Showing papers in "The Alkaloids: Chemistry and Biology in 2001"

Nitrogen-containing metabolites from marine cyanobacteria.

Abstract: Publisher Summary Marine cyanobacteria are extraordinarily prolific in their elaboration of complex and bioactive secondary metabolites. The principle biogenetic theme in the natural products chemistry of marine cyanobacteria is the integration of non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathways, in a variety of configurations, so as to produce this great structural diversity. An assortment of unusual “tailoring” enzymes is evident in cyanobacterial metabolites, as revealed by the variety of bromine and chlorine functional groups. Methylation is a prominent characteristic of most marine cyanobacterial metabolites. Cyanobacterial peptides possess an extremely high level of N -methylation, a characteristic that could possibly be advantageous in molecular genetic studies. In polyketide sections, a pronounced theme of pendant methyl groups is also evident. However, available experimental evidence suggests either a or C-2 of acetate origin for these methyl group additions. Many marine cyanobacterial metabolites possess potent biological properties.

Ibogaine: a review.

Abstract: Publisher Summary The chapter discusses ibogaine, which is a naturally occurring plant alkaloid with a history of use as a medicinal and ceremonial agent in West Central Africa and has been alleged to be effective in the treatment of drug abuse. The National Institute on Drug Abuse (NIDA) has given significant support to animal research, and the U.S. Food and Drug Administration (FDA) has approved Phase I studies in humans. The chapter discusses the first International Conference on Ibogaine. A major focus of the Conference was the possible mechanism(s) of action of ibogaine. Another important focus of the Conference was to discuss human experience with ibogaine and preclinical and clinical evidence of efficacy and safety. The Conference also featured presentations related to the sociological and anthropological aspects of the sacramental context of the use of iboga in Africa and the distinctive ibogaine subculture of the U.S and Europe. Ibogaine is the most abundant alkaloid in the root bark of the Apocynaceous shrub Tabernanthe iboga , which grows in West Central Africa. The chapter presents a timeline that outlines the historical events relating to the development of ibogaine as a treatment for drug dependence. Ibogaine and serotonin both contain an indole ring in their structure, and ibogaine has been shown to bind to the serotonin transporter and to increase serotonin levels in the nucleus accumbens (NAc). Stereotypy is a methodologic issue that might explain some of the disparate results regarding ibogaine's interaction with the locomotor response to cocaine.

Ibogaine in the treatment of heroin withdrawal.

Abstract: Publisher Summary The chapter presents a study on the role of ibogaine in the treatment of heroin withdrawal. Pharmacological treatments for heroin addiction currently employ two treatment strategies: detoxification followed by drug-free abstinence or maintenance treatment with an opioid agonist. Because agonist maintenance with methadone usually has the goal of eventual detoxification to a drug-free state, the use of medications to facilitate this transition is a clinically important treatment strategy. Anecdotal reports suggest that ibogaine has promise as an alternative medication approach for making this transition. Ibogaine has an added benefit to other detoxification strategies in that the treatment experience seems to bolster the patient's own motivational resources for change. Ibogaine is a drug with complex pharmacokinetics and an uncertain mechanism of action with regards to its alleged efficacy for the treatment of opiate dependence. Ibogaine is metabolized to noribogaine, which has a pharmacological profile that is different from that of the parent drug. The chapter presents that ibogaine is effective in blocking opiate withdrawal, providing an alternative approach for opiate-dependent patients who have failed other conventional treatments. Identifying noribogaine's mechanism of action may explain the way ibogaine promotes rapid detoxification from opiates after only a single dose. Ibogaine, like most central nervous system (CNS) drugs, is highly lipophilic and is subject to extensive biotransformation. The Opiate-Symptom Checklist (OP-SCL) was developed for the present study as a subtle assessment of withdrawal symptoms.

Simple indolizidine and quinolizidine alkaloids.

