroin use was three years, Lifetime use of cocaine was EXAMPLE 3 Len years. Subject has reamined cocaine free for two Subject,male, age 22 wasa heroin/methadoneaddict 5 months.Subject was heroin free for onemonth andthen concurrently drinking alcohol on a daily basis.Subject beganusing heroin once or twice a week. Subjectcon- had been on methadone for nine years except for a one sidered his cocaine addiction and not his heroin addic- year stay in a correctional institution, Methadone use tion as a problem prior to treatment. had beenat a 65 mg/day level for twelve months.Life- While there have beendescribed preferred embodi- time heroin use had been for fifteen years with a current IO ments of the present invention, it is apparent that nu- level of 4 gram per day supplememingmethadone use. merous alterations, omissions and additions may be A single treatment with 15 mg/kg of ibogaine inter- madewithout departingfrom the spirit thereof. rupted heroin and methadone use. SubjecI did not go I claim: through physical narcotic withdrawal. This individual 1. The method of treating poly-drug dependency attemptedheroin useonce after his treatmentat which 15 comprising(one) administeringto (one) a subject de- time he statedhe no longer liked heroinand did not go pendent on at least two drugs selected from the group back to heroin use.Alcohol usewhich had consistedof consistingof heroin,cocaine, alcohol, caffeine, amphet- daily, continuousdrinking of beerand wine with a life- amine, desoxyephedrine, nicotine, methadone and opi- time history of alcohol abuseof twelve years was re- ate narcoticsa dosagecomprising ibogaine, ibogamine, ducedby iifty to one hundredpercent per day. Subject 20 tabernanthine or a therapeutically active physiologi- left country three weeks after treatment with no further cally acceptable compound of ibogaine, ibogamine, t&king possible. tabemanthine or a mixture thereofin an amountwithin the rangeof l-60 mg/kg weight of said subject. EXAMPLE 4 2. The method of claims 1 wherein said compound ia Subject, male, age 42 was addicted to alcohol, co- 25 a non-toxicsalt of ibogaine,ibogamine, tabernanthine or Caine and heroin. Use of alcohol consistedof drinking a base thereof. distilled spirits on a daily basis with a lifetime history of 3. The methodof claim 1 wherein said dosagecom- drinking for twenty years. Heroin use was at a level of prises ibogaine, ibogamine, tabemamhine or one or ninety dollars per day for the last thirty days with a more non-toxic salts of thereof or a mixture thereof. lifetime history of heroin useof ten years.Cocaine use 30 4. The methodof claim 3 wherein said dosagecom- was twenty-five out of the last thirty days al levels of prisesa memberof a group consistingof ibogaine,taber- thirty dollarsper day. Lifetime usefor cocainewas four nanthine and ibogamine on a form selected from the years,A singledose of ibogaine(15 mg/kg) completely group consisting of a free base,a hydrochloride, tar- interruptedheroin and cocaineuse and diminished alco- trate, tannate or hydrobromide salt. hol use by fifty to eighty percenton a daily basis.Sub- 3S 5. A methodof claim 3 or 4 whereina plurality of said ject has been heroin and cocaine. free for two months. dosages are ?dministered, the administration of succes- sive dosages being separated by a plurality of days or EXAMPLE 5 partsof days. Subject, male, age 26 was using thirty to sixty dollars 6. The method. .of claim- 3 or 4 wherein said. dosage. ” . is worth of heroin per day and smoking i ounce of co- 40 admirusteredorally or by suppo%toryor rectal mtuslon. Cainebase per day. A single treatment with ibogaine 7. The method of claim 5 wherein said dosageis HCI (20 mg/kg) interrupted heroin and cocaine use administered orally or by suppository or rectal infusion. completely with no physical withdrawl. Subject had * * l * *

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