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Ibogaine: Mechanisms of Action

Ibogaine is a fascinating psychoactive alkaloid with a complex pharmacological profile that has captured the attention of researchers, clinicians, and individuals seeking alternative therapies for addiction and other mental health conditions. It can be found in the long-used entheogen Iboga and other plants. 

While most psychedelics work primarily by activating the serotonin receptors, ibogaine appears to have a unique set of effects on multiple neurotransmitter systems, including serotonin, dopamine, glutamate, sigma, opioid, and cholinergic pathways. 

These effects are thought to contribute to the hallucinogenic and therapeutic effects of the compound, but the exact mechanisms are still not fully understood.

In this article, we will delve into the various mechanisms of action and effects of ibogaine and explore how they may contribute to its potential benefits for addiction, depression, and other mental health conditions. 

Keep reading to discover the latest research on ibogaine’s impact on neurotransmitter systems and highlight the potential implications of these findings for clinical practice.

Serotonergic Effects

Serotonin is a major neurotransmitter in the brain that plays a crucial role in the brain’s function and regulation of various physiological processes. It is essential for regulating mood, sleep, appetite, cognition, pain perception, social behavior, and more!

Unlike most psychedelics, which work primarily by activating the serotonin receptors, and more specifically, 5-HT2A, ibogaine appears to be only a partial agonist (1). 

This means it activates the receptor to a certain extent but not as strongly as a full agonist would. The partial agonist effect of the alkaloid is thought to contribute to its hallucinogenic effects.

The researchers also suggest that there may be an effect of ibogaine on other serotonin receptors, such as 5-HT1A and 5-HT3, but the evidence remains uncertain.

At the same time, studies clearly show that ibogaine can reversibly inhibit the reuptake of serotonin in the brain (2). Thus, ibogaine is a non-competitive serotonin reuptake inhibitor.

This results in an increased amount of the neurotransmitter in the synaptic cleft and prolongs its effect on target cells, as shown by in vivo studies (3). 

The effect of blocking the serotonin transporters, also known as serotonin reuptake pumps (SERT), is similar to the mechanism of action of some antidepressant medications, such as SSRIs, which also increase serotonin levels in the brain.

However, the researchers note that ibogaine also stabilizes the SERT in an ‘inward-facing’ confirmation that is different compared to the effect of SSRIs (2).

These effects suggest that ibogaine may have complex and multifaceted serotonergic effects. In particular, the increased serotonin levels in the brain may mediate the potential antidepressant effects of ibogaine.

Indeed, several animal studies have found that acute administration of ibogaine induced a dose- and time-dependent antidepressant-like effect in rats without affecting animal locomotor activity (4).

Dopaminergic Effects

Dopamine is a neurotransmitter that plays a critical role in the brain’s function, particularly in the regulation of movement, motivation, reward, and pleasure. 

Yet, studies are conflicting regarding the effects of ibogaine on dopamine signaling in the brain.

Some preclinical studies have suggested that ibogaine may enhance the release of dopamine in certain brain regions, such as the striatum, while other experiments note that the alkaloid actually lowers dopamine release (5).

Scientists suggest that these complex effects may be due to an interaction between ibogaine and the dopamine transporter (DAT) in the brain which reuptakes the neurotransmitter and lowers its concentration.

By interacting with DAT, Ibogaine appears to modify and dampen the dopamine response to addictive drugs. For example, researchers reported that the alkaloid reduced morphine-induced and nicotine-induced dopamine release (6).

In contrast, the scientists report that ibogaine enhanced the cocaine-induced increase in dopamine, while other studies report the exact opposite – dampening the dopamine increase after cocaine (7). 

Studies suggest that ibogaine can upregulate the expression of DAT and ‘correct’ deficiently folded dopamine reuptake pumps (8), (9). 

The alkaloid also increases the expression of neurotrophic factors such as GDNF and BDNF in the dopaminergic pathways in the brain, especially in the midbrain, which produces the majority of dopamine in the central nervous system (10).

GDNF and BDNF are neurotrophic factors in the brain that have profound importance for brain health and nerve cell survival. The upregulation of these factors and, more specifically, GDNF may also have major implications for the long-lasting anti-addictive properties of ibogaine (11).

Ibogaine may also interact with some of the dopamine receptors in the brain, but the precise nature of this interaction is not well understood.

Regardless, ibogaine has a unique effect on modulating dopamine activity and signaling, which are related to its benefits for reducing cravings and withdrawal symptoms associated with addiction.

Thus, by dampening dopamine responses to addictive drugs, modulating DAT, and upregulating GDNF levels in the brain’s dopaminergic pathways, ibogaine may exert potent and lasting anti-addictive and anti-withdrawal properties.