Abstract: This review of simple indolizidine and quinolizidine alkaloids (i.e., those in which the parent bicyclic systems are in general not embedded in polycyclic arrays) is an update of the previous coverage in Volume 55 of this series (2001). The present survey covers the literature from mid-1999 to the end of 2013; and in addition to aspects of the isolation, characterization, and biological activity of the alkaloids, much emphasis is placed on their total synthesis. A brief introduction to the topic is followed by an overview of relevant alkaloids from fungal and microbial sources, among them slaframine, cyclizidine, Steptomyces metabolites, and the pantocins. The important iminosugar alkaloids lentiginosine, steviamine, swainsonine, castanospermine, and related hydroxyindolizidines are dealt with in the subsequent section. The fourth and fifth sections cover metabolites from terrestrial plants. Pertinent plant alkaloids bearing alkyl, functionalized alkyl or alkenyl substituents include dendroprimine, anibamine, simple alkaloids belonging to the genera Prosopis, Elaeocarpus, Lycopodium, and Poranthera, and bicyclic alkaloids of the lupin family. Plant alkaloids bearing aryl or heteroaryl substituents include ipalbidine and analogs, secophenanthroindolizidine and secophenanthroquinolizidine alkaloids (among them septicine, julandine, and analogs), ficuseptine, lasubines, and other simple quinolizidines of the Lythraceae, the simple furyl-substituted Nuphar alkaloids, and a mixed quinolizidine-quinazoline alkaloid. The penultimate section of the review deals with the sizable group of simple indolizidine and quinolizidine alkaloids isolated from, or detected in, ants, mites, and terrestrial amphibians, and includes an overview of the "dietary hypothesis" for the origin of the amphibian metabolites. The final section surveys relevant alkaloids from marine sources, and includes clathryimines and analogs, stellettamides, the clavepictines and pictamine, and bis(quinolizidine) alkaloids.

Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener.

Abstract: Publisher Summary Ibogaine, an alkaloid extracted from Tabernanthe iboga (Apocynaceae), is being used in uncontrolled clinical trials as a long-acting treatment for opioid and stimulant abuse, alcoholism, and smoking. In this study, animal models have been used to study ibogaine's interactions with drugs of abuse, to investigate its mechanisms of action, and to help develop an ibogaine derivative that will have an improved safety profile. An outline illustrating the kinds of studies conducted is presented. The chapter describes the results of these studies with ibogaine and with 18-methoxycoronaridine (18-MC), a novel iboga alkaloid congener. The structures of ibogaine and 18-MC are presented. Ibogaine has an active metabolite, noribogaine, and both ibogaine and noribogaine appear to have multiple mechanisms of action in the nervous system. 18-MC also appears to have multiple targets. The acute intraperitoneal (i.p.) administration of either ibogaine or 18-MC, 15 minutes prior to testing, dose-dependently decreased the self-administration of morphine in rats. With respect to stimulant-induced locomotion, both ibogaine and 18-MC augmented the expression of locomotor behavior in response to cocaine and amphetamines. Plasma and tissue levels of both ibogaine and 18-MC have been determined using gas chromatography-mass spectrometry. Anecdotal reports in humans indicate that ibogaine can slow heart rate.

Chapter 5 Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine

Abstract: Publisher Summary The chapter discusses the comparative neurobiology of ibogaine and noribogaine in rodent species. The chapter focuses on data collected from the laboratories of the authors and attempts to integrate the findings with the available literature on iboga alkaloids. An example of a plant-derived compound with potential utility in treating drug addiction is the indole alkaloid, ibogaine. More recently, ibogaine has gained a reputation as an “addiction interrupter,” based on findings in animals and humans. In rats, acute administration of ibogaine (40 mg/kg, i.p.) produces long-lasting decreases in the self-administration of cocaine and morphine. Ibogaine also alleviates symptoms of opioid withdrawal in morphine-dependent rats and heroin-dependent human addicts. The chapter presents a figure that shows that ibogaine is rapidly metabolized to noribogaine in rats, and the maximal blood concentration of noribogaine exceeds that of ibogaine by more than two-fold. The chapter also summarizes the effects of gender and gonadectomy on blood levels of ibogaine and noribogaine after i.p. ibogaine injection. Ibogaine and noribogaine are equipotent in their ability to evoke a transient stimulation of dopamine (DA) metabolism that is characterized by profound depletion of tissue DA (∼50% reduction) in mesolimbic, mesocortical, and mesostriatal terminal projection areas.

