The Ibogaine Dossier
NYU Conference on Ibogaine Nov 5-6, 1999
T. iboga roots
Ibogaine is extracted from
the bark of the root
Pharmacology of Ibogaine and Ibogaine-Related Alkaloids
Piotr Popik, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
and Phil Skolnick, Neuroscience Discovery, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA
Appeared as Chapter #3, in "THE ALKALOIDS", Vol.52, pp. 197-231. 1998, San Diego, USA. ISBN 0-12-469552-3. Edited by G.A. Cordell.
© 1998 by Academic Press
Order The Alkaloids, Vol. 52
Ibogaine (12-methoxyibogamine, NIH 10567, Endabuse)
is one of the psychoactive indole alkaloids found in the West African shrub,
iboga. For over a century, both extracts of T. Iboga
constituent alkaloids, including ibogaine, have been used as medicinals
(1). What makes this alkaloid of particular interest to contemporary
pharmacology are anecdotal observations indicating that ibogaine possesses
"anti-addictive" properties. Thus, ibogaine (6-25 mg/kg, in humans) has
been claimed to attenuate both dependence and withdrawal symptoms to a
variety of abused drugs including opiates, alcohol, nicotine and psychostimulants
(2-9). Preclinical studies demonstrating that ibogaine reduces self-administration
of both cocaine and morphine, and attenuates the symptoms of morphine-withdrawal,
are consistent with these claims [reviewed in (Popik and Glick (10)].
This chapter reviews the pharmacological properties of ibogaine and related
alkaloids. Since our last comprehensive review (11), more than one
hundred new reports on the pharmacological actions of ibogaine and ibogaine-like
alkaloids have appeared. The chemistry of ibogaine has been reviewed by
Taylor in this series (12,13).
Ibogaine is derived from Tabernanthe iboga,
a shrub indigenous to Central-West Africa. The iboga shrub, a member of
the family Apocynaceae (order Contortae), is typically found in the undergrowth
of tropical forests (14). The roots of Tabernanthe iboga
were used in tribal initiation rites (15,16). Although the details
of such ceremonies vary, it was believed that iboga root enabled initiates
to make contact with ancestors in the spirit world. Ibogaine has also been
found in Tabernanthe crassa (17). Nineteenth century reports
from French and Belgian explorers first described the stimulant and aphrodisiac
effects of eating iboga root (1,16). The first botanical description
of the plant, was made by Baillon in 1889 (18).
Dybovsky and Landrin (19), as well as Haller
and Heckel (20), were the first to isolate a crystalline alkaloid
from iboga root, which they called "ibogaine" or "ibogine". In 1901 French
pharmacologists found ibogaine to have an unusual type of excitatory effect
in animals (21-23). Phisalix (23) suggested that ibogaine
could produce hallucinations based on observations of unusual behavior
in dogs. The alkaloid was subsequently tested in Western clinical settings,
and was recommended as a stimulant for the treatment of convalescence and
neurasthenia (24). Despite such recommendations, ibogaine never
enjoyed wide clinical use and was neglected by researchers for almost 30
years. In the 1940's Raymond-Hamet and coworkers published a series of
papers describing the pharmacological properties of ibogaine on isolated
tissues and the cardiovascular system (25-32).
Lambarene, an extract of
the roots of the iboga relative Tabernanthe manii, was sold in France
during the 1930's. It contained about 8 mg of ibogaine, and was described
as a stimulant. Iperton, another ibogaine extract, was also used as a tonic
or stimulant (33). Ibogaine has been used by athletes as a performance
enhancing drug (34). In many countries, including the United States,
ibogaine use is prohibited, perhaps because of its purported hallucinogenic
effects (widely publicized in the late 1960's) and its appearance on the
illicit drug market. In 1970, the United States Food and Drug Administration
classified ibogaine as a Schedule I substance (all non-research use forbidden).
Beginning in 1985, a series of patents was issued
for the use of ibogaine as a rapid means of interrupting addiction to narcotics
(morphine and heroin) (3), cocaine and amphetamine (4), alcohol (5), nicotine
(6) and poly-drug dependency syndrome (35). These patents claim
that an oral or rectal dose of ibogaine (4-25 mg/kg) interrupts the dependence
syndrome, allowing patients to maintain a drug-free lifestyle for at least
Based on open clinical studies, it has been claimed
(36) that ibogaine therapy resulted in 25% of patients remaining
drug-free without craving for 6 months. This group included those who were
both highly motivated to quit and had relatively stable home environments.
Another 40-50% of patients had their addictions interrupted successfully,
and required psychotherapy. Twenty to 30% of patients had returned to drug
use within a month following treatment. Somewhat lower success rates (10-15%)
are cited by Touchette (37).
In the absence of appropriately controlled clinical
studies, the efficacy of ibogaine as an anti-addictive agent cannot be
rigorously assessed at the present time. Nonetheless, interest in ibogaine
as a treatment for addiction has increased. In 1985 NDA International,
Inc. (Staten Island, NY, USA) began a campaign to persuade the U.S. government
to initiate controlled clinical trials with ibogaine (38). At the
same time, the use of ibogaine for treating opioid dependence has increased
in Europe (39). At present, clinical trials to evaluate the safety
of ibogaine are underway at the University of Miami and are planned in
New York. Clinical trials to test the anti-addictive efficacy of ibogaine
are underway in The Netherlands and Panama (38,40-44). According
to Ali et al., (45), the U.S. Food and Drug Administration
and the National Institute for Drug Abuse has approved the use of ibogaine
on a limited basis to treat cocaine addiction.
CHEMICAL STRUCTURE AND PROPERTIES.
Although ibogaine was first isolated and identified
in 1901, (19-21,46), the structure of this and related alkaloids
(Fig. 1) were first established by Taylor in 1957 (47) [see also
Taylor (12,13)]. Total synthesis from nicotinamide was reported
using a 13- (48) or 14-step (49) sequence. The 13C
NMR spectra of several iboga alkaloids were published in 1976 (50).
The synthesis of tritiated ibogaine was recently reported (51,52).
Ibogaine (mol. wt. 310.44) has a melting point of
153° at 0.01 mm Hg and a pKa of 8.1 in 80% methylcellosolve.
The absorption maxima in methanol are 226 (log e
4.39) and 296 (log e 3.93) nm. Ibogaine crystallizes
from alcoholic solutions into small, reddish prismatic needles; it is levorotatory
[a ]D -53° (in 95% ethanol) and is
soluble in ethanol, methanol, chloroform and acetone, but insoluble in
water. Ibogaine hydrochloride (freezing point 299°C, [a
]D -63° (ethanol), [a ]D
-49° (H2O)) is soluble in water, ethanol and methanol, is slightly
soluble in acetone and chloroform, and is practically insoluble in ether
(53). Ibogaine is heat- and light-sensitive (54) and can
spontaneously oxidize in solution, giving iboluteine and ibochine (16,34).
Alkaloids structurally related to ibogaine include tabernanthine, ibogamine,
iboxigaine, gabonine, iboquine, kisantine and ibolutenine. Structural similarities
between ibogaine and other indole alkaloid hallucinogens have also been
reported (55). The synthesis of several ibogaine derivatives has
recently been published by Repke and coworkers (56).
After parenteral administration, ibogaine has been
identified in various biological materials, including blood and urine (humans)
and in the liver, kidney and brain of laboratory animals (54,57-59).
One hour after intraperitoneal administration, high concentrations of ibogaine
were present in rat liver and kidneys (60). After intravenous injection
of 10 mg/kg to mice, maximal brain concentrations (48 µg/g of wet weight
[~133 µM]) were achieved in 10 sec (61).
Recently, Gallagher et al., (62) have
developed a highly sensitive and specific method to quantify ibogaine in
plasma and tissues. This method uses organic extraction, derivatization
with trifluroacetic anhydride, and detection by gas chromatography-mass
spectrometry (GC/MS). Similar methods were developed by Hearn et al.,
et al., (64) and Ley et al.,
(65). Using a GC/MS method, Pearl and colleagues (66) reported
that 1, 5 and 19 hours after intraperitoneal administration of 40 mg/kg
of ibogaine, the whole brain levels of ibogaine were 10, 1 and 0.7 µM in
female rats and 6, 0.9 and 0.2 µM in male rats, respectively. Hough et
al., (67) studied the tissue distribution of ibogaine after
i.p. and s.c. administration in rats. One hour after i.p. dosing (40 mg/kg),
drug levels ranged from 106 ng/ml (~ 0.3 µM)
in plasma to 11,308 ng/g (~ 36 µM) in fat,
with significantly higher values after s.c. administration of the same
dose. Drug levels were 10-20 fold lower 12 hours later. These data indicate
that ibogaine is subject to a significant "first pass" effect after i.p.
dosing, and that there is a marked propensity for ibogaine to be deposited
in adipose tissue, reflecting its lipophilicity. Consistent with its lipophilicity,
ibogaine levels in adipose tissue were very high for at least 12 hours
after administration. Based on these data, it was suggested that a single
dose of ibogaine may provide a long-acting, depot-like time course of action
The reported long-term effects of ibogaine (e.g.
