Noribogaine is the primary active metabolite of ibogaine, a psychoactive compound found in the West African shrub Tabernanthe iboga. For centuries, ibogaine has been used in spiritual ceremonies and has recently gained attention for its potential to treat substance use disorders. When ibogaine is consumed, the body processes it into noribogaine, which is responsible for many of the long-term therapeutic effects. This has led researchers to investigate noribogaine as a standalone treatment for addiction.
From Ibogaine to Noribogaine
When a person ingests ibogaine, it undergoes a transformation within the body, primarily in the liver. This metabolic process converts ibogaine into several substances, the primary one being noribogaine. The conversion happens through the action of a liver enzyme called cytochrome P450 2D6 (CYP2D6), which chemically alters the ibogaine molecule.
This conversion is a form of first-pass metabolism, occurring rapidly in the liver after oral administration. As a result, levels of noribogaine in the bloodstream can quickly surpass those of ibogaine. An individual’s genetic makeup can influence how efficiently their CYP2D6 enzyme works, leading to different metabolism rates and varying concentrations of noribogaine.
A significant difference between the two compounds is how long they remain in the system. Ibogaine has a relatively short half-life and is eliminated from the plasma in about 4 to 7 hours. In contrast, noribogaine is lipophilic and can be stored in body fat, resulting in a much longer elimination half-life of 28 to 49 hours, allowing it to exert its effects long after ibogaine is cleared.
How Noribogaine May Interrupt Addiction
Noribogaine’s therapeutic potential in treating addiction stems from its complex interactions with multiple neurotransmitter systems. One of its primary actions is as a serotonin reuptake inhibitor (SSRI). By blocking the serotonin transporter, noribogaine increases the levels of this neurotransmitter in the synaptic cleft, the space between nerve cells. Elevated serotonin levels can help regulate mood and reduce drug cravings during withdrawal.
Noribogaine also interacts with the body’s opioid system, binding to both mu- and kappa-opioid receptors. Its action at the kappa-opioid receptor may help reset the brain’s reward pathways that have been altered by chronic substance use. This interaction is thought to alleviate withdrawal symptoms without producing the addictive properties associated with conventional opioid agonists.
While early reports suggested noribogaine was a full agonist at the mu-opioid receptor, recent findings indicate it may be a partial agonist. This means it activates the receptor to a lesser degree than full agonists like heroin. This partial activation could be sufficient to reduce withdrawal discomfort and cravings without creating a strong potential for abuse. Animal studies also suggest noribogaine may increase the expression of Glial Cell Line-Derived Neurotrophic Factor (GDNF), a protein that supports dopamine neurons implicated in addiction.
The Pursuit of Noribogaine as a Standalone Treatment
Researchers are pursuing noribogaine as a standalone treatment to harness the anti-addictive benefits of ibogaine while avoiding its drawbacks. The primary goal is to isolate the long-acting therapeutic properties from ibogaine’s intense psychedelic effects. These effects can be distressing and create risks of misuse.
Clinical research into noribogaine, sometimes known by development names like DMX-1001, is underway. Phase 1 clinical trials are evaluating the safety, tolerability, and pharmacokinetics of oral noribogaine in healthy volunteers. These studies aim to find a safe dosage range before testing its effectiveness in patients with substance use disorders.
A non-psychedelic treatment would be more accessible than ibogaine, which is a Schedule I substance in the United States. Scientists hope to create a medication that provides a “self-tapering” effect, blocking withdrawal and cravings for an extended period. Preclinical studies in animal models have shown that noribogaine can reduce the self-administration of substances like alcohol, cocaine, and opioids.
Safety Considerations and Known Risks
A primary safety concern with both ibogaine and noribogaine is cardiotoxicity. Both compounds can cause QT prolongation, a delay in the heart’s electrical recharging process between beats. This condition is visible on an electrocardiogram (ECG) and increases the risk of a dangerous heart arrhythmia known as Torsades de Pointes (TdP), which can lead to sudden cardiac arrest.
This cardiotoxic effect results from the compounds blocking hERG potassium channels in the heart, which are necessary for the proper repolarization of cardiac cells. Because noribogaine has a much longer half-life than ibogaine, its potential to cause these cardiac issues can persist for days. Fatalities reported hours or even days after ibogaine ingestion may be attributable to the lingering cardiotoxic effects of noribogaine.
The risk is further complicated by drug-drug interactions. Since ibogaine is metabolized by the CYP2D6 enzyme, taking it with other drugs that inhibit this same enzyme can lead to dangerously high blood concentrations of both compounds. Careful screening for pre-existing cardiac conditions and concurrent medication use is a standard part of clinical protocols to mitigate these risks.