Case studies of ibogaine treatment: implications for patient management strategies.

Abstract: Publisher Summary The chapter discusses the use of ibogaine in three different contexts: a drug user group, a self-help organization, and a clinical research setting. Each discussion is followed by the self-report of a subject who has taken ibogaine within the setting being reviewed. These settings contrast with the use of iboga in Gabon, Africa as a practice of the Bwiti, an African religion sometimes referred to as an initiation society, during which ibogaine-containing plants are provided in rites to assist in the transition from adolescence into adulthood, for psychiatric healing, or for other purposes. With regard to the future of ibogaine therapy, a look at methadone therapy may provide an understanding of what might go right and what might go wrong in the development of effective medications to treat chemical dependence. If a reduction in chemical dependence is to be accomplished, whether with ibogaine, its analogs, or other modalities, it will require that patients be better treated and better respected. The chapter concludes by stating that ibogaine therapy offers a unique opportunity both for the physician and the patient.

A contemporary history of ibogaine in the United States and Europe.

Abstract: Publisher Summary The chapter focuses on a contemporary history and description of the medical subculture of the informal treatment scenes of the United States and Europe, and the political subculture of ibogaine advocacy. In 1995, Dr. Curtis Wright, then the U.S. Food and Drug Administration (FDA) ibogaine project officer passed a statement that intimates a relationship of public opinion to regulatory scientific policy. The statement was made at a time when the FDA, partly in response to highly motivated and organized public advocacy, was modifying its drug development process to accommodate the more rapid evaluation and approval of agents used to treat the human immunodeficiency virus (HIV). As with treatments for HIV, ibogaine has been associated with a vocal activist subculture, which has viewed its mission as advocating the availability of a controversial treatment to a stigmatized and marginalized minority group of patients who suffer from a life-threatening illness. Wright's perception of significant public interest in ibogaine was derived from two related subcultural contexts. One such context is the medical subculture of the informal ibogaine treatment scene, and the other is the political subculture of advocacy for the development and availability of ibogaine. The period of time spanned by the history presented in this chapter extends from the early 1960s to the present, and it is thus termed a “contemporary” history of ibogaine. Ibogaine has a long history of use as a ritual hallucinogen in Africa. However, the early 1960s marked the advent of the attempt to develop ibogaine as a treatment for substance dependence in the United States and Europe.

"Returning to the path": the use of iboga[ine] in an equatorial African ritual context and the binding of time, space, and social relationships.

Abstract: Publisher Summary The chapter presents a study on the re-examination of the late 1950s ethnographic work among iboga(ine) users in Equatorial Africa in light of Western societies' current questions regarding the craving for, addiction to, withdrawal from, and relapse back into the hard drugs. The possibility of the addiction interruption obtained by this alkaloid for harder drugs in the West relates to its use in Africa as transitional to the rediscovery of a fully consecrated and dedicated existence. Initiates and members of Bwiti, the religious movement that regularly used iboga(ine) to obtain its ritual effects, were what is now called “consonant addicts,” if one can talk about iboga addiction at all. They ingested the alkaloid willingly and without noticeable regret or remorse, and almost exclusively as a ritually circumscribed routine. They regarded iboga(ine) as a sacred substance capable of both prolonging and enhancing their weekly religious experience and confirming and consecrating them in a revitalized relation to their ancestors and to their descendants. This consonance causes to reflect on the words “addiction,” “craving,” “withdrawal,” or “relapse” so central to the “drug wars” of the West, and prompts to reexamine the ritual context and social consequences of iboga(ine)'s use in Bwiti. In this autochthonous context, the words hardly have equivalent meanings to those of the West, for iboga is there regarded as crucial to the management of space and time and generational relationships. It effects a time and space binding of social experience in the broadest sense.

The ajmaline group of indole alkaloids.

