Unconventional Psychiatric Treatments

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Ibogaine

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Ibogaine is a naturally-occurring psychoactive compound found in a number of plants in nature, principally in a member of the dogbane family known as iboga (Tabernanthe iboga). Ibogaine-containing preparations are used in medicinal and ritual purposes by African spiritual traditions of the Bwiti who claim to have learned it from the Pygmy. In recent times it has been identified as having anti-addictive properties. Ibogaine is an indole alkaloid which is obtained either by extraction from the iboga plant or by semi-synthesis from the precursor compound voacangine, another plant alkaloid. A full organic synthesis of ibogaine has been achieved, but is too expensive and challenging to produce any commercially significant yield.

In the early 1960s, ibogaine was accidentally discovered to cause sudden and complete interruption of heroin addiction without withdrawal in a matter of hours. Since that time it has been the subject of scientific investigation into its abilities to interrupt addictions to heroin, alcohol, and cocaine. Anecdotal reports also suggest that ibogaine may have potential to drive introspection that helps elucidate the psychological issues and behavior patterns that drive addiction or other problems. However, ibogaine therapy for drug addiction is the subject of some controversy. Due to its hallucinogenic properties as well as risks for patients with certain health problems, it has been placed in the strictest drug prohibition schedules in the United States and a handful of other countries.
While ibogaine's prohibition has slowed scientific research into ibogaine's anti-addictive properties, the use of ibogaine for drug treatment has grown in the form of a large worldwide medical subculture.[1] Ibogaine is now used by treatment clinics in 12 countries on 6 continents to treat addictions to heroin, alcohol, powder cocaine, crack cocaine, and methamphetamine as well as to facilitate psychological introspection and spiritual exploration.

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[edit] Psychoactive effects
At doses of around 3-5 mg/kg of body weight, ibogaine has a mild stimulant effect. The high-dose ibogaine experience of 10 mg/kg or greater, often called the "flood", most commonly occurs as two distinct phases: the visionary phase, and introspective phase.
The visual phase is characterized by open-eye visuals, closed-eye visuals, and dreamlike sequences. Objects may be seen as distorted, projecting tracers, or having moving colors or textures. With the eyes closed, extremely detailed and vivid geometric and fractal visions may be seen. Subjective reports often include a movie-like recollection of earlier life experiences as well as dreamlike sequences with symbolism of one's present or anticipated future. Other effects in the visionary phase may include laughing, sensations of euphoria or fear, and temporary short-term memory impairment. The visionary phase usually ends after 1-4 hours, after which the introspective phase begins.
The introspective phase is typically reported to bring elevated mood, a sense of calm and euphoria, and a distinct intellectual and emotional clarity. Subjects often report being able to accomplish deep emotional and intellectual introspection into psychological and emotional concerns. It is also during this period that opioid addicts first notice the absence of withdrawal cravings. The duration of the introspective phase is highly variable, usually lasting hours but sometimes lasting days.


[edit] Side effects and safety
One of the first noticeable effects of large-dose ibogaine ingestion is ataxia, a difficulty in coordinating muscle motion which makes standing and walking virtually impossible without assistance. Xerostomia (dry mouth), nausea, and vomiting may follow. These symptoms are long in duration, ranging from 4 to 24 hours in some cases. Ibogaine is sometimes administered by enema to help the subject avoid vomiting up the dose. Psychiatric medications are strongly contraindicated in ibogaine therapy due to adverse interactions. Some studies also suggest the possibility of adverse interaction with heart conditions. In one study of canine subjects, ibogaine was observed to increase sinus arrhythmia (the normal change in heart rate during respiration).[2] Ventricular ectopy has been observed in a minority of patients during ibogaine therapy.[3] It has been proposed that there is a theoretical risk of QT-interval prolongation following ibogaine administration.[4]

There are 12 documented fatalities that have been loosely associated with ibogaine ingestion.[5] Exact determinations of the cause of death have proven elusive due to the quasi-legal status of ibogaine and the unfamiliarity of medical professionals with this relatively rare substance. No autopsy to date has implicated ibogaine as the sole cause of death. Causes given range from significant pre-existing medical problems to the surreptitious consumption of other drugs in conjunction with ibogaine. Most legal and illegal psychoactive drugs are strongly contraindicated during or immediately after ibogaine treatment, which presents a risk in undersupervised or self-treating subjects.