(68-70)), have led to the hypothesis that this alkaloid may be metabolized
to an active principle with a long half life (71). At present, there
is no direct evidence to support this hypothesis. Ibogaine was reported
to disappear from the rat at a rate of ~4% of the administered dose per
hour with ~ 5% of the injected dose eliminated unchanged in urine. Elimination
kinetics from brain yielded a half-life of 60 min in rodents (60,61)
and suggest a one-compartment model. After administration of ibogaine (10
mg/kg, p.o.) to rabbits, urine concentrations reached a maximum 4-5 hours
later, then decreased rapidly and disappeared after 6 hours (54,60).
Taken together, these data suggest that ibogaine is extensively metabolized.
Inspection of ibogaine's structure (Fig. 1) led us to hypothesize that
a likely degradation pathway is O-demethylation at C12. Based on
this hypothesis, O-desmethylibogaine (also known as noribogaine
or 12-hydroxyibogamine), was synthesized by Dr. C. Bertha at the National
Institutes of Health in 1994. At the same time, O-tert-butyl-O-desmethylibogaine
was synthesized in an attempt to make an ibogaine derivative resistant
to O-demethylation (Fig. 1). Thus, the first compound was synthesized
to investigate the potential pharmacological actions of a likely ibogaine
metabolite. The second compound permitted examination of the pharmacological
effects of an ibogaine derivative that would not be degraded by O-demethylation.
The synthesis of these compounds was described by Layer et al.,
Recent studies have indeed demonstrated that ibogaine
is metabolized, and that O-desmethylibogaine can be detected in
human plasma (73) as well as in the plasma and brains of ibogaine-treated
rats (66). Behavioral and neurochemical studies in rodents have
established that O-desmethylibogaine is pharmacologically active
Following an i.p. dose of ibogaine (40 mg/kg), Pearl
al., (66) reported brain O-desmethylibogaine concentrations
of 20, 10 and 0.8 µM in female rats and 13, 7 and 0.1 µM in male rats,
respectively, at 1, 5, and 19 hours after administration. These data suggest
that gender differences in pharmacological responses to ibogaine may be
attributed to pharmacokinetic, rather than pharmacodynamic, factors. While
a report of one human subject (73) indicated that O-desmethylibogaine
persisted in plasma at high levels for at least 24 hours after oral ibogaine
administration, it is not clear if this pattern will be representative.
There is evidence indicating that the various pharmacological
effects of ibogaine may be attributable, at least in part, to its metabolite(s).
For example, the tremorigenic effects of ibogaine dissipate much more rapidly
than its ability to attenuate the morphine withdrawal syndrome in rats
(74). This finding suggests that an active principle(s) responsible
for one action may be more rapidly metabolized than compound(s) involved
in other actions. Alternatively, the various pharmacological effects of
ibogaine may involve different neurotransmitter pathways (discussed later).
GENERAL PHARMACOLOGICAL ACTIONS.
Ibogaine produces complex effects on locomotor activity
in rodents. A dose of 20 mg/kg (i.p.) slightly increased locomotor activity
in mice (75) while Sershen et al., (76) reported that
40 mg/kg (i.p.) decreased locomotor activity in male mice at 1, but not
24, hours after injection. The same dose inhibited locomotion in female
rats during the first hour after injection, whereas one week later locomotor
activity was increased (69).
Recently, Pearl and colleagues (66) noted
gender differences in the effects of ibogaine on locomotor activity (40
mg/kg, i.p., 5 or 19 hours before test). In control males and females the
locomotor activity decreased during the second hour of observation. Ibogaine
treatment in females prevented this decrease in locomotor activity. In
females, but not males, ibogaine decreased locomotor activity when given
19 hours before the test (66). Another study revealed that in male
rats, a single dose of 40 mg/kg inhibited locomotor activity 4 hours after
injection; a dose of 80 mg/kg decreased motor activity 24 hours after injection
Rats injected with doses of 20-60 mg/kg of ibogaine
displayed slower response times on sensory and sensory-motor tests and
were also impaired in performing specific motor reflexes at doses of 40-60
mg/kg. Furthermore, these rats exhibited a marked reduction in locomotor
activity as well as in emotionality at doses ranging from 10- 40 mg/kg.
At higher doses (40 mg/kg), rats appeared
virtually inactive (78). In other studies, at doses above 25 mg/kg,
ibogaine produced ataxia, splayed hind limbs, outstretched forelimbs, Straub
tail and hyperexcitability (79).
One hour after O-desmethylibogaine or 18-methoxy-coronaridine
injection (40 mg/kg), locomotor activity was increased during the second
hour of observation (66,80). In our studies, high doses (120 mg/kg)
of O-desmethylibogaine and O-t-butyl-O-desmethylibogaine
produced profound ataxia and convulsions (72). Ibogaine, O-desmethylibogaine,
and O-t-butyl-O-desmethylibogaine, (80 mg/kg) did
not significantly influence rotorod performance in mice (72).
Effects on locomotor activity induced by other drugs
Ibogaine has been found to affect the motor stimulant
properties of amphetamine, cocaine, and morphine in rodents (hyperlocomotion
induced by these drugs is believed to reflect their "psychotomimetic" qualities
in man). Although the results of these studies are not uniform, in general,
it has been found that in female rats this alkaloid potentiates
the locomotor response to amphetamine and cocaine, whereas opposite effects
were reported in male rats and mice.
Sershen et al., (81) found that ibogaine
(40 mg/ kg i.p., 2 or 18 hours before amphetamine) enhanced amphetamine
(1 mg/kg) - induced hypermotility in female rats. In other studies, an
amphetamine-induced increase in locomotor activity was potentiated in female
rats pretreated with ibogaine (40 mg/kg, i.p.) 19 hours earlier (82).
Cocaine-induced hypermotility in female rats was also potentiated by ibogaine
(83,84). Broderick et al., (85,86) reported that ibogaine
(20-40 mg/kg, i.p.) administration to male rats for four days reduced cocaine
(20 mg/kg) - induced hypermotility. Ibogaine (40 mg/kg, i.p.) administration
also reduced cocaine- (25 mg/kg, s.c.) induced hypermotility in male mice
(76), a finding in agreement with the amphetamine (1 mg/kg) - ibogaine
interaction (81) in this gender and species. Recent data demonstrate
that the effects of ibogaine on cocaine (20 mg/kg) -induced hyperactivity
in female rats are time dependent. Thus, given 1 h before cocaine, ibogaine
and O-desmethylibogaine (40 mg/kg) inhibited cocaine-induced hyperactivity,
but when given 19 h before cocaine they produced the opposite effect (80).
Ibogaine pretreatment (40 mg/kg, i.p. 19 hours before
measurement) decreased or blocked the locomotor stimulation induced by
morphine (0.5-20 mg/kg) in rats (69,71). Ibogaine administered one
week (but not one month) before morphine (5 mg/kg) reduced the motor stimulant
effects of this opiate (69). Pearl et al., (87) found
that ibogaine (5-60 mg/kg) is more potent in inhibiting morphine-induced
hyperlocomotion in rats pretreated with morphine for several (1-4) days
compared to non-pretreated rats. Doses of ibogaine (5-10 mg/kg) that alone
were inactive in drug-naive animals attenuated morphine-induced hyperactivity
in the morphine pretreated rats. The inhibitory effects of ibogaine on
morphine-induced hyperlocomotion appear gender related, because ibogaine
is more potent in female rats (66). Ibogaine-induced inhibition
of morphine - induced hyperlocomotion can be reversed by coadministration
of a kappa antagonist (norbinaltorphine, 10 mg/kg) and an NMDA agonist
(NMDA, 20 mg/kg). However, neither norbinaltorphine nor NMDA alone blocked
this action of ibogaine (88).
O-Desmethylibogaine (10-40 mg/kg) also inhibited
morphine-induced hyperlocomotion in female rats. However in male rats,
the dose of 10 mg/kg potentiated and 40 mg/kg inhibited morphine-induced
Like the somewhat structurally related alkaloid
harmaline, ibogaine produces tremors. In mice, ibogaine is tremorigenic
both when given intracerebrally (ED50 127 nmol/g brain, ~ 46
g/g with a latency to tremor of about 1 minute) (90), and systemically
(ED50 12 mg/kg, s.c.) (61). In rats, ibogaine produced
fine tremors, flattening of body posture, and flaccid hind limbs up to
2 hours after administration of 40 mg/kg (i.p.) (91). Low-amplitude
whole body tremors appearing within 10 min after administration of as little
as 10 mg/kg of ibogaine have also been reported (92). O'Hearn et
al., (93) reported that a high dose of ibogaine (100 mg/kg)
produced ataxia and high-frequency tremor of the head and trunk in rats.