Abstract: Publisher Summary This chapter discusses an area of indole alkaloids, which has been neglected in the series for over 30 years—namely, the ajmaline group of alkaloids, where numerous advances in chemistry and biosynthesis have been made recently. The number of known ajmaline structures has grown markedly in recent years to a present count of 77. Some of these might be artefacts and a few structures have not been convincingly determined. In addition, seven bisindole alkaloids containing at least one monomeric ajmalan unit have been isolated, increasing the total number to 84. Ajmaline alkaloids contain the polycyclic ajmalan ring system. The “biogenetic numbering” of Le Men and Taylor is used throughout the chapter. The priority sequence for the C-17 substituents in the Cahn–Ingold–Prelog system is different in the absence and presence of the COOCH, substituent at C-16. All of the ajmaline alkaloids found thus far occur in the plant family Apocynaceae. They have been recognized in the following genera Alstonia , Aspidospenna , Cabucala , Melodinus , Rauvolfia , Tonduzia (Alstonia), and Vinca .

Sigma receptors and iboga alkaloids.

Abstract: Publisher Summary Current evidence indicates that ibogaine and other iboga alkaloids might produce some of their neurotoxic effects by interaction with sigma-2 receptors Sigma receptors are membrane proteins that bind several psychotropic drugs with high affinity Two major subclasses of sigma receptors have been identified These have been termed “sigma-1” and “sigma-2,” and they are differentiated by their pharmacological profile, function, and molecular size Both subtypes have high to moderate affinity for typical neuroleptics, with haloperidol exhibiting the highest affinity for both sites The sigma-1 receptor has been cloned in guinea pig, mouse, rat, and human, and shown to be a novel protein with > 90% species homology Some of the functions attributed to sigma-1 receptors include the following: (1) modulation of synthesis and release of dopamine and acetylcholine, (2) modulation of NMDA-type glutamatergic receptor electrophysiology, (3) modulation of NMDA-stimulated neurotransmitter release, (4) modulation of muscarinic receptor-stimulated phosphoinositide turnover, (5) neuroprotective and antiamnesic activity, (6) modulation of opioid analgesia, and (7) alteration of cocaine-induced locomotor activity and toxicity The ability of sigma ligands to induce morphological changes and apoptosis led to an investigation of the signaling mechanisms that are utilized by sigma-2 receptors

Ellipticine, uleine, apparicine, and related alkaloids.

Abstract: Publisher Summary This chapter reviews the indole alkaloids that have, in common, the absence of the two-carbon side-chain of the biosynthetic precursor tryptophan—that is, the two carbons (C-5 and C-6) that normally link the indole β-position (C-7) to the non-aromatic nitrogen, though in some, a one-carbon residue remains. This chapter discusses the chemistry of the alkaloids (ellipticine, uleine, and apparicine) and their synthesis. To emphasize the common biosynthetic origins of the alkaloids, biogenetic numbering is used in the chapter. Ellipticine continues to be a strong candidate to win the competition for alkaloid most often synthesized by the most different routes. Recent syntheses of pyridocarbazoles have thrown ingenious routes to ellipticine, congeners, and non-natural analogs, into the competition. The chapter presents the studies aimed at the natural bases.

The isoxazole alkaloids

Abstract: Publisher Summary Natural products based on the isoxazole (1,2-oxazole) skeleton constitute a small, heterogeneous group of natural products encompassing at present more than 90 structures. This group has not traditionally been classified as a special alkaloid group and has never been reviewed as a group previously. The reason may well be that in contrast to many other alkaloid groups the discovery of the isoxazole alkaloids is of comparative recent date. For example, in a review of isoxazole chemistry from 1963 only one naturally occurring compound was known—namely, cycloserine. Otherwise, in the review literature these alkaloids are scattered under other compilations such as miscellaneous alkaloids, marine natural products, or alkaloids from mushrooms. Even though the number is small, some isoxazole alkaloids are well-known compounds, such as the commercial antibiotic, cycloserine, originally isolated from several Streptomyces species and the mushroom toxin muscimol from the fly agaric Amanita muscaria . Apart from bacteria and mushrooms, members of this group have been described from higher plants, a few from larvae, and the vast majority has been isolated from marine sponges. The structures of the isoxazoles from bacteria and fungi are all exceedingly simple, while the compounds from plants and sponges are of a more complex nature.

Ibogaine as a glutamate antagonist: relevance to its putative antiaddictive properties.

