Opiate Withdrawals:

This article is an abstract from the Journal of Ethnopharmacology:
(The full article can be viewed at http://www.ibogaine.org/subculture.html )

Journal of Ethnopharmacology xxx (2007) xxx–xxx
The ibogaine medical subculture
Kenneth R. Alper a,b,∗, Howard S. Lotsof c, Charles D. Kaplan d
a Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA
b Department of Neurology, New York University School of Medicine, New York, NY 10016, USA
c Dora Weiner Foundation, 46 Oxford Place, Staten Island, NY 10301, USA
d Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands
Received 7 June 2007; received in revised form 21 August 2007; accepted 21 August 2007

1.4. Mechanisms of action
Initially, ibogaine’s mechanism of action was hypothesized to involve antagonism at the N-methyl-d-aspartate-type glutamate (NMDA) receptor (Skolnick, 2001). However, 18-MC, which has negligible NMDA receptor affinity, also reduces opiate withdrawal and drug self-administration in the animal model (Glick et al., 2001). Antagonism of the _3_4 nicotinic acetylcholine receptor (nAChR) is a possible mechanism of action, as indicated by a series of studies of iboga alkaloids and nicotinic
agents (Fryer and Lukas, 1999; Glick et al., 2002a,b; Pace et al., 2004; Taraschenko et al., 2005). The _3_4 nAChR is relatively concentrated in the medial habenula and interpeduncular nucleus, where 18-MC’s antagonism of _3_4 nAChRs diminishes sensitized dopamine efflux in the NAc (Taraschenko et al.,
2007a,b). Ibogaine’s mechanism of action has frequently been suggested to involve the modification of neuron adaptations related to prior drug exposure (Rabin and Winter, 1996b; Popik and Skolnick, 1998; Alper, 2001; Glick et al., 2001; Sershen et al., 2001; Levant and Pazdernik, 2004). Ibogaine may modulate
intracellular signaling linked to opioid receptors, and potentiates the morphine-induced inhibition of adenylyl cyclase (AC) (Rabin and Winter, 1996b), an effect that is opposite to the activation of AC that is classically associated with opioid withdrawal (Sharma et al., 1975). In animals, ibogaine enhances the
anti-nociceptive effect of morphine or other _ opioids without by itself having an effect on nociception (Schneider and McArthur, 1956; Schneider, 1957; Frances et al., 1992; Bagal et al., 1996), and inhibits the development of tolerance to morphine anti-nociception (Cao and Bhargava, 1997). Prior exposure to  morphine potentiates ibogaine’s diminution of sensitized dopamine efflux in the NAc in response to morphine (Pearl et al., 1996) or ibogaine’s enhancement of morphine anti-nociception (Sunder Sharma and Bhargava, 1998), suggesting an effect on neuron-adaptations related to opioid tolerance or dependence.
Increased glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area has been suggested to mediate decreased ethanol consumption following the administration of ibogaine to rats (He et al., 2005; He and Ron, 2006). GDNF enhances the regeneration of dopaminergic function (Ron and
Janak, 2005) and is increased by antidepressant treatment (Hisaoka et al., 2007). The hypothesis that GDNF may mediate improvement in hedonic functioning and mood in chronic withdrawal from addictive substances is appealing, but does not appear likely to explain efficacy in acute opioid withdrawal. Although designated as a hallucinogen, ibogaine’s use in opioid withdrawal distinguishes it from other compounds
that are commonly termed “psychedelics”, namely the serotonin type 2A receptor agonist classical hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and mescaline, or the serotonin releasing substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA). In contrast
with ibogaine, there is no preclinical or case report evidence that suggests a significant therapeutic effect of classical hallucinogens or MDMA in acute opioid withdrawal. Ibogaine’s effects in opioid withdrawal do not appear to involve serotonin agonist or releasing activity (Wei et al., 1998; Glick et al., 2001). Serotonergic neurotransmission does not appear to play a significant role in mediating the expression of the opioid withdrawal syndrome, which remains unchanged even after extensive lesioning of the raphe (Caille et al., 2002). The phenomenology of the subjective state produced by Ibogaine has been attributed with the quality of a “waking dream” and distinguished from the state associated with classical hallucinogens (Goutarel et al., 1993; Lotsof and Alexander, 2001). The visual phenomena associated with ibogaine tend to occur with greatest intensity with the eyes closed, and to be suppressed with the eyes open, and often involve a sense of location within an internally represented visual or dream landscape, in contrast to an alteration of the visual environment experienced with the eyes open while awake which is often reported with classical hallucinogens. The occurrence of an atropine-sensitive electroencephalogram (EEG) rhythm in animals treated with ibogaine (Schneider and Sigg, 1957; Depoortere, 1987) suggests a waking neurophysiological state with an analogy to rapid eye movement sleep (Goutarel et al., 1993; Alper, 2001).

Cravings:

The Following is an abstract from a lecture prepared by Dana Beal, President of “Cures not Wars” and aids activist:

Beal, D. Abstract from lecture at the International Harm Reduction Conference, Barcelona, Spain, 2008.

GDNF "Re-Sprouting" of Dopamine Neurons Elucidates Therapeutic Iboga Effects Seen in Addicts.

Ibogaine, noribogaine, and the synthetic 18 methoxycoronaridine are in the beta-carboline subfamily of indolealkaloids, with a completed third ring attached to a stimulant sidechain, congeners varying according to the location of methoxy groups. A few published case studies show efficacy in treatment of opioid dependence in humans, with 67% or more abstinent for 2 months or longer after a single treatment. A medical ethnographic study of 3414 treatments worldwide found that 53% used ibogaine for the indication of acute opioid withdrawal. In animals, ibogaine reduces self-administration of opiates, alcohol, nicotine, amphetamines and cocaine--drugs that hijack the dopaminergic VTA/nucleus accumbens/pre-frontal cortex pathway that mediates craving and reward involving food and sex. Training pairing a reward with a stimulus provokes a dopamine spike anticipating the reward--producing craving, or compulsion. By raising dopamine levels, addictive drugs mimic reward, fostering intense craving. The synthetic Iboga alkaloid 18-MC, developed to accommodate NIDA objections to Ibogaine, eliminates both sigma 2 toxicity and the NMDA antagonism originally thought to mediate ibogaine's anti-addictive effects, yet is more effective for nicotine and amphetamines. Receptor effects common to Ibogaine and 18 MC (and therefore actually anti-addictive) were kappa opioid, alpha 3 beta 4 nicotinic acetylcholine blockade, plus slow release of a mood-enhancing serotonergic metabolite from ibogaine sequestered in bodyfat. Recently, ibogaine was also found to switch on a growth factor, GDNF, that not only re-sprouts dopamine neurons suppressed by amphetamines, alcohol, etc., but also back-signals to cell nucliei to express more GDNF mRNA, setting up an auto-regulating loop--no additional ibogaine needed. Nicotinic blockade seems to allow REM-like iboga effects consistent with regrowth/immune modulation, while iboga alkaloids may mimic melatonin and other endogenous (betacarboline) stimulation of growth factors such as GDNF. ACh potentiates quantum computational wave states that collapse into cascades of neurotransmitters, including neurotropins, whereby (REM-like) wave activity "programs" neuronal regeneration; viz. Plato: Mind "persuades" matter