Ibogaine-induced tremor preferentially involves the head and upper extremity
in rats and mice (94). Ibogaine (20 mg/kg) - induced tremors in
mice were blocked more potently by CCK-8 and ceruletide compared to other
reference compounds, including prolyl-leucylglycine amide (MIF), atropine,
haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam
Zetler et al., (61) established the
tremorigenic structure-activity relationship of several ibogaine-like compounds
in descending order of potency: tabernanthine > ibogaline > ibogaine >
iboxygaine > O-desmethylibogaine. Glick et al., (96)
found that at behaviorally effective doses (2-80 mg/kg) ibogaine, desethylcoronaridine,
harmaline and tabernanthine produced tremors for at least 2-3 hours. Both
the R and S enantioners of ibogamine and coronaridine were
devoid of this action. The ibogaine-like alkaloids, 18-methoxycoronaridine
and O-desmethylibogaine were also found to lack tremorigenic effects
The tremorigenic properties of ibogaine and related
compounds have been attributed to an action on GABAergic pathways (98-100)
and to the blockade of voltage-dependent sodium channels.
Anxiety and fear.
Schneider and Sigg (101) described the behavioral
effects of ibogaine in cats. The authors concluded that after intravenous
administration of 2-10 mg/kg, ibogaine produced fear-like reactions that
persisted for 10-20 minutes with a normal appearance observed 1-2 hours
after injection. The electroencephalographic pattern obtained after ibogaine
administration (2-5 mg/kg) showed a typical arousal syndrome, resembling
that observed after direct stimulation of the reticular formation. This
arousal syndrome was inhibited by atropine (2 mg/kg) (101). Gershon
and Lang (102) described the effects of ibogaine in dogs, which
become more tense and alert, interpreted as the appearance of anxiety.
Moreover, they observed that the dogs exhibited a lack of recognition of
both their regular handlers and environment.
Recently, Benwell et al., (103) reported
reductions in open arm entries in the elevated plus-maze test when rats
were tested 22 hours after pretreatment with ibogaine (40 mg/kg, i.p.).
In mice, ibogaine (2.5 mg/kg) exhibited anxiogenic actions, whereas a dose
of 1 mg/kg had anxiolytic effects (104). These are perhaps the most
compelling preclinical data that ibogaine may influence anxiety levels
because anxiolytic agents (e.g. benzodiazepines) increase open arm entries
in this test.
Effects on self-administration of other drugs.
Ibogaine (40 mg/kg, i.p.) inhibits the self-administration
of cocaine in rodents. Cappendijk and Dzoljic (105) trained male
Wistar rats to intravenously self-administer cocaine; a single dose of
ibogaine (40 mg/kg) decreased cocaine intake by 40-60% for several days,
and repeated treatment with ibogaine at one-week intervals decreased cocaine
self-administration by 60-80%. This decrease was maintained for several
weeks. Similar effects were found in mice that developed a preference for
cocaine in the drinking water. Thus, ibogaine administration (two weeks
after the beginning of a choice period, 2 doses of 40 mg/kg, 6 hours apart)
diminished cocaine preference for five days (70). According to Vocci and
London (106), some investigators have failed to replicate ibogaine's
effect on cocaine self-administration in the rat (107) and rhesus
monkey (108). Also Dworkin et al., (109) reported
that neither 40 mg/kg of ibogaine given 60 min prior to the session, nor
80 mg/kg given 24 hour before the session, suppressed responding maintained
by intravenous cocaine infusions. In this study, cocaine self-administration
was inhibited by pretreatment with ibogaine (80 mg/kg) either 60 or 90
min prior to the session (109). However, because this dose of ibogaine
reduced scheduled food intake, these latter effects of ibogaine on cocaine
self-administration appear to be unspecific.
Glick et al., (96) demonstrated that
ibogaine and several
iboga alkaloids (tabernanthine, R- and
and S- ibogamine, desethylcoronaridine, and harmaline) reduced cocaine
self-administration in rats in a dose-related fashion (2.5-80 mg/kg). For
some alkaloids, these effects were seen the day after injection.
(40 mg/kg) (89) and 18-methoxycoronaridine (97) were also
reported to inhibit cocaine self-administration.
Ibogaine dose dependently (2.5-40 mg/kg) reduced
intravenous morphine self-administration in female Sprague-Dawley rats
immediately after injection as well as on the next day (68). In
some animals, a reduced morphine intake was observed for several days;
other rats required several doses of ibogaine to achieve a prolonged reduction.
Similar effects were demonstrated for other ibogaine-like alkaloids including
(89), tabernanthine, R- and S-coronaridine,
and S- ibogamine, desethylcoronaridine, harmaline (96) and
18-methoxycoronaridine (97). However, data from another study revealed
somewhat different results. Thus, Dworkin et al., (109) found
that ibogaine (40 or 80 mg/kg) diminished heroin self-administration in
male Fisher rats only on the day it was administered. Moreover, the same
study revealed that ibogaine treatment resulted in a 97% decrease in responding
for a food reinforcement schedule, suggesting that its effects on heroin
self-administration were unspecific.
Ibogaine-induced inhibition of morphine self-administration
has been found to be reversed by sequential administration of a kappa antagonist
(norbinaltorphine, 10 mg/kg) and an NMDA agonist (NMDA, 20 mg/kg). Neither
norbinaltorphine nor NMDA alone were effective in this respect (88).
Ibogaine (10-60 mg/kg) reduced alcohol intake in
alcohol-preferring Fawn Hooded rats, without affecting either blood alcohol
concentrations or food intake (110,111). The authors concluded that
a metabolite could be involved, because ibogaine was effective in this
measure when administered intraperitoneally and intragastrically, but not
subcutaneously (112). A recent study demonstrated an attenuation
of alcohol consumption by the ibogaine congener, 18-methoxycoronaridine
in rats (113).
Effects on drug dependence.
Repeated administration of ibogaine (10 or 40 mg/kg)
did not produce dependence in rats as measured using the Primary Physical
Dependence test (114).
In morphine-dependent rats, the opioid antagonist
naloxone induces a withdrawal syndrome, characterized (in rats) by increased
rearing, digging, jumping, salivation and "wet-dog" head shaking. Ibogaine
dose-dependently reduced the frequency of some of these withdrawal symptoms
(jumping, rearing, digging, head hiding, chewing, teeth chattering, writhing,
penile licking) after both intracerebroventricular (4-16 µg) (115)
and i.p. administration (40 and 80 mg/kg) (74,116). However, these
effects could not be replicated in other studies in either rats (39,117)
or mice (118). At least the second failure to replicate can be attributed
to the fact that in the Frances et al., (118) study, ibogaine
was administered to animals that developed a full withdrawal syndrome.
In morphine-dependent monkeys, ibogaine (2 and 8 mg/kg, s.c.) partially
suppressed the total number of withdrawal signs (114). Our studies
(72,119) demonstrate that ibogaine inhibits the morphine withdrawal
syndrome in mice in a dose-related fashion. This effect was reversed by
combining ibogaine treatment with glycine. Structure-activity studies revealed
that among various ibogaine-like compounds (including O-desmethylibogaine
and O-t-butyl-O-desmethylibogaine), only ibogaine
inhibited the intensity of morphine withdrawal (72). Both the ability
of glycine to inhibit this effect of ibogaine and the failure of other
ibogaine derivatives to potently inhibit the binding of noncompetitive
NMDA antagonists (e.g., [3H]–N-[1-(2-thienyl)cyclo-hexyl]-3,4-pipenoline
(TCP) and [3H]–MK-801) suggests that the NMDA antagonist actions
of ibogaine are responsible for its anti-withdrawal effects. This hypothesis
is supported by the observation that while O-desmethylibogaine and
had much higher affinities for kappa opioid receptors than ibogaine did,
only ibogaine exhibited a significant affinity for NMDA receptors.
Pain and analgesia.
Ibogaine did not mimic the analgesic action of morphine
in either the tail flick (1-40 mg/kg, i.p.) or hot plate (up to 20 mg/kg,
i.p.) tests, although it exhibited analgesic activity in the phenylquinone
writhing test (ED50 9.7 mg/kg) (114,120,121). Ibogaine
did not exhibit antinociceptive activity when given twice a day for 4 days
(122). Ibogaine either increased (120,123) or did not affect
(114,121) morphine analgesia in the tail flick test. Similarly,
it did not influence analgesia produced by either a kappa opioid agonist
(U-50,488H) or a delta opioid agonist [D-Pen2,D-Pen5]enkephalin
(DPDPE) (121). Ibogaine has been reported to decrease analgesia
in rats when given 19 hours prior to morphine (123), but another
report indicates ibogaine is not effective when given 4-24 hours prior
to morphine administration in mice (121). In addition, Cao and Bhargava
(122) demonstrated that ibogaine (40-80 mg/kg) inhibited the development
of analgesia to mu, but not kappa or delta, agonists in mice.