Abstract: Publisher Summary The chapter presents a discussion on ibogaine as a glutamate antagonist. The chapter presents an overview data demonstrating that pharmacologically relevant concentrations of ibogaine produce a blockade of N methyl-D-aspartate (NMDA) receptors and relates the relevance of these findings to its antiaddictive properties. If the neurochemical and electrophysiological studies with ibogaine are pharmacologically meaningful, then like other NMDA antagonists, ibogaine should protect against NMDA receptor-mediated neurotoxicity. The chapter presents in vitro data that provide compelling evidence on ibogaine acting as an NMDA antagonist. Glycine is a coagonist at NMDA receptors. Because of the presence of specific transporters that appear colocalized with NMDA receptors, it is unlikely that these strychnine-insensitive glycine sites are saturated under physiological conditions. Like other NMDA antagonists, memantine (a lowaffinity, uncompetitive NMDA antagonist) blocks the expression of morphine withdrawal in mice.

Characterization of multiple sites of action of ibogaine

Abstract: Publisher Summary The chapter presents a study on the characterization of multiple sites of action of ibogaine. This chapter describes findings that indicate support for the use of ibogaine, its metabolite, and/or ibogaine-related compounds in the treatment of addiction, based on their ability to target relevant multiple neurotransmitter sites appropriate for the drug of abuse examined. Because of the multiple components of reward systems, a “dirty” drug like ibogaine that affects multiple neurotransmitter systems should not be excluded from consideration. Indeed, it is a likely positive attribute. Based on radioligand binding and other in vivo/in vitro studies, and several behavioral assays, to characterize its effects, ibogaine has been reported to have affinities to at least the dopamine and serotonin transporters, and to the glutamatergic (NMDA), sigma, kappa- and mu-opioid, and nicotinic acetylcholine receptors. Cocaine also binds and inhibits the uptake of serotonin and norepinephrine, with equal potency. “Knockout” models of rodents missing dopamine reuptake transport still self-administer cocaine. Psychostimulants act predominantly to elevate brain dopamine, either by their ability to release dopamine, as is the case for amphetamine, or by blockade of the reuptake transporter, as in the case of cocaine.

Ibogaine neurotoxicity assessment: electrophysiological, neurochemical, and neurohistological methods.

Abstract: Publisher Summary The chapter presents an assessment of neurotoxicity of ibogaine through electrophysiological, neurochemical, and neurohistological methods. Ibogaine is also reportedly effective in the blockade of morphine self-administration and decreasing the signs of opiate withdrawal. A complex ibogaine interaction with other neurotransmitter receptor sites is suggested to have modulatory effects on the dopamine system. The chemical structure of ibogaine is similar to serotonin (5-HT) and melatonin. Several in vitro and in vivo studies indicated that the serotonergic system plays a role in ibogaine actions. Electroencephalography (EEG) is a technique applied in the assessment of spontaneous electrocerebral activity using either scalp (surface) electrodes, or in the case of the electrocorticogram (ECoG), from electrodes implanted in specific brain regions. Electrophysiological studies suggest that ibogaine stimulates monoaminergic neurons and may lower the threshold for cocaine induced electrographic seizures. Neuropathological studies reveal that ibogaine administered at high doses produces selective neuronal degeneration. It is concluded that ibogaine might have potential utility for the treatment of drug addiction, but may also be neurotoxic at high doses.

Chapter 12 Anxiogenic action of ibogaine

Abstract: Publisher Summary The chapter presents a discussion on the anxiogenic action of ibogaine. The neurochemical actions of ibogaine and related alkaloids were intensively investigated during the past decade, which has witnessed increasing growth of information attempting to explain the “antiaddictive” effects of ibogaine. Operant and classical conditioning, habituation, and sensitization play important roles in determining the level of drug tolerance, addiction, dependence, and craving. Thus, inhibitory effects of ibogaine on drug addiction could be linked to a general interference with learning and memory processes. In humans, ibogaine has been reported to produce anxiety, fear, and apprehension. Anxiogenic effect of ibogaine may confound several measures of drug-seeking and taking behavior in animal models of drug addiction. The chapter presents a study to determine if the same effects on anxiety could be identified in mice following the administration of lower doses of ibogaine given after a shorter time interval. The elevated plus maze offers a reliable means of investigating anxiety in rodents. Ibogaine and picrotoxin reduced the percentage of open/total time as well as percentage of open/total arm entries, indicating that these compounds increased the anxiety.