[edit] Therapeutic uses

[edit] Addiction Interruption

The most studied long-term therapeutic effect is that ibogaine seems to catalyze partial or complete interruption of addiction to opioids. An integral effect is the alleviation of symptoms of opioid withdrawal. Research also suggests that ibogaine may be useful in treating dependence to other substances such as alcohol, methamphetamine, and nicotine, and may affect compulsive behavioral patterns not involving substance abuse or chemical dependence.
Proponents of ibogaine treatment for drug addiction have established formal and informal clinics or self-help groups in Canada, Mexico, the Caribbean, Costa Rica, the Czech Republic, France, Slovenia, the Netherlands, Brazil, South Africa, the United Kingdom and New Zealand where ibogaine is administered as an experimental drug. Although the full nature of Ibogaine is still emerging, it appears that the most effective treatment paradigm involves visionary doses of ibogaine of 10 to 20 mg/kg, producing an interruption of opiate withdrawal and craving. Many users of ibogaine report experiencing visual phenomena during a waking dream state, such as instructive replays of life events that led to their addiction, while others report therapeutic shamanic visions that help them conquer the fears and negative emotions that might drive their addiction. It is proposed that intensive counseling and therapy during the interruption period following treatment is of significant value. Some patients require a second or third treatment session with ibogaine over the course of the next 12 to 18 months as it will provide a greater efficacy in extinguishing the opiate addiction or other drug dependence syndrome. A minority of patients relapse completely into opiate addiction within days or weeks. A comprehensive article (Lotsof 1995) on the subject of ibogaine therapy, detailing the procedure, effects and aftereffects is found in, "Ibogaine in the Treatment of Chemical Dependence Disorders: Clinical Perspectives".[6]


[edit] Chronic pain management
In 1957, Jurg Schneider, a pharmacologist at CIBA, found that ibogaine potentiates morphine analgesia.[7] Further research was abandoned and no additional data was ever published by Ciba researchers on ibogaine/opioid interactions. Almost 50 years later Patrick Kroupa and Hattie Wells released the first treatment protocol for concomitant administration of ibogaine with opioids in human subjects indicating ibogaine reduced tolerance to opioid drugs.[8] Kroupa, et al., published their research in the Multidisciplinary Association for Psychedelic Studies (MAPS) Journal demonstrating that administration of low "maintenance" doses of ibogaine HCl with opioids decreases tolerance.


[edit] Psychotherapy
Ibogaine has been used as an adjunct to psychotherapy by Claudio Naranjo, documented in his book The Healing Journey.[9]


[edit] Recreational use
Casual use of ibogaine in a social or entertainment context is nearly unknown due to its high cost, constrained availability, long duration of effects, and uncomfortable short-term side effects. In the clandestine markets, ibogaine is typically sought as a drug addiction treatment, for ritual spiritual purposes, or psychological introspection.

[edit] History
It is uncertain exactly how long iboga has been used in African spiritual practice, but its activity was first observed by French and Belgian explorers in the 19th century. The first botanical description of the T. iboga plant was made in 1889. Ibogaine was first isolated from Tabernanthe iboga in 1901 by Dybowski and Landrin[10] and independently by Haller and Heckel in the same year using T. iboga samples from Gabon. In the 1930's, ibogaine was sold in France in 8mg tablets under the name "Lambarene". The total synthesis of ibogaine was accomplished by G. Büchi in 1966.[11] Since then, several further totally synthetic routes have been developed.[12] The use of ibogaine in treating substance use disorders in human subjects first observed by Howard Lotsof in 1962, for which he was later awarded U.S. Patent 4,499,096  in 1985. In 1969, Claudio Naranjo was granted a French patent for the use of ibogaine in psychotherapy.

