Ibogaine Mechanisms of Action
The following has been taken from: The Ibogaine Medical Subculture (Section 1.4), Journal of Ethnopharmacology 115 (2008) 9-24. Authors: Kenneth R. Alper, Howard S. Lotsof, Charles D. Kaplan.
“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 α3β4 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 α3β4 nAChR is relatively concentrated in the medial habenula and interpeduncular nucleus, where 18-MC’s antagonism of α3β4 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 neuroadaptations 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 antinociceptive 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 antinociception (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 antinociception (Sunder Sharma and Bhargava, 1998), suggesting an effect on neuroadaptations 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).”