Modulation of the effects of rewarding drugs by ibogaine.

Abstract: Publisher Summary The chapter discusses some of the evidences that ibogaine modulates drug effects in animals. Results of research with ibogaine indicate that the alkaloid may modulate the rewarding properties of drugs and interfere with withdrawal reactions in animals. Ibogaine has been reported to modulate the development of morphine tolerance in rats. There are two commonly used methods for evaluating drug reward in animals” drug self-administration and place preference conditioning. In drug self-administration, an animal must make some response, such as a lever press, which is followed by a presentation of the drug reward. The place-conditioning paradigm is an alternative measure of drug reward. With this procedure, during a training period, rats are confined to one distinctive compartment following injection of a drug and an alternative compartment following injection of an inert substance. Advocates for ibogaine—as an antiaddictive medication—argue that ibogaine modulates a variety of addictive disorders, not only opiate addiction. Animal evidence reported above also indicates that ibogaine modulates the rewarding properties of stimulants when evaluated in the self-administration paradigm or in the place preference paradigm.

From the roots up: ibogaine and addict self-help.

Abstract: Publisher Summary The chapter offers information on the formation of International Addict Self-Help (INTASH), the introduction of ibogaine in the addict self-help scene in Holland, and the contribution of the addict self-help movement to the development of ibogaine treatment. The chapter also describes the INTASH intake, treatment, and aftercare procedures and the importance of addict self-help involvement in future developments with the clinical use of ibogaine. Ibogaine was introduced to the addict community in 1990 by Howard Lots of and Bob Sisko from the International Coalition for Addict Self Help (ICASH). The late Nico Adriaans, Josien Harms, and others formed an informal organization, Dutch Addict Self Help (DASH), which today is called “INTASH,” to treat addicts with ibogaine. INTASH performed four initial treatments with ibogaine on opiate-dependent poly-drug users, some of whom had been in methadone maintenance programs for many years. The successful results of these treatments were impressive. The goal of the self-help organization was to provide treatment with ibogaine in a nonjudgmental and trusting environment. A clinical argument can be made that ibogaine is safer and more effective than ultra-rapid detoxification with naltrexone or naloxoneIbogaine already is available in the currently existing international black market where it is being bought and sold in the streets and used without the proper medical screening and attention that is needed, which can lead to possibly hazardous situations.

Chapter 4 Drug discrimination studies with ibogaine

Abstract: The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT 2A , 5-HT 2C , and σ 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, σ 1 , PCP/MK-801, 5-HT 3 , and 5-HT 1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with σ 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested ( 34 ), would support a role for 5-HT 2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized when it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoro-naridine ( 35 ). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxy-coronaridine?

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Changes in gene expression and signal transduction following ibogaine treatment.

Abstract: Publisher Summary The chapter presents a study on the changes in gene expression and signal transduction following ibogaine treatment. Drug addiction may not be mediated by one neurochemical pathway and brain structure, but by a complex interaction of programs of gene expression with specific signal transduction pathways and environmental factors. The putative antiaddictive effect of ibogaine may result from the restoration of altered or disrupted programs of central and peripheral neuroadaptative processes involving programmed genes and their associated signaling mechanisms. One new hypothesis being explored is that both the peripheral and central actions of abused substances contribute to drug addiction. One new hypothesis being explored is that both the peripheral and central actions of abused substances contribute to drug addiction. Treatment with cocaine influences the regulation of certain genes in the brain, as indicated by the activation and inhibition of the expression sequence tags (ESTs) that have been isolated. The cAMP-responsive element binding protein (CREB), the first CRE-binding factor to be characterized ( 5 ), is a transcription factor of general importance in both neuronal and other cells. CREB phosphorylation on Ser-133 promotes the activation of genes with an upstream CRE element. If anxiety or stress is a factor in drug dependency, then the anti-addictive property of ibogaine in vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety.