Endabuse40, 12-methoxyibogamine40

Ibogaine is a psychedelic tryptamine alkaloid first isolated in 1901 from the root bark of the Tabernanthe iboga shrub (also called iboga) of Central Africa,1 and the root bark of a shrub in the genus Tabernaemontana found in the Congo.2 Since that time, ibogaine has been isolated from several plant species particularly those in the family Apocynaceae to which T. iboga belongs.

Iboga plants have been used for centuries in the religious rituals of people living in the western part of Central Africa in countries such as the Republic of the Congo, Gabon, and Cameroon.3 The ceremonial cocktails contained a mixture of the naturally-occurring molecules found in the plant. Harrison G. Pope of the Harvard Botanical Museum theorized in 1969 that humans learned about the effects of iboga by watching the behavior of animals.4 First-hand accounts describe native animals like porcupines, boars, and gorillas digging up and eating iboga roots. After ingesting the roots, they would enter “a wild frenzy.” These indigenous people also use less potent versions of ibogaine cocktails to treat fatigue, hunger, and thirst.

In the 1930s, French pharmacists developed ibogaine as a pure drug, not a full plant extract, which was sold as a stimulant under the trade name Lambaréné.5 The drug was taken off the market in the 1960s when France declared ibogaine illegal.

The Chemistry of Ibogaine

Ibogaine was first isolated by Dybowski and Landrin in 1901.1 The crystalline structure of ibogaine was determined in 1960.6 It was first synthesized in 19667 and a simplified total synthesis was published in 2012.8 A detailed summary of ibogaine synthesis is found in Wasko et al., 2018.9 Ibogaine has two separate chiral centers and four stereoisomers but they are difficult to resolve.10

Ibogaine crystallizes into prismatic needles from ethanol.11 In addition to ethanol, it is soluble in ether, chloroform, acetone, and benzene. It is practically insoluble in water. The hydrochloride salt of ibogaine is soluble in water, as well as methanol and ethanol. It is slightly soluble in acetone and chloroform, but practically insoluble in ether.

The Pharmacology of Ibogaine

Ibogaine is cardiotoxic at micromolar levels.12–15 Specifically, studies have noted a prolongation of the heart’s QTc interval. Ibogaine has also been shown to be neurotoxic in rodents.16 At higher doses, the effects include tremors, convulsions, nervous behavior, and paralysis of the limbs.17 However, the doses used in these studies are below what would be used in a clinical setting.12

In terms of pharmacodynamics, ibogaine shows no clear preferences, having a moderate to weak affinity for a variety of receptors and transport proteins (see summary in Wasko et al. 2018). As a result, the hallucinogenic effects of ibogaine cannot be attributed to the activation of the serotonin 5-HT2A receptor (Ki = 16 µM).16 However, ibogaine’s principal metabolite noribogaine has sub-micromolar affinity (0.61 µM) as a partial agonist of the kappa opioid receptor.18 The mechanism of the dissociative effects caused by ibogaine may be similar to that of ketamine and other NMDA (N-methyl-D-aspartate) channel blockers.19,20

Ibogaine also binds in the low micromolar range to the mu opioid receptor, as does noribogaine in sub-micromolar range.21,22 This may explain the ability of ibogaine to decrease self-administration of morphine in rats.23,24

Studies indicate that ibogaine’s anti-opiate effects may be due to its noncompetitive antagonist action at nicotinic acetylcholine receptor subtypes including α1ß1 and α3ß4.25,26

The Applications and Potential of Ibogaine

Howard Lotsof was the first person to realize the potential of ibogaine to treat substance addictions.27 He was a heroin addict when he tried ibogaine in 1962 with several of his friends who were also addicts. They were surprised to find it caused marked reductions in their cravings and withdrawal symptoms. All of them quit using heroin as a result. Lotsof went on to become a scientist and dedicated his life to studying ibogaine for treating addiction.

In 1988, Dzoljic et al. were the first to publish on the ability of ibogaine to relieve withdrawal from narcotics addiction.28 Maisonneuve et al. elucidated the pharmacological interactions between ibogaine and morphine in 1991.24 After this, several other researchers showed ibogaine’s ability to reduce or interrupt the self-administration of opiates in rats and mice and alter their behaviors.23,29–32 Additional study results showed ibogaine was more effective in multiple administrations over time than from a single dose.23,29

Recent review papers and meta-analyses have concluded that ibogaine is effective for treating substance addiction and warrants further investigation.33–35 Several current studies have found ibogaine effective for treating opioid addiction.36–39

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