Ibogaine was placed in US Schedule 1 in 1967 as part of the US government's strong response to the upswing in popularity of psychedelic substances, though iboga itself was scarcely known at the time. Ibogaine's ability to attenuate opioid withdrawal confirmed in the rat was first published by Dzoljic et al. (1988).[13] Ibogaine's use in diminishing morphine self-administration in preclinical studies was shown by Glick et al. (1991)[14] and ibogaine's capacity to reduce cocaine self-administration in the rat was shown by Cappendijk et al. (1993).[15] Animal model support for ibogaine claims to treat alcohol dependence were established by Rezvani (1995).[16]

The name "indra extract" in strict terms refers to 44kg of an iboga extract manufactured by an unnamed European industrial manufacturer in 1981. This stock was later purchased by Carl Waltenburg, who distributed it under the name "Indra extract". Waltenburg used this extract to treat heroin addicts in Christiana, Denmark, a squatter village where heroin addiction was widespread in 1982.[17] Indra extract was offered for sale over the internet until 2006, when the Indra web presence disappeared. It is unclear whether the extracts currently sold as "Indra extract" are actually from Waltenburg's original stock, or whether any of that stock is even viable or in existence. Ibogaine and related indole compounds are susceptible to oxidation when exposed to oxygen[18] as opposed to their salt form which is stable. The exact methods and quality of the original Indra extraction was never documented, so the real composition of the product remains uncertain.

Data demonstrating ibogaine's efficacy in attenuating opioid withdrawal in drug dependent human subjects was published by Alper et al. (1999)[19] and Mash et al. (2000).[20]

[edit] Formulations

Pure crystalline ibogaine hydrochloride is the most standardized formulation dosing and typically must be produced by the semi-synthesis from voacangine in commercial laboratories. In Bwiti religious ceremonies, the rootbark is pulverized and swallowed in large amounts to produce intense psychoactive effects. In Africa, iboga rootbark is sometimes chewed, which releases small amounts of ibogaine to produce a stimulant effect. Ibogaine is also available in a total alkaloid extract of the Tabernanthe iboga plant, which also contains all the other iboga alkaloids and thus has only about 1/5th the potency by weight as standardized ibogaine hydrochloride.[21]
Total alkaloid extracts of T. iboga are often loosely called "Indra extract". However, that name actually refers to a particular stock of total alkaloid extract produced in Europe in 1981. The fate of that original stock (as well as its original quality) is unknown.

[edit] Pharmacology

The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously.[22][23] Because of its fairly low potency at any of its target sites, ibogaine is used in doses anywhere from 5 milligrams per kilogram of body weight for minor effect to 30 mg/kg in the cases of strong polysubstance addiction. It is unknown whether doses greater than 30mg/kg in humans produce effects that are therapeutically beneficial, medically risky, or simply prolonged in duration.

[edit] Mechanism and Pharmacodynamics
Among recent proposals for ibogaine mechanisms of action is activation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) of the brain. The work has principally been accomplished in preclinical ethanol research where 40 mg/kg of ibogaine caused increases of RNA expression of GDNF in keeping with reduction of ethanol intake in the rat, absent neurotoxicity or cell death.[24]

Ibogaine is a noncompetitive antagonist at ?3?4 nicotinic receptors, binding with moderate affinity.[25] Several other ?3?4 antagonists are known, and some of these such as bupropion (Wellbutrin or Zyban), and mecamylamine have been used for treating nicotine addiction. This ?3?4-antagonism correlates quite well with the observed effect of interrupting addiction. Co-administration of ibogaine with other ?3?4-antagonists such as 18-MC, dextromethorphan or mecamylamine had a stronger anti-addictive effect than when it was administered alone.[26] Since ?3?4 channels and NMDA channels are related to each other and their binding sites within the lumen bind a range of same ligands (e.g. DXM, PCP),[27] some "older" sources suggested that ibogaine's anti-addictive properties may be (partly) due to it being an NMDA receptor antagonist.[28] However, ligands, like 18-MC, selective for ?3?4- vs. NMDA-channels showed no drop-off in activity.

It is suspected that ibogaine's actions on the opioid and glutamatergic systems are also involved in its anti-addictive effects. Persons treated with ibogaine report a cessation of opioid withdrawal signs generally within an hour of administration.
Ibogaine is a weak 5HT2A receptor agonist[29] and although it is unclear how significant this action is for the anti-addictive effects of ibogaine, it is likely to be important for the hallucinogenic effects.[30] Ibogaine is also a sigma2 receptor agonist.[31]


[edit] Metabolites
Ibogaine is metabolized in the human body by cytochrome P450 2D6, and the major metabolite is noribogaine (12-hydroxyibogamine). Noribogaine is most potent as a serotonin reuptake inhibitor and acts as moderate ?- and weak µ-opioid receptor full agonist and has therefore also an aspect of an opiate replacement similar to compounds like methadone. Both ibogaine and noribogaine have a plasma half-life of around 2 hours in the rat [6], although the half-life or noribogaine is slightly longer than the parent compound. It is proposed that ibogaine is deposited in fat and metabolized into noribogaine as it is released.[32] Noribogaine shows higher plasma levels than ibogaine and may therefore be detected for longer periods of time than ibogaine. Noribogaine is also more potent than ibogaine in rat drug discrimination assays when tested for the subjective effects of ibogaine.[33] Noribogaine differs from ibogaine in that it contains a hydroxy instead of a methoxy group at the 12 position.


[edit] Analogs
A synthetic derivative of ibogaine, 18-methoxycoronaridine (18-MC) is a selective ?3?4 antagonist that was developed collaboratively by the neurologist Stanley D. Glick (Albany) and the chemist Martin E. Kuehne (Vermont).[34]

[edit] Research

An ibogaine research project was funded by the US National Institute on Drug Abuse in the early 1990s. The National Institute on Drug Abuse (NIDA) abandoned efforts to continue this project into clinical studies in 1995, citing other reports that suggested a risk of brain damage with extremely high doses and fatal heart arrhythmia in patients having a history of health problems, as well as inadequate funding for ibogaine development within their budget. However, NIDA funding for ibogaine research continues in indirect grants often cited in peer reviewed ibogaine publications.
In addition, after years of work and a number of significant changes to the original protocol, on August 17, 2006, a MAPS-sponsored research team received "unconditional approval" from a Canadian Institutional Review Board (IRB) to proceed with a long-term observational case study that will examine changes in substance use in 20 consecutive people seeking ibogaine-based addiction treatment for opiate dependence at the Iboga Therapy House in Vancouver.

[edit] Legal status
Ibogaine and its salts were regulated by the U.S. Food and Drug Administration in 1967 pursuant to its enhanced authority to regulate stimulants, depressants, and hallucinogens granted by the 1965 Drug Abuse Control Amendments (DACA) to the Federal Food, Drug, and Cosmetic Act. In 1970, with the passage of the Controlled Substances Act, it was classified as a Schedule I controlled substance in the United States, along with other psychedelics such as LSD and mescaline. Since that time, several other countries, including Sweden, Denmark, Belgium, and Switzerland, have also banned the sale and possession of ibogaine.

In early 2006, a non-profit foundation addressing the issue of providing ibogaine for the purpose of addiction interruption within establishment drug treatment care was formed in Sweden.[35]

