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| Other names | 12-Hydroxyibogamine; Ibogamin-12-ol;O-Desmethylibogaine;O-Demethylibogaine;O-Noribogaine; (–)-Noribogaine |
| Routes of administration | Oral[1][2] |
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| Eliminationhalf-life | 24–50 hours[3][1][2] |
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| Chemical and physical data | |
| Formula | C19H24N2O |
| Molar mass | 296.414 g·mol−1 |
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Noribogaine, also known asO-desmethylibogaine or12-hydroxyibogamine, is the principalpsychoactivemetabolite of theoneirogenibogaine. It is thought to be involved in theantiaddictive effects of ibogaine-containing plant extracts, such asTabernanthe iboga.[4][5][6][7]
The drug appears to have a complexmechanism of action, with many different observed activities.[3][8][9][10][11] Some of its mostpotent actions is atypicalκ-opioid receptoragonism[12] andserotonin reuptake inhibition.[13] Noribogaine has potentpsychoplastogenic effects similarly to ibogaine.[14][15][16]
Noribogaine was first described in thescientific literature by at least 1958[17] and was first identified as a metabolite of ibogaine by 1995.[18] It was first studied in humans in 2015.[1][2]
Noribogaine is the majoractive metabolite of theoneirogenibogaine and is thought to be primarily though not exclusively responsible for its effects.[19][8] In contrast to ibogaine, noribogaine has been limitedly evaluated in humans.[19] It was noted in 2007 that administration of noribogaine to humans had not yet been reported.[19] In 2015 and 2016 however, twoclinical studies of noribogaine were published.[1][2] It was tested at relatively low doses of 3 to 180 mg in these studies.[1][2] At these doses, nohallucinations,dream-like states, or otherhallucinogenic effects were reported.[1][2] Similarly, it produced noμ-opioid receptoragonisticpharmacodynamic effects, such aspupil constriction oranalgesia.[1] At higher doses, in the area of 400 to 1,000 mg or more, ibogaine has been reported to produce hallucinogenic effects.[19][20][21]
Side effects of noribogaine includevisual impairment (specifically increased light perception sensitivity),headache,nausea,vomiting, andQT prolongation.[1][2]
| Target | Affinity (Ki, nM) | Species |
|---|---|---|
| 5-HT1A | >100,000 (Ki) IA (EC50Tooltip half-maximal effective concentration) | Rat Human |
| 5-HT1B | >100,000 (Ki) IA (EC50) | Calf Human |
| 5-HT1D | >100,000 (Ki) IA (EC50) | Calf Human |
| 5-HT1E | ND (Ki) IA (EC50) | ND Human |
| 5-HT1F | ND (Ki) IA (EC50) | ND Human |
| 5-HT2A | >100,000 (Ki) IA (EC50) | Rat Human |
| 5-HT2B | ND (Ki) IA (EC50) | ND Human |
| 5-HT2C | >100,000 (Ki) IA (EC50) | Calf Human |
| 5-HT3 | >100,000 (Ki) ND (EC50) | Mouse/rat ND |
| 5-HT4 | ND (Ki) IA (EC50) | ND Human |
| 5-HT5A | ND (Ki) IA (EC50) | ND Human |
| 5-HT6 | ND (Ki) IA (EC50) | ND Human |
| 5-HT7 | ND | ND |
| α1A–α1D | ND | ND |
| α2A–α2C | ND | ND |
| β1–β3 | ND | ND |
| D1,D2 | >10,000 | Calf |
| D3 | >100,000 | Calf |
| D4,D5 | ND | ND |
| H1–H4 | ND | ND |
| M1 | 15,000 | Calf |
| M2 | 36,000 | Calf |
| M3–M5 | ND | ND |
| nAChTooltip Nicotinic acetylcholine receptor | ND (Ki) 6,820 (IC50Tooltip half-maximal inhibitory concentration) | ND Human |
| I1,I2 | ND | ND |
| σ1 | 11,000–15,006 | Calf/guinea pig |
| σ2 | 5,226–19,000 | Calf/rat |
| MORTooltip μ-Opioid receptor | 1,520 (Ki) 7,420–16,050 (EC50) 3–36% (EmaxTooltip maximal efficacy) | Human Human Human |
| DORTooltip δ-Opioid receptor | 5,200–24,720 (Ki) IA (EC50) | Calf Human |
| KORTooltip κ-Opioid receptor | 720 (Ki) 110–8,749 (EC50) 13–85% (Emax) | Human Human Human |
| NOPTooltip Nociceptin receptor | >100,000 | Bovine |
| TAAR1Tooltip Trace amine-associated receptor 1 | ND | ND |
| PCP | 5,480–38,200 | Various |
| SERTTooltip Serotonin transporter | 41 (Ki) 280–326 (IC50) 840 orIA (EC50) ~30% orIA (Emax) | Human Human Human Human |
| NETTooltip Norepinephrine transporter | ND (Ki) 39,000 (IC50) ND (EC50) | ND Bovine ND |
| DATTooltip Dopamine transporter | 2,050 (Ki) 6,760 (IC50) ND (EC50) | Human Human ND |
| VMAT2Tooltip Vesicular monoamine transporter 2 | 570–29,500 (IC50) | Human |
| OCT2Tooltip Organic cation transporter 2 | 6,180 (IC50) | Human |
| VGSCTooltip Voltage-gated sodium channel | 17,000 (Ki) | Bovine |
| VGCCTooltip Voltage-gated calcium channel | ND (IC50) | ND |
| hERGTooltip human Ether-à-go-go-Related Gene | 1,960 (Ki) 2,860 (IC50) | Human Human |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified.Refs:[22][23][3][8][9][10][11][15][14][24] [25][26][27][28][29][30][31] | ||
Noribogaine has been determined to act as abiased agonist of theκ-opioid receptor (KOR).[12] It activates theG protein (GDP-GTP exchange) signaling pathway with 75% the efficacy ofdynorphin A (EC50 = 9 μM), but it is only 12% as efficacious at activating theβ-arrestin pathway.[12] With anIC50 value of 1 μM, it can be regarded as anantagonist of the latter pathway.[12]
The β-arrestin signaling pathway is hypothesized to be responsible for theanxiogenic,dysphoric, oranhedonic effects of KOR activation.[32] Attenuation of the β-arrestin pathway by noribogaine may be the reason for the absence of theseaversive effects,[12] while retaininganalgesic andantiaddictive properties. This biased KOR activity makes it stand out from the otheriboga alkaloids likeibogaine and the derivative18-methoxycoronaridine (18-MC).[12] Some other examples of atypical or biased KOR agonists includeRB-64,6'-GNTI,herkinorin, andnalfurafine.
Noribogaine is a potentserotonin reuptake inhibitor,[13] but does not affect thereuptake ofdopamine.[33] Unlike ibogaine, noribogaine does not bind to thesigmaσ2 receptor.[34][35] Similarly to ibogaine, noribogaine acts as a weakNMDA receptor antagonist and binds toopioid receptors.[36] It has greater affinity for each of the opioid receptors than does ibogaine.[37] Noribogaine has been reported to be a low-efficacyserotonin releasing agent, although findings are conflicting and other studies have found that it is inactive as a serotonin releasing agent.[30][29]
Noribogaine is ahERG inhibitor and appears at least as potent as ibogaine.[38] The inhibition of the hERGpotassium channel delays therepolarization ofcardiac action potentials, resulting inQT intervalprolongation and, subsequently, inarrhythmias and suddencardiac arrest.[39]
Ibogaine and thestructurally relatedhallucinogenharmaline aretremorigenic, whereas noribogaine is not or is much less so.[15][11][40][41]
Noribogaine, but not ibogaine, producespotentpsychoplastogenic effectsin vitro inpreclinical research.[42][43][43][14][15][30][16] This can be blocked by the serotonin 5-HT2A receptor antagonistketanserin, by themTOR inhibitorrapamycin, and by aTrkB antagonist.[42][16]
Noribogaine is highlylipophilic and shows highbrainpenetration in rodents.[10][3]
Theelimination half-life of noribogaine is 24 to 50 hours.[3][1][2]
Analogues of noribogaine includeibogaine,ibogamine,desethylibogamine,voacangine,tabernanthine,coronaridine,oxa-noribogaine, andGM-3009, among others.
Noribogaine was first described in thescientific literature by at least 1958.[17][41] It was first identified and described as ametabolite of ibogaine by 1995.[18][44][37][45] The first evaluation of noribogaine in humans was published in 2015.[1][2]
Visual changes involving change in light perception were reported shortly after dosing, mainly by subjects dosed with 120–180 mg. These changes only occurred during the drug absorption phase, being first reported 1 hour after dosing, and had disappeared by 2.5–3 hours. No hallucinations or dream-like states were reported. In contrast higher ibogaine doses produced symptoms including light sensitivity and closed-eyed dream-like states for 4–8 hours.15
Unlike LSD, mescaline, and psilocybin, the hallucinogenic properties of ibogaine cannot be ascribed to 5-HT2A receptor activation.