O-Desmethylibogaine (40 mg/kg) potentiated
morphine-induced analgesia in rats (123) and mice (121).
This effect was no longer apparent 19 hours after its administration (123).
The potentiation of morphine-induced analgesia may be attributed to the
relatively high affinity of O-desmethylibogaine at opioid mu (Ki
2.66 ± 0.62 µM)
and kappa (Ki 0.96 ± 0.08 µ
M) receptors (124). However, this interpretation appears unlikely
because O-desmethylibogaine pretreatment did not influence either
kappa - or delta - opioid agonist - induced antinociception (121).
Ibogaine (10-40 mg/kg) completely blocked the antinociceptive
effect of (–)-epibatidine in rodents, but was ineffective when given at
a dose of 40 mg/kg 24 h before epibatidine. These data suggest that this
was an effect of ibogaine and not that of its putative, long-lasting metabolite
(125). This blockade of the antinociceptive effect of epibatidine
is not surprising, because epibatidine-induced analgesia is mediated by
a mechanism fundamentally different from that of the opioids.
Compared to other psychoactive compounds (e.g. psilocybin,
JB-336, and bufotenine), ibogaine (10 mg/kg) had a negligible effect on
the aggressiveness of isolated mice and muricidal behavior in rats (126).
Animals can be trained to "recognize" similarities
among drugs. Such discriminative (interoceptive) properties may suggest
a similar mechanism of action not necessarily related to the structure
of a compound.
No generalization between ibogaine and serotonergic
ligands (e.g. fenfluramine,
[TFMPP], 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [DOI], methyl-enedioxymethamphetamine
[MDMA], quipazine or LSD) was found in drug-discrimination paradigms (127,128).
However, Palumbo and Winter (129) did observe a generalization between
ibogaine (15-20 mg/kg) and dimethoxymethylamphetamine [DOM] (0.6 mg/kg),
as well as between ibogaine and LSD (0.1 mg/kg) in a two-lever discrimination
task. Because pizotyline (BC-105) blocked DOM-appropriate and LSD-appropriate
responses, an involvement of 5-HT2 or 5-HT1 receptors
in the stimulus properties of ibogaine was suggested. Similarly, no generalization
between ibogaine and CGS 10476B (a dopamine release-inhibiting agent) was
found in a drug-discrimination paradigm (127).
In contrast, ibogaine substituted as an interoceptive
cue in mice trained to recognize MK-801 (dizocilpine) (119), but
not to [(+)-HA-966] (a low efficacy partial agonist of the glycine site
at the NMDA receptor) (130) in a T-maze drug discrimination paradigm.
Helsley and colleagues (131) studied the
interoceptive cue produced by ibogaine in male Fisher rats. The time course
of the ibogaine (10 mg/kg) cue revealed that a maximum of ibogaine-appropriate
responses were observed at a 60 min pretreatment time, and, that at the
pretreatment time of 8 hours, no ibogaine-like responses were observed.
These findings, together with observation that O-desmethylibogaine
substituted only partially to the ibogaine cue, suggest that the subjective
effects of ibogaine are not due to this putative metabolite. The same study
however, revealed that harmaline completely substituted as an ibogaine
cue (131). This later finding indicates that animals may recognize
the tremorigenic effects of ibogaine.
Ibogaine does not appear to possess rewarding or
aversive effects as measured in the conditioned place preference/aversion
test (132), a preclinical procedure that can predict abuse potential
in humans. Nonetheless, the same authors reported that ibogaine (40 mg/kg)
may attenuate the acquisition, but not expression of morphine and amphetamine
place-preference in male rats (77,132,133). This dose of ibogaine
did not interfere with the acquisition of conditioned place aversion induced
by either naloxone or lithium chloride (132). Ibogaine (40 mg/kg,
22 hours before the test) attenuated the establishment of lithium- and
morphine-induced conditioned taste aversion (134). These results
suggest a specific action of ibogaine on the neurochemical and behavioral
(both reinforcing and aversive) actions of morphine rather than on opioid
system(s), because the reinforcing effects of naloxone were unaffected.
In support to these findings, it has been reported that ibogaine (20 or
40 mg/kg, 24 h before the test) neither decreased the preference for a
sweet solution nor attenuated conditioned preference for a flavor previously
associated with sweet taste (135).
Effects on learning and memory.
At a dose used in the majority of contemporary behavioral
studies in rodents (40 mg/kg), ibogaine has been found to attenuate the
acquisition of spatial memory, perhaps due to reductions in locomotor activity
and in detection of sensory information (78). However, at much lower
doses (0.25 - 2.5 mg/kg), ibogaine as well as O-desmethylibogaine
(but not O-t-butyl-O-desmethylibogaine) facilitated
spatial memory retrieval (136). Using a spatial memory task, Helsley
al., (92) found that: 1) two doses of ibogaine (50 mg/kg, spaced
by 8 hours) decreased the response rate, but did not affect acquisition
rate; 2) ibogaine, even at the highest doses of 30 and 46 mg/kg given 20
min before the learning trial did not affect task acquisition; 3) 30 mg/kg
of ibogaine administered just after the learning trial facilitated the
consolidation of memory trace.
Gershon and Lang (102) found that ibogaine
produced a rise in blood pressure and increased heart rate in conscious
dogs. These effects were blocked by atropine (137). However, in
anesthetized dogs, ibogaine produced a fall in blood pressure and reduced
heart rate reduction, leading the authors to propose an interaction between
anaesthesia and the cardiovascular effects of ibogaine (102). Schneider
and Rinehart (137) postulated a centrally mediated stimulatory effect
of ibogaine. Ibogaine also potentiated the pressor response to both adrenaline
and noradrenaline. More recently, Hajo-Tello et al., (138)
found that tabernanthine (an alkaloid closely related to ibogaine) induced
a negative inotropic effect in electrically stimulated myocardial tissue
and a negative chronotropic effect in the perfused rat heart. Tabernanthine
also produced bradycardia and hypotension in anesthetized rats and dogs
(139). Binienda et al. (140) reported that ibogaine
(50 mg/kg) reduced heart rate in rats immediately after injection; this
reduction persisted up to 90 minutes after injection.
Numerous psychotropic actions of ibogaine have been
reported. These actions seem to depend on both dose and setting. In addition,
the psychoactive effects of iboga extracts (which are likely to contain
additional alkaloids and are usually taken in a ritualistic setting) may
be different from those of ibogaine. Thus, users of the crude extract of
iboga taken in sufficiently high doses have reported fantastic visions,
feelings of excitement, drunkenness, mental confusion and hallucinations
when (101). The total extract of iboga shrub is certainly a central
stimulant, and in higher doses may lead to convulsions, paralysis and finally
respiratory arrest. The psychotropic actions of the plant extract include
visual sensations; objects are seen to be surrounded by specters or rainbows.
In high doses it may produce auditory, olfactory and taste synesthesias.
The state of mind has been reported to vary from profound fear to frank
When given orally, both ibogaine and the total iboga
extract elicits subjective reactions that last for approximately 6 hours.
Fifty percent of subjects are reported to experience dizziness, incoordination,
nausea, and vomiting (7,33,142). Typically, the drug produced a
state of drowsiness in which subjects did not want to move, open their
eyes, or attend to the environment. Many subjects were light-sensitive,
and covered their eyes or asked that the lights be turned off. Sounds or
noises were disturbing. Ibogalin (0.1-1.2 mg/kg, p.o.), an alkaloid closely
related to ibogaine and a constituent of the total iboga extract, did not
produce psychotomimetic effects in humans (143). Ibogalin also differs
from ibogaine in pharmacokinetics and tremorigenic activity (90).
The psychoactive properties of ibogaine and related
compounds were studied by Naranjo (33,142) who reported that patients
described the psychic state produced by ibogaine (~ 300 mg) as similar
to a dream state without loss of consciousness. Ibogaine-induced
fantasies [often described as a "movie run at high speed" or "slide
show" (7)] were reported as rich in archetypal contents, involving
animals and/or the subject with or without other individuals. These fantasies
were easy to manipulate by both the subjects and the psychotherapist (33,142).
At higher doses, ibogaine appears to produce visual and other hallucinations
associated with severe anxiety and apprehension (101,144,145).
LETHALITY AND NEUROTOXIC EFFECTS.
The LD50 of ibogaine has been determined
in guinea pig (82 mg/kg, i.p.) and rat (327 mg/kg, intragastrically and
145 mg/kg, i.p.) (60,146).
No significant pathological changes in rat liver,
kidney, heart and brain following chronic ibogaine treatment (10 mg/kg,
for 30 days or 40 mg/kg, for 12 days, i.p.) were reported (60).