Effects on Opioid Receptors

Ibogaine and its metabolites have shown affinity to several opioid receptors, namely mu, kappa, and delta. 

The mu-opioid receptors are the ones activated by classic opiates such as morphine, and they play a role in processes related to the perception of pain, reward mechanisms, and forming of addictions (12).

Ibogaine appears to act as an agonist to the mu-opioid receptors (13). However, other researchers report the alkaloid and its metabolites may also have partial antagonistic effects (14).

Due to its complex effects on the mu-opioid receptors, ibogaine does not exert any of the effects of classic opioids. However, it appears to re-sensitize users to the effects of opioids.

Delta receptors are also involved in pain perception and also modulate emotional reactivity (15). Ibogaine binds weakly to those receptors, but in theory, this may have benefits for mood disorders.

Kappa receptors are also involved in mood, reward, and pain perception (16). Activation can lead to feelings of unease and discomfort, problems with coordination, and hallucinogenic effects.

Ibogaine is a reversible agonist to the kappa opioid receptors, and studies suggest that this agonism may play a role in the alkaloid’s putative anti-addictive effects (17), (18). Ultimately, the benefits of ibogaine regarding its affinity to the opioid receptors may be for mood, reduced symptoms of withdrawal, re-sensitization, and anti-addiction.

Cholinergic Effects

The cholinergic receptors are two main subtypes, nicotinic and muscarinic. Ibogaine interacts with both subtypes of receptors and appears to be a relatively potent inhibitor (19).

Most notably, studies suggest that ibogaine and its metabolites may block the α3β4 receptors, which are a type of nicotinic acetylcholine receptor (nAChR) (20).

These receptors are particularly abundant in the mesolimbic dopamine system, which is involved in reward, motivation, and addiction. They are activated by the neurotransmitter acetylcholine but also by nicotine and other compounds.

In fact, the α3β4 receptor subtype has been of particular interest in addiction research, as it is believed to play a key role in the reinforcing effects of nicotine and other addictive substances. 

Recent research suggests that the inhibition of α3β4 nicotinic acetylcholine receptors (nAChRs) represents another probable mechanism of action for ibogaine’s potent anti-addictive properties (21).

It’s also important to note that the blockade of ibogaine to the nicotinic receptors is not completely reversible, which indicates long-term effectiveness.

Effects on Glutamate Receptors

Glutamate is the primary excitatory neurotransmitter in the brain, and its activity is important for a wide range of physiological processes, including learning and memory, neural development, and synaptic plasticity (22). 

However, excessive glutamate release can lead to excitotoxicity and contribute to neuronal damage in conditions such as stroke and traumatic brain injury. Glutamate receptors can be AMPA, NMDA, and Kainate receptors.

Ibogaine appears to interact primarily with NMDA receptors, although the exact mechanisms through which it does so are not fully understood. Studies suggest that it blocks them by working as a competitive antagonist for the NMDA receptors (23).

Furthermore, studies show that by inhibiting NMDA receptors, ibogaine exerts long-term protective effects in experimental models against NMDA-induced seizures (24). 

According to the researchers, this may also be related to its long-lasting anti-addictive properties (25). One of the mechanisms is related to the fact that by antagonizing the NMDA receptors, ibogaine also inhibits the NMDA-evoked release of dopamine.

Ultimately, the researchers suggest that by interacting with the NMDA receptors, ibogaine can help “rewire” the brain and promote long-term anti-addictive effects.

Effects on Sigma Receptors

The σ (sigma) 1 and σ 2 receptors are intracellular, mitochondrial membrane chaperone proteins that act as signal transduction amplifiers in the brain and modulate the release and uptake of neurotransmitters.

Ibogaine has a high affinity for sigma-2 receptors, which are found primarily in the peripheral and central nervous systems, and a much lower affinity for sigma-1.

The effects of ibogaine on sigma-2 receptors are unique, but the exact mechanisms through which it interacts with these receptors are still not fully understood.

Research suggests that this interaction may play a role in ibogaine’s anti-addictive effects. That’s because ibogaine’s interaction with sigma-2 receptors may modulate dopamine release in the brain, which could explain its complex effects on dopamine levels (25).

Other ibogaine-related alkaloids also activate the sigma-2 receptors in the brain, which is thought to mediate several benefits for the brain, such as antidepressant effects (26). 

In addition, ibogaine has been shown to have neuroprotective effects in certain cell and animal models through its interaction with sigma-1 receptors. More specifically, the alkaloid may have the potential to attenuate autoinflammation in neural tissues (27). 

Ultimately, the effect of ibogaine on the sigma receptors may be a major factor in mediating its anti-addictive, antidepressant, and neuroprotective properties.

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