[edit] See also


[edit] References

  1. ^ K.R. Alper, H.S. Lotsof, C.D. Kaplan (2008). "The Ibogaine Medical Subculture". J. Ethnopharmacology 115: 9-24. Retrieved on 2008-02-22. 
  2. ^ [1]
  3. ^ [2]
  4. ^ [3]
  5. ^ [4]
  6. ^ H.S. Lotsof (1995). Ibogaine in the Treatment of Chemical Dependence Disorders: Clinical Perspectives (Originally published in MAPS Bulletin (1995) V(3):19-26)
  7. ^ Jurg Schneider (assignee: Ciba Pharmaceuticals), Tabernanthine, Ibogaine Containing Analgesic Compositions. US Patent No. 2,817,623 (1957) (pdf)
  8. ^ Patrick K. Kroupa, Hattie Wells (2005): Ibogaine in the 21st Century. Multidisciplinary Association for Psychedelic Studies. Volume XV, Number 1: 21-25 (pdf)
  9. ^ C. Naranjo. The Healing Journey. Chapter V, Ibogaine: Fantasy and Reality, 197-231, Pantheon Books, Div. Random House,ISBN 0394488261, New York (1973)
  10. ^ J. Dybowski, E. Landrin (1901). "PLANT CHEMISTRY. Concerning Iboga, its excitement-producing properties, its composition, and the new alkaloid it contains, ibogaine". C. R. Acad. Sci. 133: 748. Retrieved on 2006-06-23. 
  11. ^ G. Büchi, D.L. Coffen, Karoly Kocsis, P.E. Sonnet, and Frederick E. Ziegler (1966). "The Total Synthesis of Iboga Alkaloids" (pdf). J. Am. Chem. Soc. 88 (13): 3099-3109. Retrieved on 2006-06-23. 
  12. ^ C. Frauenfelder (1999) Doctoral Thesis, page 24 (pdf)
  13. ^ E.D. Dzoljic et al. (1988): "Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats" Arch. Int. Pharmacodyn. Ther. 294, 64-70
  14. ^ Glick S.D., Rossman K., Steindorf S., Maisonneuve I.M., and Carlson J.N. (1991). "Effects and aftereffects of ibogaine on morphine self-administration in rats". Eur. J. Pharmacol 195 (3): 341-345. Retrieved on 2006-06-24. 
  15. ^ Cappendijk SLT, Dzoljic MR (1993). "Inhibitory effects of ibogaine on cocaine self-administration in rats". European Journal of Pharmacology 241: 261-265. Retrieved on 2006-06-25. 
  16. ^ Rezvani, A., Overstreet D., and Lee, Y. (1995). "Attenuation of alcohol intake by ibogaine in three strains of alcohol preferring rats.". Pharmacology, Biochemistry, and Behaviour 52: 615-620. Retrieved on 2006-06-25. 
  17. ^ A Contemporary History of Ibogaine in the United States and Europe
  18. ^ a)Taylor WI (1965): "The Iboga and Voacanga Alkaloids" (Journal?), Pages 203, 207 and 208. Oxidation products: peroxides; indolenine, iboquine and iboluteine. pdf b) Also compare PMID 16959135
  19. ^ Alper et al. (1999) "Treatment of acute opioid withdrawal with ibogaine." Am J Addict. 1999 Summer;8(3):234-42 (pdf)
  20. ^ D.C. Mash, et al. (2000). Ibogaine: Complex Pharmacokinetics, Concerns for Safety, and Preliminary Efficacy Measures (pdf). Neurobiological Mechanisms of Drugs of Abuse Volume 914 of the Annals of the New York Academy of Sciences, September 2000.
  21. ^ Jenks CW (2002)
  22. ^ P. Popik, P. Skolnick (1998). Pharmacology of Ibogaine and Ibogaine-Related Alkaloids. The Alkaloids 52, Chapter 3, 197-231, Academic Press, Editor: G.A. Cordell
  23. ^ K.R. Alper (2001). Ibogaine: A Review. The Alkaloids 56, 1-38, Academic Press (pdf)
  24. ^ He, Dao-Yao et al. (2005): "Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption." Journal of Neuroscience, 25(3), pp. 619–628. Fulltext
  25. ^ Glick SD, Maisonneuve IM, Kitchen BA, Fleck MW. Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. European Journal of Pharmacology. 2002 Mar 1;438(1-2):99-105.
  26. ^ Glick SD, Maisonneuve IM, Kitchen BA. Modulation of nicotine self-administration in rats by combination therapy with agents blocking alpha 3 beta 4 nicotinic receptors. European Journal of Pharmacology. 2002 Jul 19;448(2-3):185-91.
  27. ^ Fryer JD, Lukas RJ. Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. Journal of Pharmacology and Experimental Therapeutics. 1999 Jan;288(1):88-92.
  28. ^ Popik P, Layer RT, Skolnick P (1994): "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex." Psychopharmacology (Berl), 114(4), 672-4. Abstract
  29. ^ Glick SD et al. (1999): "(±)-18-Methoxycoronaridine: A Novel Iboga Alkaloid Congener Having Potential Anti-Addictive Efficacy." CNS Drug Reviews, Vol. 5, No. 1, pp. 27-42, see p. 35. Fulltext
  30. ^ Helsley S, Fiorella D, Rabin RA, Winter JC. Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus. Pharmacology, Biochemistry and Behaviour. 1998 Feb;59(2):419-25.
  31. ^ Mach RH, Smith CR, Childers SR (1995): "Ibogaine possesses a selective affinity for sigma 2 receptors." Life Sciences, 57(4), PL57-62. Abstract
  32. ^ Lindsay B. Hough, Sandra M. Pearl and Stanley D. Glick. Tissue Distribution of Ibogaine After Intraperitoneal and Subscutaneous Administration. Life Sciences 58(7) (1996): 119–122. Abstract
  33. ^ C Zubaran MD, M Shoaib Ph.D, IP Stolerman Ph.D, J Pablo MS and DC Mash Ph.D. Noribogaine Generalization to the Ibogaine Stimulus: Correlation with Noribogaine Concentration in Rat Brain. Neuropsychopharmacology (1999) 21 119-126.10.1038/sj.npp.1395327. [5]
  34. ^ Christopher J. Pace, Stanley D. Glick, Isabelle M. Maisonneuve, Li-Wen Heb, Patrick A. Jokiel, Martin E. Kuehne, Mark W. Fleck. Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. European Journal of Pharmacology 492 (2004): 159–167.
  35. ^ Stiftelsen Iboga´s web site