Sanchez-Ramos and Mash (42) found no evidence of gross pathology
in African green monkeys given ibogaine in doses of 5-25 mg/kg, p.o. for
4 consecutive days.
However, O'Hearn et al., (147,148)
and O'Hearn and Molliver, (93) reported that repeated administration
of ibogaine (100 mg/kg, i.p.) to rats caused the degeneration of a subset
of Purkinje cells in the cerebellar vermis. This degeneration was accompanied
by a loss of microtubule-associated protein 2 (MAP-2) and calbindin. Argyrophilic
degeneration, astrocytosis and microgliosis were also observed. The damage
seemed to be dependent on the presence of an intact inferior olivary nucleus
(149). Ibogaine-induced cerebellar toxicity seem to be independent
on its action at NMDA receptors, because neither MK-801 nor phencyclidine
produce the same pattern of degeneration (150). The neurotoxic effects
of high doses of ibogaine were confirmed in rats, but not mice, by Scallet
al., (151,152) and Molinari
et al., (153), who,
in addition found that the "typical" dose of 40 mg/kg did not produce significant
damage to female rat cerebellum. The lack of neurotoxicity after lower,
behaviorally active doses of ibogaine was also demonstrated by showing
that chronic administration (60 days) of 10 mg/kg of ibogaine produced
no change in the number of Purkinje cerebellar cells (154).
In spite of these findings, examination of cellular
markers that are more sensitive toneurotoxic agents than gross histology
indicates that ibogaine administration may produce significant change in
many other brain structures. Thus, O'Callaghan et al., (155,156)
examined the effects of acute and chronic administration of ibogaine on
glial fibrillary acidic protein (GFAP) levels. Acutely, ibogaine increased
GFAP in both sexes; whereas chronic administration (14 days) produced increases
only in females. Ibogaine - induced changes in GFAP were dose-related,
and, contrary to other studies, observed in other brain structures including
hippocampus, olfactory bulb, brain stem and striatum. In addition, these
authors reported that in females treated chronically with ibogaine, severe
hippocampal damage was present as measured by increases in the cytoskeletal
proteins neurofilament 68 (NF-68) and beta-tubulin. These latter markers
indicate a damage-induced sprouting response (156). Ibogaine administration
also produced an increase in c-fos immunostaining in several brain regions
of mice and rats; the effects in rats were observed in all cortical layers
while in mice the response was limited to cortical layer 2 (152).
Human SK-N-SH neuroblastoma cells cultured in the presence of 3-30 µ
M ibogaine (but not O-desmethylibogaine or 18-methoxycoronaridine)
demonstrated concentration- and time-dependent morphological changes characterized
by the loss of processes, cell rounding, detachment and ultimately cell
death (157). Similar results were observed with primary cultures
of rat cerebellar granulae cells. Because in this study only alkaloids
that had marked affinity at sigma2 sites were neurotoxic, Vilner
al., (157) proposed that sigma2 sites may be implicated
in the neurotoxicity of ibogaine. The neurotoxic effects of ibogaine have
been recently reviewed by Vocci and London (106).
Acute treatment with the ibogaine-like alkaloid,
18-methoxycoronaridine (100 mg/kg) did not produce gross pathological changes
in the cerebellum (97). In contrast, another indole alkaloid, harmaline,
produced ibogaine-like degeneration of Purkinje cells in the cerebellar
It has been reported that multiple doses of a non-NMDA
antagonist (GYKI 52466) resulted in a substantially greater loss of Purkinje
cells and microglial activation compared to ibogaine (50-100 mg/kg) alone
(158). On the other hand, the noncompetitive NMDA antagonist MK-801
(1 mg/kg) markedly attenuated the degree of Purkinje cell loss caused by
ibogaine (158). This later finding strongly supports the notion
that the loss of cerebellar Purkinje cells produced by ibogaine is unrelated
to its NMDA antagonist properties (159). In fact, ibogaine can also
exhibit neuroprotective properties, reducing glutamate-induced neurotoxicity
in primary cultures of cerebellar granule cell neurons with an EC50
of 4-5 µM (119). These neuroprotective effects of ibogaine have
recently been patented by Olney (160). Consistent with its properties
as an NMDA antagonist, ibogaine inhibited NMDA - induced lethality in mice
in a dose-dependent manner (161), and also protected mice from maximal
electroshock seizures (ED50 ~ 31 mg/kg) (162).
Phase I toxicity studies in drug-addicted individuals
are in progress at the University of Miami (42,163).
EFFECTS ON SPECIFIC NEUROTRANSMITTER SYSTEMS
Ibogaine Effects on Dopaminergic Systems.
Ibogaine (at concentrations £
100 µM) does not affect radioligand binding
to dopamine receptors (D1, D2, D3, D4)
(164-166). The affinity of ibogaine for dopamine transporters as
measured by inhibition of [3H]WIN 35,248, [125I]RTI-121
or [125I]RTI-55 binding was ~ 1.5 - 4 µ
M (73,76,166,167). However, in another study, ibogaine did not affect
binding of [3H]GBR-12935, a ligand that also appears to label
dopamine transporters (85). Ibogaine inhibited [3H]dopamine
uptake in porcine kidney cells transfected with dopamine transporter with
a Ki ~86 µM (168).
The in vivo and ex vivo effects of
ibogaine on dopamine metabolism in mesolimbic areas of the rodent brain
(striatum, nucleus accumbens) are controversial and highly inconsistent.
In an attempt to reconcile several contradictory findings, one may note
Dopamine concentrations are reduced and dopamine
metabolites dihydroxyphenyl-acetic acid (DOPAC) and homovanilic acid (HVA)
are increased by ibogaine under certain experimental conditions. For example,
when either measurements are taken shortly (within 2 h) after ibogaine
administration or when relatively high concentrations (£
100 µM) are used (69,71,76,81,169-173).
Reductions in extracellular dopamine concentrations were also observed
after administration of a number of ibogaine derivatives, including O-desmethylibogaine
(89) and 18-methoxycoronaridine (97).
When dopamine is measured at longer periods after
ibogaine administration (e.g., up to a week) or low concentrations (e.g.,
10 µM) are applied, brain concentrations appear
unchanged and metabolite concentrations are decreased (69,71,76,81,82,169,170,172).
The increased levels of extracellular dopamine metabolites
together with decreased or unchanged levels of dopamine suggests that ibogaine
increases dopamine turnover shortly after administration. This may be followed
by a decrease in turnover that may persist for some time after ibogaine
administration. French et al., (91) demonstrated that doses
of ibogaine (~ 1.5 mg/kg, i.v.), much lower than a "typical" dose of 40-80
mg/kg, markedly excited dopaminergic neurons in the ventral tegmental area
of the rat.
Dopaminergic effects: Pharmacological Specificity.
Administration of a kappa antagonist (norbinaltorphimine,
10 mg/kg) and NMDA (10 mg/kg) (either jointly or individually) reversed
ibogaine (40 mg/kg) induced decreases in striatal dopamine and increases
in dopamine metabolites (88). Similarly, Reid et al., (172)
observed that the decrease in dopamine levels produced by ibogaine (100
M ) was reversed by either naloxone (1 µM)
or norbinaltorphimine (1-10 µM). However, functionally
opposite effects were observed by Sershen et al., (174,175)
who reported that the ability of the kappa opioid agonist (U-62066) to
inhibit electrical- or cocaine-induced [3H]dopamine release
from mouse striatum was attenuated by pretreatment of mice with ibogaine
(40 mg/kg, i.p., 2 hours prior; or 2 x 40 mg/kg, 6 hours apart, killed
18 hours later) (174,175).
Ibogaine-induced dopamine release from the isolated
mouse striatum has been studied by Harsing et al., (176).
Ibogaine increased basal tritium outflow ([3H]dopamine (DA)
and [3H]DOPAC), but was without effect on electrically stimulated
tritium overflow. This dopamine releasing effect was: a) reduced by the
dopamine uptake inhibitors cocaine and nomifensine, b) unaltered by omission
of Ca++ from the perfusion buffer, c) tetrodotoxin insensitive,
d) unaffected by an agonist (quinpirole) or an antagonist (sulpiride) of
the D2 dopamine receptor, and e) unaffected by pretreatment
with reserpine. In this study, ibogaine did not affect dopamine uptake,
whereas Reid et al., (172) found that both ibogaine and harmaline
(10 µM-1 mM) inhibited it. As mentioned above,
ibogaine has been reported to inhibit radioligand binding to the dopamine
transporter with relatively high affinity.