Indeed, an active metabolite of ibogaine, noribogaine, has already been well characterized both in vivo (e.g., 2,3) and in vitro (e.g., 35,36). Although some investigators (37) consider noribogaine to be the major determinant of ibogaine's pharmacology in vivo, studies in this laboratory (20) indicated that the elimination of noribogaine was also too fast for it to be responsible for all of ibogaine's prolonged effects. [...] The short-half lives of ibogaine and 18-MC strongly suggest that the pharmacological actions of both alkaloids are attributable to one or more active metabolites; although noribogaine has been proposed (2,37) as the mediator of ibogaine's prolonged action, it would appear that noribogaine alone cannot account for ibogaine's effects since brain levels of noribogaine also decline rapidly after ibogaine administration to rats (20).
Like the structurally relate harmaline, ibogaine produces tremors. In mice, ibogaine is tremorigenic, both when given intracerebrally (ED50 127 nmol/g brain, pg/g with a latency to tremor of about 1 min) (Singbarth et al., 1973) and systemically (ED50 12 mg/kg subcutaneous) (Zetler et al., 1972). Zetler et al. (1972) also established the tremorigenic structure-activity relationship of several ibogaine-like compounds, with the descending order of potency: tabernanthine > ibogaline > ibogaine > iboxygaine > noribogaine. Recently, Glick et al. (1994) found that, whereas ibogaine and tabernanthine produced tremors, ibogamine and coronaridine were devoid of such an effect.
Notably, the anti-addictive alkaloid ibogaine (Alper, 2001; Belgers et al., 2016) was the only psychedelic tested that had absolutely no effect (Figure S4). This was a surprising result because we hypothesized that ibogaine's long-lasting anti-addictive properties might result from its psychoplastogenic properties. Previous work by He et al. (2005) clearly demonstrated that ibogaine increases the expression of glial cell line-derived neurotrophic factor (GDNF) and that this plasticity-promoting protein is critical to ibogaine's anti-addictive mechanism of action. Because several reports have suggested that noribogaine, a metabolite of ibogaine, might actually be the active compound in vivo (Zubaran et al., 1999; Baumann et al., 2000, 2001), we decided to test its ability to promote neuritogenesis in cultured cortical neurons. Gratifyingly, noribogaine robustly increased dendritic arbor complexity with an EC50 value comparable to ketamine (Figure S3), providing additional evidence suggesting that it may be the active compound in vivo.
Ibogaine is an active hallucinogen in the 400 milligram area and has been clinically studied for the treatment of heroin addiction. In this latter role, the dosages employed may range as high as 1500mg. A primary human metabolism is via O-demethylation to give the free phenol 12-hydroxyibogamine. This metabolite, misnamed nor-ibogaine in the literature, appears to be pharmacologically active in its own right.
In what may be the most detailed mechanistic study to this day, Ly et al. (2018) have shown LSD, DMT, noribogaine, psilocybin, DOI, and, to a lesser extent, MDMA, to increase neuritogenesis and dendritic spine density in rat cortical cell cultures, through a 5-HT2A-dependent mechanism. Although BDNF levels were not significantly altered, these effects could be abolished by co-administration of a TrKB antagonist or rapamycin, suggesting a causal involvement of the mTOR pathway via BDNF-TrKB signaling (Ly et al., 2018). [...] Ly et al. (2018) confirmed the absence of ibogaine effect on BDNF levels but nonetheless showed increased synaptogenesis. It is likely that this molecule's complex pharmacology (low-affinity 5-HT2A interaction, weak SERT inhibition, NMDA antagonism, and kappa-opioid agonism) obscures our exploration of these mechanisms. Indeed, the 5-HT2A receptors seem involved as the intra-VTA infusion of DMT induces comparable anti-addictive effects to that of ibogaine (Vargas-Perez et al., 2017), and the synaptogenesis induced by ibogaine is blocked by ketanserin, a 5-HT2A/2C antagonist (Ly et al., 2018).
Significantly, when assessing the structural and functional plasticity of both IBO and NOR, it was found that NOR, rather than IBO, induces neural plasticity. NOR specifically increases dendritic arbor complexity with an EC50 value comparable to ketamine (Ly et al., 2018). Despite a weak binding affinity, this effect seems to be at least partially mediated by the 5-HT2A receptor, since ketanserin, a selective 5-HT2 serotonin receptor antagonist, blocked this effect (Ly et al., 2018).