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[edit] Further reading

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AL-LADDBTDETDiPT5-MeO-?-MTDMT2,?-DMT?,N-DMTDPTEiPT?-ETETH-LADHarmalineHarmine4-HO-DBT4-HO-DET4-HO-DiPT4-HO-DMT5-HO-DMT4-HO-DPT4-HO-MET4-HO-MiPT4-HO-MPT4-HO-pyr-TIbogaineLSDMBT4,5-MDO-DiPT5,6-MDO-DiPT4,5-MDO-DMT5,6-MDO-DMT5,6-MDO-MiPT2-Me-DET2-Me-DMTMelatonin5-MeO-DET5-MeO-DiPT5-MeO-DMT4-MeO-MiPT5-MeO-MiPT5,6-MeO-MiPT5-MeO-NMT5-MeO-pyr-T6-MeO-THH5-MeO-TMT5-MeS-DMTMiPT?-MTNETNMTPRO-LADpyr-TTryptamineTetrahydroharmine?,N,O-TMS

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References

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Determination of ibogaine and noribogaine in biological fluids and hair by LC-MS/MS after Tabernanthe iboga abuse Iboga alkaloi

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Forensic Sci Int. 2008 Mar 21;176(1):58-66. Epub 2007 Nov 19.
Chèze M, Lenoan A, Deveaux M, Pépin G.

Laboratoire TOXLAB, 7 rue Jacques Cartier, F-75018 Paris, France.

Tabernanthe iboga belongs to the Apocynaceae family. In this study, we report the case of a 37-year-old black male working as a security agent in Paris and found dead naked on the beach in Gabon after consumption of iboga. Autopsy revealed a drowning fatality and a myocardial abnormality (myocardial bridging). Samples of blood, urine, bile, gastric content, liver, lungs, vitreous, spleen and hair were taken. Biological fluids were liquid-liquid extracted with saturated NH4Cl pH 9.5 and methylene chloride/isopropanol (95/5, v/v) in presence of clonazepam-d(4), used as internal standard. After decontamination with dichloromethane, hair was cut into small pieces then sonicated for 2h in saturated NH4Cl pH 9.5 before extraction by methylene chloride/isopropanol (95/5, v/v). After evaporation the residues were reconstituted in methanol/ACN/formate buffer pH 3, from which 10 microL were injected into an ODB Uptisphere C(18) column (150 mm x 2.1mm, 5 microm) and eluted with a gradient of acetonitrile and formate buffer delivered at a flow rate of 200 microL/min. A Quantum Ultra triple-quadrupole mass spectrometer was used for analyses. Ionization was achieved using electrospray in the positive ionization mode (ESI). For each compound, detection was related to three daughter ions (ibogaine: m/z 311.4-->122.1, 174.1 and 188.1; noribogaine: m/z 297.4-->122.1, 159.1 and 160.1; clonazepam-d(4): m/z 319.9-->218.1, 245.1 and 274.1). Ibogaine and noribogaine were detected in all autopsy samples. Hair segmentation was not possible as hair was very short and frizzy. Concentrations of 1.2 and 2.5 ng/mg, respectively were detected. Neither other licit or illicit drugs nor alcohol were found. The presence of ibogaine and noribogaine in all autopsy samples was consistent with the recent absorption of Tabernanthe iboga, which was assumed to be responsible of the drowning fatality. The history of exposure, regarding hair analysis, is discussed. LC-MS/MS appears to be the best method for analyzing complex and poorly volatile alkaloids in autopsy samples and particularly in hair, due to the presence of a nitrogen ring and the relatively low concentrations to be measured.