Sershen et al., (177) reported an
involvement of serotonin receptors in the regulation of dopamine release
by ibogaine. Thus, administration of ibogaine blocked the ability of a
5HT1B agonist (CGS-12066A [10 µM])
to increase [3H]dopamine increase in striatal slices. In other
studies, a concentration of ibogaine (1 µM)
that was without effect on dopamine efflux inhibited both NMDA (25 µ
M) and (± )pentazocine (100 nM) - induced dopamine
release in striatal slices (178).
There are few reports of the effects of ibogaine-like
alkaloids on dopamine metabolism. Like ibogaine, O-desmethylibogaine
acutely decreases dopamine release in the rat nucleus accumbens and striatum
(89). Administration of the R- entantiomers of coronaridine
and ibogamine decreased dopamine levels in both nucleus accumbens and striatum,
whereas the S-enantiomers produced no significant changes in dopamine
levels in either region (96).
In an attempt to reconcile several conflicting findings,
Staley et al., (167) proposed that ibogaine might promote
redistribution of intraneuronal dopamine from vesicular to cytoplasmic
pools. Ibogaine displays micromolar affinity for vesicular monoamine transporters
labeled with [125I]-tetrabenazine (167); these sites
are crucial for the translocation of dopamine into synaptic vesicles. The
inhibitory effect of ibogaine on vesicular monoamine transporters could
result in redistribution of dopamine in the cytoplasm. Under such conditions,
rapid metabolism of dopamine by monoamine oxidase would account for the
decrease in tissue dopamine content and the parallel increase in its metabolites.
Multiple transmitter systems have been shown to
modulate dopaminergic function in the central nervous system. Because ibogaine
can interact with many of these systems, including kappa opioid receptors,
NMDA receptors, serotonin receptors, and dopamine transporters, it is not
surprising that this alkaloid can produce complex (and sometimes apparently
opposite) effects on dopaminergic function. Thus, the effects of ibogaine
on dopaminergic function described in this section likely reflect the dose
(or concentration) of alkaloid, preparation employed (e.g., slice versus
intact animal), and brain region studied.
Ibogaine alters the effects of abused drugs on dopaminergic systems.
In general, ibogaine attenuates the increases in
mesolimbic dopamine produced by drugs (e.g, nicotine, morphine) that appear
to act preferentially at dopaminergic cell bodies. In the case of drugs
that act at terminal regions (e.g., cocaine and amphetamine), a gender
difference has been observed. In female rats, ibogaine enhances stimulant-induced
increases in dopamine concentrations, whereas it decreases the effects
of these stimulants in male rats and mice.
Neurochemical studies were performed in male mice
given two doses of ibogaine (40 mg/kg, i.p., 18 hours apart) followed by
amphetamine (5 mg/kg) administered 2 hours after the second dose of ibogaine
(81). Striatal levels of dopamine and dopamine metabolites [DOPAC,
HVA and 3-methoxytyramine (3-MT)] measured 1 hour after amphetamine were
decreased in mice that received ibogaine relative to saline-pretreated,
amphetamine-treated controls. Compared to controls, levels of DOPAC and
HVA were decreased in the amphetamine and ibogaine groups, and further
decreased in the group that received ibogaine and amphetamine. However,
in female rats, amphetamine-induced increases in extracellular dopamine
concentrations in both the striatum and the nucleus accumbens were further
potentiated by ibogaine (40 mg/kg, i.p., 19 hours preceding amphetamine)
(82). Similarly, Glick et al., (169) found that ibogaine
potentiated amphetamine-induced increases in extracellular dopamine concentrations
in female rat nucleus accumbens and striatum. In this study, however, no
effect of ibogaine was seen on amphetamine-induced decreases in extracellular
concentrations of dopamine metabolites. Similarly, ibogaine potentiated
cocaine-induced increases in extracellular dopamine levels in striatum
and nucleus accumbens of female rats (84). However, quite opposite
data were obtained by Broderick et al., (85,86) who examined
dopamine release in male rats using semiderivative in vivo voltametry.
In these experiments, ibogaine (40 mg/kg i.p. given for four days) reduced
the increase in dopamine release from nucleus accumbens induced by cocaine
(20-40 mg/kg, s.c.). A presynaptic mechanism for these actions was suggested.
An inhibitory effect of ibogaine on amphetamine metabolism has been proposed
(179), because amphetamine levels were higher after ibogaine administration
in female rats. However, ibogaine administration had no effect on brain
cocaine levels (169).
Ibogaine (40 mg/kg, i.p. in rats) given 19 hours
before morphine (5 mg/kg) prevented the increase in extracellular dopamine
concentration in the striatum, prefrontal cortex and nucleus accumbens
typically observed in rats (71,83). However, in the ibogaine plus
morphine group, the levels of dopamine metabolites were increased
(as was observed in the morphine group), suggesting that ibogaine did not
prevent morphine from activating dopamine neurons. The authors suggest
that ibogaine treatment may change the properties of dopaminergic neurons
in such a way that dopamine release is unaffected under normal conditions,
but altered when stimulated (in this case, by morphine). Nineteen hours
after placebo or ibogaine (10 mg/kg, i.p.), female rats responded similarly
with increased dopamine release in nucleus accumbens following a morphine
challenge (180). However, in rats that received two doses of morphine
during two days preceding the experiment, ibogaine pretreatment had inhibitory
effects on dopamine response to a morphine challenge. A pharmacokinetic
explanation for the effects of ibogaine on morphine-induced actions is
unlikely, because ibogaine (40 mg/kg, i.p. 19 hours before measurement)
did not modify brain levels of morphine (10 mg/kg) in rats (71).
Benwell et al., (103) reported that
ibogaine (given 22 hours before nicotine) attenuated the increase in dopamine
overflow in the nucleus accumbens evoked by nicotine administration. Similar
effects were demonstrated, when ibogaine was administered 19 hours prior
to nicotine infusion (181).
At concentrations of up to 100 µM, ibogaine was
reported not to affect [3H]carfentanil or [3H]enkephalin
binding indicating that this alkaloid does not affect mu or delta opioid
receptors (124,165). In contrast, Pearl et al., (124)
and Sweetnam et al., (166) demonstrated that ibogaine inhibited
radioligand binding to mu opioid receptors with Ki values ~
11-20 µM. Ex vivo studies demonstrated that ibogaine and O-desmethylibogaine
enhanced the inhibition of adenylyl cyclase activity by a maximally effective
concentration of morphine in the rat frontal cortex, midbrain and striartum
(182). This later effect is not likely mediated via a direct action
at opioid receptors because it was observed at maximally effective concentration
Ibogaine inhibits (Ki ~2-4 µM)
[3H]U-69593 binding to kappa opioid receptors (56,72,124,165).
This binding is reversible, suggesting that the long-term effects of ibogaine
cannot be attributed to an irreversible effect at this site. Recently,
Codd (183) demonstrated that ibogaine inhibits binding to sites
labeled by [3H]naloxone characterized by a two-site model, with
Ki values of 130 nM and 4 µM.
O-Desmethylibogaine had a higher affinity
than ibogaine for all of the opioid receptors studied: kappa Ki
~ 1 µM, mu Ki ~ 2.7 µM and delta Ki ~ 24.7 µM (124)
(a recent study showed much higher affinity of O-desmethylibogaine
at the mu receptor; Ki ~ 160 nM (184)). Our work (72)
demonstrated that O-desmethylibogaine had a 10- to 100-fold higher
affinity for kappa receptors compared to ibogaine. The magnitude of this
potency difference was species-specific (e.g., in rats: IC50
~ 0.3 µM for O-desmethylibogaine and IC50 ~30 µM for
ibogaine). The same study demonstrated a moderate affinity of O-t-butyl-O-desmethylibogaine
for kappa receptors (IC50 ~17 µM in rat forebrain) suggesting
that if any of ibogaine's in vivo actions are produced at kappa
receptors, then O-t-butyl-O-desmethylibogaine would
be active. In this respect, O-t-butyl-O-desmethylibogaine
did not influence the morphine withdrawal syndrome (72) at doses
comparable to ibogaine.
Ibogaine (at concentrations up to 1 µM)
had no effect on [3H]serotonin binding (185) and concentrations
of up to 3.5 µM had no effect on [3H]LSD
binding (186). More recent studies using serotonin subtype selective
ligands are discrepant. Deecher et al., (165) reported that
ibogaine did not displace ligands acting at 5-HT1a, 5-HT1b,
5-HT1c, 5-HT1d, 5-HT2, or 5-HT3
receptors. However, Repke et al., (56) reported that ibogaine
inhibited binding of 5-HT1a, 5-HT2a, or 5-HT3
ligands with low affinity (Ki values: >100, 12.5 and >100 µM,
respectively) and Sweetnam et al., (166) reported IC50
values of ~ 4 µM to inhibit radioligand binding
to both 5-HT2, and 5-HT3 receptors.