The ibogaine medical subculture.

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Alper KR, Lotsof HS, Kaplan CD
J Ethnopharmacol. 2008 Jan 4;115(1):9-24. Epub 2007 Aug 25.

Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.

AIM OF THE STUDY: Ibogaine is a naturally occurring psychoactive indole alkaloid that is used to treat substance-related disorders in a global medical subculture, and is of interest as an ethnopharmacological prototype for experimental investigation and possible rational pharmaceutical development. The subculture is also significant for risks due to the lack of clinical and pharmaceutical standards. This study describes the ibogaine medical subculture and presents quantitative data regarding treatment and the purpose for which individuals have taken ibogaine. MATERIALS AND METHODS: All identified ibogaine "scenes" (defined as a provider in an associated setting) apart from the Bwiti religion in Africa were studied with intensive interviewing, review of the grey literature including the Internet, and the systematic collection of quantitative data. RESULTS: Analysis of ethnographic data yielded a typology of ibogaine scenes, "medical model", "lay provider/treatment guide", "activist/self-help", and "religious/spiritual". An estimated 3414 individuals had taken ibogaine as of February 2006, a fourfold increase relative to 5 years earlier, with 68% of the total having taken it for the treatment of a substance-related disorder, and 53% specifically for opioid withdrawal. CONCLUSIONS: Opioid withdrawal is the most common reason for which individuals took ibogaine. The focus on opioid withdrawal in the ibogaine subculture distinguishes ibogaine from other agents commonly termed "psychedelics", and is consistent with experimental research and case series evidence indicating a significant pharmacologically mediated effect of ibogaine in opioid withdraw

Ketamine in the treatment of Depression

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http://en.wikipedia.org/wiki/Ketamine

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was the treatment of the patient's pain. It was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS. Based on this result, it was thought that a low-dose (subanesthetic) infusion of ketamine was worth a trial in patients who were suffering from treatment-resistant depression without other physical or psychiatric illness.

Correll, et al gave ketamine intravenously to patients commencing at 15–20 mg/h (0.1–0.2 mg/kg/h) and the dose increased until a maximum tolerated dose was achieved. This dose was assumed to be a therapeutic dose and was maintained for 5 days. Patients were able to eat, drink, watch television, or read. They could feel inebriated and/or unsteady when walking. If hallucinations occurred, the dose was to be reduced. The patients' normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients were described with impressive[weasel words] improvement in depression being maintained for 12 months in patient A and recurrence at 2.5 months and 9 months in patient B.[24]

The National Institute of Health News reports that a study of 18 patients has found that ketamine significantly improved treatment-resistant major depression within hours of injection.[25] The improvement lasted up to one week after the single dose.[26] The patients in the study were previously treatment resistant, having tried an average of six other treatments that failed. NIMH director Dr. Thomas Insel said in the paper:

"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist.[27] Those findings of Zarate et al corroborate earlier findings by Berman et al.[28] However Zarate et al do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

The findings by Zarate et al. are confirmed by Liebrenz et al, who substantially[weasel words] helped a 55-year-old male subject with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.[29]<[30]

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.[31]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[32] Ketamine was well tolerated and prolonged seizure duration overall, but particularly in those who had a seizure duration shorter than 25 seconds with methohexital at the maximum available stimulus intensity. Ketamine also increased midictal EEG slow-wave amplitude. Thus, a switch to ketamine may be useful when it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[33] They studied 70 patients with major depression and 25 patients as the control (Group C). The depressed patients were divided randomly into two groups; patients in Group A, initial HAMD 12,7 (n = 35) were induced with propofol, fentanyl, and ketamine and patients in Group B, initial HAMD 12,3 (n = 35) were induced with propofol and fentanyl. Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in Group A as compared with Group B. The group receiving ketamine also had significantly lower postoperative pain.

Acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. The increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action.[34]

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A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

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Arch Gen Psychiatry. 2006 Aug;63(8):856-64.Click here to read Links A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD 20892, USA. zaratec@mail.nih.gov CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health.Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in th

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1: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Aug 8; Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J. Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil. Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor. Clinical findings point to a rapid onset of action for ketamine on the treatment of major depression. Considering that classic antidepressants may take long-lasting time to exhibit their main therapeutic effects, the present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of ketamine and imipramine in rats. To this aim, rats were acutely treated with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavioral was assessed in the forced swimming and open-field tests. Afterwards, BDNF protein hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA-sandwich assay. We observed that ketamine at the doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time compared to saline group, without affecting locomotor activity. Interesting enough, acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. In conclusion, our findings suggest that the increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action.

Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of the AMPA receptor.

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Biol Psychiatry. 2007 Jul 20; [Epub ahead of print]Click here to read Links Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of alpha-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17643398&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services, Bethesda, Maryland. BACKGROUND: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. METHODS: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. CONCLUSIONS: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.

Intravenous ketamine therapy in a patient with a treatment-resistant major depression.

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Swiss Med Wkly. 2007 Apr 21;137(15-16):234-6.
Intravenous ketamine therapy in a patient with a treatment-resistant major depression.
Liebrenz M, Borgeat A, Leisinger R, Stohler R.

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Psychiatric University Hospital, Research Group on Substance Use Disorders, Zurich, Switzerland.

BACKGROUND: Recently, reports from North America have indicated that the intravenous infusion of ketamine hydrochloride (an N-methyl-d-aspartate receptor antagonist) results in a sudden and robust improvement of depression symptoms.

OBJECTIVE: To corroborate antidepressant effectiveness of IV ketamine in a patient with a co-occurring substance use disorder for the first time in a European clinical setting.

DESIGN: Open label trial Methods: A 55-year-old male subject with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence received an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes. Effects were assessed by means of a clinical interview, the 21-item Hamilton Depression Rating scale (HDRS), and the 21-item Beck Depression Inventory (BDI) at baseline, 1 hour, 1 day, 2 days, and 7 days after intervention.

RESULTS: Following the administration of ketamine the subject experienced a significant improvement of his symptoms peaking on the 2nd day post infusion (HDRS from 36 to 16; -56.6%, BDI from 26 to 9; -65.4%). The subject first reported improvements 25 min. into the infusion and continued to describe positive effects throughout the subsequent 7 days. CONCLUSION: Ketamine not only seems to have strong antidepressant effects but also to act very swiftly. These actions were unaffected by an alcohol or benzodiazpine dependence.

Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression.

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Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression. World J Biol Psychiatry. 2007 Jul 10;:1-4 Liebrenz M, Stohler R, Borgeat A. Research Group on Substance Use Disorders, Psychiatric University Hospital, Zurich, Switzerland. Background: The intravenous administration of ketamine, an N-methyl-d-aspartate receptor antagonist, results in a great improvement of depression symptoms, but it is not clear for how long. This single-case trial was conducted to explore the duration of improvement and the effects of a second administration on the clinical outcome. Methods: In an open label trial, a 55-year-old male patient with treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence received two intravenous infusions of 0.5 mg/kg ketamine over the course of 6 weeks. Depression severity was assessed by means of a weekly clinical interview, the 21-item Hamilton Depression Rating Scale (HDRS), and the 21-item Beck Depression Inventory (BDI). Results: The first ketamine infusion lead to a pronounced improvement of symptoms, peaking on the second day post infusion (HDRS -56.6%, BDI -65.4%). Positive effects started fading by day 7, reaching baseline by day 35. The second infusion was less efficacious: HDRS and BDI were reduced by 43 and 35%, respectively, and returned to baseline by day 7. Conclusion: In this patient with a co-occurring substance use disorder, repeated administrations of ketamine produced positive results. Since the second application has been less efficacious, doses and schedule of administrations need to be further investigated.