Despite these discrepancies, both ex vivo
and in vivo studies suggest that ibogaine can affect serotonergic
transmission. Ex vivo studies indicate that ibogaine and O-desmethylibogaine
enhance the inhibitory effects of serotonin on adenylyl cyclase activity
in rat hippocampus (182). Broderick et al., (86) reported
that ibogaine (40 mg/kg, i.p. for 4 days) increased 5-HT concentrations
in rat nucleus accumbens. Consistent with this finding, Ali et al.,
(171) demonstrated that ibogaine increased 5-HT levels in striatum.
Sershen et al., (76) reported that ibogaine (40-50 mg/kg)
decreased levels of the serotonin metabolite 5-hydroxy-indoleacetic acid
[5-HIAA] in mouse frontal cortex, hippocampus and olfactory tubercle 2
and 24 hours after injection. Ibogaine also decreased 5-HIAA levels in
rat nucleus accumbens and striatum (103,171), but increased 5-HIAA
and decreased 5-HT (lasting at least 7 days) in medial prefrontal cortex
(103). Long and Lerrin (187) demonstrated that ibogaine is
a reversible inhibitor of the active transport of serotonin into blood
platelets, a finding supported by a recent observation that ibogaine inhibited
serotonin transporters (in a porcine kidney cell line) with a Ki
~ 10 µM (168).
Sershen et al., (177) demonstrated
that ibogaine inhibited the ability of a 5-HT1b agonist (CGS-12066A)
to increase stimulation-evoked [3H]dopamine release from both
rat and mouse striatal slices. Additionally, ibogaine increased the ability
of a 5-HT3 agonist (phenylbiguanide) to enhance stimulation-evoked
[3H]dopamine release from the mouse striatal slice (174).
In these studies, ibogaine (40 mg/kg, i.p.) was administered 2 hours prior
to slice preparation. In other studies, ibogaine (20 mg/kg) enhanced cocaine-induced
reductions in serotonin concentration in the nucleus accumbens (rat), an
action attributed to a presynaptic release mechanism (85,86). However,
Sershen et al., (175) reported that cocaine increased [3H]serotonin
efflux in striatal slices and this efflux was absent in mice pretreated
with either ibogaine or a 5-HT1b agonist. These later findings
led Sershen to suggest an action of ibogaine at the HT1b receptor
that is likely unrelated to the ability of cocaine to inhibit serotonin
reuptake blockade (188). The inhibitory effect of the kappa-opioid
agonist U-62066 (1µM) on [3H]serotonin
release in striatal slices could be blocked by in vivo ibogaine
Ibogaine (80 µM) non-competitively
antagonized calcium-induced contraction of rat aorta and mesenteric artery
(138), which was interpreted as an action on intracellular calcium
metabolism. Tabernanthine, an alkaloid related to ibogaine, inhibited depolarization-stimulated
influx and contractions in the rat aorta (189). Ibogaine inhibited
the binding of [3H]isradipine (an L-type calcium channel blocker)
in the mouse cerebral cortex with an IC50 of ~28 µM (11).
Ibogaine (at concentrations of up to 100 µM) was
reported not to inhibit the binding of ligands acting at nicotinic or muscarinic
receptors (165). However, subsequent studies demonstrated that ibogaine
inhibited the binding of muscarinic M1, M2 and M3
ligands at concentrations of ~ 31, 50 and 12.5 µM, respectively (56).
et al., (166) showed that ibogaine inhibited radioligand
binding to M1, and M2 receptors with IC50
values of 5-7 µM. These authors also reported
that ibogaine did not inhibit the binding of [3H]NMCI, a nonselective
ligand at nicotinic receptors. Ex vivo studies have shown that neither
ibogaine nor O-desmethylibogaine affect the inhibitory action of
the muscarinic acetylcholine agonist, carbachol on adenylyl cyclase activity
in the rat (182).
In a recent study, Badio et al., (125)
demonstrated that ibogaine potently (IC50 ~ 20 nM) blocked 22NaCl
influx through nicotinic receptor channels in rat pheochromocytoma cells.
This effect was seen in the cells expressing ganglionic, but not neuromuscular,
nicotinic receptor subtypes. This inhibition was noncompetitive because
it was not overcome by increasing concentrations of agonist. Moreover,
the blockade was not completely reversible, suggesting that ibogaine may
have a long-lasting effect. O-Desmethylibogaine and O-t-butyl-O-desmethylibogaine
were 75- and 20-fold less potent, respectively, than ibogaine in blocking
nicotinic receptor-mediated responses. The same study demonstrated that
ibogaine, as expected for a noncompetitive blocker, had a relatively low
affinity (Ki ~ 4 µM) as an inhibitor
of the binding of an agonist [3H]nicotine. In support to these
findings, Schneider et al., (190) reported recently that
ibogaine (£ 10 µ
M) had an inhibitory action on nicotinic receptor-mediated catecholamine
release in bovine adrenal chromaffin cells. Consistent with the Badio et
al., (125) study, these inhibitory effects appeared to be long-lasting.
Gamma-Aminobutyric Acidergic [GABAergic] Systems.
Two independent studies (165,166) did not
find any effect of ibogaine (at concentrations of up to 100 µM) on radioreceptor
binding to GABAA receptors. In addition, ibogaine did not influence
uptake through GABA-gated channels (165) or GABA-evoked currents
in rat cultured hippocampal neurons (162).
Voltage-Dependent Sodium Channels.
Ibogaine inhibited (Ki ~ 8.1 µM) [3H]batrachotoxin
A 20-a-benzoate binding to voltage-dependent sodium channels in depolarized
mouse neuronal preparations (165). Ibogaine analogs, including ibogamine,
tabernanthine and coronaridine, exhibited potencies similar to ibogaine
in this assay.
Our studies (159) indicate that ibogaine
is a competitive inhibitor of [3H]MK-801 binding (Ki
~1 µM) to NMDA receptor-coupled ion channels.
In contrast, ibogaine did not affect [3H](±
)- a -amino-3-hydroxy-5-methylisoxazole-4-propionic
acid ([3H]AMPA), [3H]kainate or [3H]glutamate
to either the NMDA or metabotropic receptor sites, binding. These findings
are consistent with a specificity of ibogaine for NMDA receptor-coupled
cation channels (159,162,166). The potency of ibogaine to inhibit
[3H]MK-801 binding was also examined in 8 distinct brain regions
of Sprague-Dawley male rats and compared with the dissociation constants
for [3H]MK-801 estimated using saturation analyses. A high correlation
(r=0.976, p=0.0004) was obtained between the Ki of ibogaine
and Kd of [3H]MK-801 in these brain regions (119),
consistent with the notion that these compounds share a common binding
site. The ability of ibogaine to act as a non-competitive NMDA antagonist
can also be demonstrated using [3H]1-[1-(2-thienyl)cyclohexyl]piperidine
([3H]TCP), a thienyl derivative of phencyclidine, resulting
in a Ki ~1.5 µM in rat forebrain (119).
Structure-activity studies were performed using
a series of ibogaine analogs, including the putative ibogaine metabolite
its metabolism resistant analog O-t-butyl-O-desmethylibogaine,
the iboga alkaloids [(± )-ibogamine, (±
)-coronaridine, tabernanthine], harmaline, and indolotropanes. Ibogaine
was the most potent inhibitor of [3H]MK-801 binding (Ki
~ 1.2 µM); the compounds with the greatest
structural similarity to ibogaine, O-desmethylibogaine and O-t-butyl-O-desmethylibogaine
were much less potent (Ki ~ 5.5 and 179.0 µ
M respectively) (72). A ~ 5 fold lower affinity of O-desmethylibogaine
compared to ibogaine at [3H]MK-801 binding sites was also reported
by Mash et al., (191).
Consistent with these neurochemical studies, ibogaine
produced a voltage-dependent block of NMDA-evoked currents in hippocampal
cultures (119,162). In addition, ibogaine (100 µ
M) and O-desmethylibogaine (1 mM) blocked the ability of NMDA (100
M, 5 sec) to depolarize frog motoneurons in a non-competitive and use-dependent
In our studies (11), ibogaine inhibited [3H]pentazocine
(a sigma1 receptor ligand) binding, to high (IC50
~86 nM) and low (IC50 ~5.6 µM) affinity
sites in mouse cerebellum. Bowen et al., (193) demonstrated
that ibogaine had high affinity for sigma2 sites (Ki
~ 200 nM) and low affinity for sigma1 sites (Ki ~
8.5 µM), a ~ 43- fold selectivity for sigma2
sites. The affinities of tabernanthine (13-methoxyibogamine) and (±
)-ibogamine for sigma2 sites were similar to that of ibogaine.
had a markedly reduced affinity for sigma2 sites (Ki
~ 5 µM) and also lacked affinity for sigma1
sites. The related alkaloids, (± )-coronaridine
[(± )-18-carbomethoxyibogamine] and harmaline
lacked affinity for both sigma receptor subtypes. O-t-Butyl-O-desmethylibogaine
inhibited radioligand binding to sigma1 sites with a Ki
~ 3.5 µM and sigma2 sites with a
Ki ~ 346 nM [c.f. Bowen et al, (72)]. The much
higher affinity of ibogaine for sigma2 sites compared to sigma1
sites was also reported by Mach et al., (194). Bowen et
al., (195) examined the ability of ibogaine and related compounds
to modulate calcium release from intracellular stores in indo-1 loaded
human SK-N-SH neuroblastoma cells. Consistent with its affinity at sigma2
sites, ibogaine produced a concentration-dependent increase (13-45%) in
intracellular calcium levels. O-Desmethylibogaine, was ineffective
in this measure at concentrations up to 100 µ
M. These data suggest that the shared in vivo effects of ibogaine
and O-desmethylibogaine are probably not mediated by sigma sites.
Miscellaneous Actions of Ibogaine.
Deecher et al., (165) reported that
ibogaine (up to 100 µM) did not inhibit radioligand binding to cannabinoid
receptors. Ibogaine and O-desmethylibogaine had no influence on
basal or forskolin-stimulated adenylyl cyclase in the rat frontal cortex,
midbrain or striatum (182).
O-Desmethylibogaine, but not
ibogaine, produced concentration - dependent increases in the generation
of [3H]inositol phosphates that were not altered by inclusion
of tetrodotoxin, cadmium or omega-conotoxin (196). These results
suggest that the effect of O-desmethylibogaine on phosphoinositide
hydrolysis was not secondary to the release of one or more neurotransmitters.
Ali et al., (45) reported that ibogaine (0.5-250 µ
M) reduced nitric oxide synthase activity in mouse brain; similar effects
were noted in the striatum, hippocampus and cerebellum of mice treated
parenterally with ibogaine (50 mg/kg). In radioligand binding studies,
no effect of ibogaine has been found on alpha1, alpha2
or beta1 adrenergic receptors (165). Moreover, ibogaine
(20 mg/kg) did not modify cerebral noradrenaline levels in rats (197).
Binienda et al., (140,198) reported that although ibogaine
(50 mg/kg) challenge in rats was associated with a decrease in delta, theta,
alpha and beta power spectra of cortical EEG during the first 30 min, and
subsequent recovery of all except delta bands in the next 15 min, MK-801
(1 mg/kg) treatment was followed by a decrease in power of all four frequency
bands for the entire time of recording. The selective power decrease in
delta EEG frequency band of the cortical EEG may suggest the activation
of dopamine receptors.
In the anesthetized rat, ibogaine produced a slight
hypoglycemia (60). After administration of 50 mg/kg of ibogaine,
elevations of corticosterone levels were noted 15 - 120 min, but not 24
hours later (170,171,173). The same dose of ibogaine rapidly and
transiently increased plasma prolactin levels (171,173). Bunag and Walaszek
(199) reported that ibogaine antagonized the contractile responses
produced in guinea pig ileum by substance P and angiotensin. Alburges and
Hanson (200) reported that ibogaine administration produced increases
of neurotensin-like immunoreactivity in striatum, nucleus accumbens and
substantia nigra and substance P -like immunoreactivity in striatum and
substantia nigra. Ibogaine or harmaline suppressed several (T-cell regulatory
and effector, B-cell, and natural killer cell) immune functions in vitro
(201). Van Beek et al., (17) reported that ibogaine
showed activity against the gram-positive Bacillus subtilis. Ibogaine
did not alter colonic temperature in mice, nor did it affect morphine-
or kappa [U-50,488H]–opioid induced
The renewed interest in ibogaine during the past
decade stems from anecdotal clinical observations that ibogaine offers
a novel means of treating drug addictions. Preclinical studies are, in
general, consistent with these claims. Thus, ibogaine reduces self-administration
of cocaine and morphine, attenuates morphine withdrawal, and blocks conditioned
place preference produced by morphine and amphetamine. Preclinical studies
also suggest there is no abuse liability associated with ibogaine. At doses
that interfere with tolerance and dependence phenomena, brain concentrations
of ibogaine are at levels that can affect a variety of neurotransmitter
systems. Many of these effects (e.g., use dependent block of NMDA receptor-coupled
cation channels, interactions with dopamine transporters and kappa opioid
receptors) have previously been implicated in drug seeking phenomena. However,
at the present time, the only mechanism that can be invoked to explain
ibogaine's effects on drug seeking phenomena with some certainty is its
ability to inhibit naloxone-precipitated jumping through blockade of NMDA
receptors. Nonetheless, it is still uncertain whether the anti-addictive
properties of ibogaine result from a single mechanism or are produced at
The involvement of dopaminergic pathways in drug
seeking phenomena can be considered dogma, and ibogaine undoubtedly affects
these pathways. Nonetheless, based on available data no clear picture has
emerged about how this interaction contributes to the anti-addictive properties
of ibogaine, or any other anti-addictive medications. Additional systematic
studies are obviously needed. Anecdotal reports claim long term effects
of ibogaine on drug seeking following a single administration or short
course of therapy. This claim has been borne out, at least in part, by
preclinical studies. Based on these observations, it is unlikely that ibogaine
serves simply as substitution therapy. It has been hypothesized that a
long-lived metabolite is responsible for ibogaine's putative anti-addictive
properties, but additional studies are required in this area.
One of the central issues regarding the molecular
mechanisms responsible for the anti-addictive actions of ibogaine is whether
its NMDA antagonist action is sufficient to explain these effects. Thus,
there is an established body of preclinical data (and an emerging body
of clinical data) demonstrating that NMDA antagonists interrupt drug seeking
phenomena to a variety of addictive substances. Although it is now well
established that ibogaine is a noncompetitive NMDA antagonist (albeit 1000-fold
less potent than the prototype compound, dizocilpine), with the exception
of its ability to block naloxone precipitated jumping in morphine-dependent
mice, it is uncertain if these effects can be attributed to other mechanisms.
Recent structure activity studies demonstrate that
which is less potent than ibogaine at NMDA receptors, appears as active
as ibogaine in acutely blocking morphine and cocaine self-administration.
This observation strongly suggests that other mechanisms may be operative.
A similar argument can be made for harmaline, which is somewhat structurally
related to ibogaine and shares some of its pharmacological actions (e.g.,
tremor and neurotoxic effects, reductions in cocaine and morphine self-administration),
but is not an NMDA antagonist. Although inhibition of drug self-administration
by harmaline may be due to unspecific effects (e.g., general malaise),
these findings nonetheless raise the possibility that ibogaine's anti-addictive
properties may be produced through multiple mechanisms. The involvement
of sigma sites in these phenomena appears to be even more obscure because
in contrast to ibogaine, harmaline has no appreciable affinity at sigma
O-desmethylibogaine lacks affinity at a sigma2
site, yet all three block cocaine and morphine self-administration.
Ibogaine can affect several aspects of serotonergic
transmission at concentrations that are readily achieved in the brain following
pharmacologically relevant doses [reviewed by Sershen et al., (188)].
Because multiple serotonin receptor subtypes, as well as serotonin reuptake,
are modulated by ibogaine, it is not surprising that the effects of this
alkaloid on steady state levels of serotonin and its metabolites (whether
in situ or ex vivo) are complex. Clearly, additional
clinical studies are necessary to examine the efficacy of ibogaine as an
anti-addictive agent. Similarly, additional preclinical studies will be
required to elucidate the molecular mechanism(s) responsible for these
The authors thank Dr. H. Sershen for helpful discussions
on the effects of ibogaine on dopaminergic and serotonergic transmission.
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Table 1. Interactions of ibogaine with neurotransmitter systems: radioligand
||Ki or IC50†
||7.2 ± 3.0†
||3.5 ± 0.6†
|Monoamine transporter (vesicular)
||7.6 ± 0.7†
||5.9 ± 1.4†
||4.0 ± 0.6
||0.02 ± 0.007†
|NMDA ion channel
||1.0 ± 0.1
|NMDA ion channel
|NMDA ion channel
||5.6 ± 0.8†
|NMDA ion channel
|NMDA ion channel
||MK-801 or TCP
||0.01-0.05 and 2-4
|NMDA ion channel
||1.5 ± 0.3
||0.13 ± 0.03
||2.1 ± 0.2
||3.77 ± 0.81
||4.8 ± 1.4†
||3.9 ± 1.1†
||0.55 ± 0.03
||9.3 ± 0.63
||8.6 ± 1.1
||0.0904 ± 0.0101
||0.201 ± 0.023
||batrachotoxin A 20-a- benzoate
||8.1 ± 1.3
LEGEND TO TABLE 1. Presented are Ki or
IC50 (†) values for various neurotransmitter systems affected
by ibogaine with affinities higher than 10 µ
M. The affinities of O-desmethylibogaine for the corresponding receptors
are presented in footnotes.
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