Background

Ketamine and LSD are also known as psychoplastogens and have been noted to promote neuroplasticity within short periods of time following a single use. These effects can translate into long-lasting behavioral changes, which make them promising treatments for anxiety and depression (Olsen 2018). Neuroplasticity is a function that is greatly implicated in learning as well as the creation of new connections within the brain. Our brains are largely plastic when we are developing from childhood but become much less plastic as we reach adulthood, making repairing damaged neuronal circuits difficult. Mood and anxiety disorders such as depression can cause disruptions in neuroplasticity that may require artificial plasticity promoters to treat (Liu, et al. 2017; Olsen 2018).

Psychoplastogens have neuroplasticity-promoting benefits that are often accompanied with psychedelic, hallucinogenic trips. While some may say the trips directly contribute to the substances’ therapeutic effects, they can be detrimental or even, in some cases, traumatizing to individuals, which can completely negate the benefits. Most of these substances have a myriad of potential downsides, such as ketamine having the potential for abuse and causing long-term gastrointestinal and urinary damage (Bokor & Anderson 2014). LSD can produce psychedelic disturbances, or “bad trips” if taken in high doses (Nichols & Grob 2018).

In 2020, Lindsay Cameron, Robert Tombari, David Olson, and others studied the potential of safer, non-hallucinogenic, synthetic analogues of ibogaine. Cameron et al. describe ibogaine as a naturally occurring plant compound that can potentially be used to treat substance use disorders. Some major limitations of ibogaine include its toxicity, non-polarity, hallucinogenic properties, and ability to cause fatal cardiac arrhythmias (Alper, et al. 2012). Cameron, et al. believe that ibogaine’s anti-addictive properties may be a result of psychoplastogens reducing drug-seeking behaviors by promoting structural and functional neuroplasticity. This “rewiring” of neural circuitry can potentially create broad anti-addictive properties rather than only blocking one particular substance.

Ibogaine has been used as a psychedelic in African religious ceremonies but became relevant to scientists once it was rumored to reduce drug cravings and abuse in humans (Brown 2013). One study indicates that ibogaine increases the expression of glial cell-line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA) to reduce alcohol-seeking behavior in rodents when it is infused into that brain area (He 2005). Other studies have implicated ibogaine in reducing brain-derived neurotrophic factor (BDNF) expression in the nucleus accumbens (NAcc) whose presence seems to promote addictive behaviors (Graham 2007; Marton, et al. 2019). 

Cameron, et al. studied the structural features of ibogaine to produce an analogue that did not have the toxic and hallucinogenic properties while retaining its behavioral, anti-addictive effects. They identified three characteristic structural features of ibogaine: an indole, tetrahydrozepine, and bicyclic isoquinuclidine. They systematically removed each element to determine what features were essential to the function of ibogaine. The tetrahydroazepine ring was identified to be a crucial component of ibogaine in promoting neurogenesis and neuroplasticity. One analogue, tabernanthalog (TBG), was shown to have lower hallucinogenic properties compared to ibogaine evidenced by reduced head twitching in rodents. TBG also showed reduced cardiac effects and toxicity at low doses in zebrafish. This suggests that TBG is a remarkably safer alternative to ibogaine in its current state, with the added benefit of being able to be synthesized in a single step from existing materials. 

Methods

To evaluate TBG’s effectiveness as a therapeutic equivalent to ibogaine, Cameron, et al. determined its potential as an antidepressant by using a forced-swim test on mice that were subjected to unpredictable, mild stress. TBG showed antidepressant-like effects on both the stressed and not-stressed mice by reducing immobility during the test only a day after treatment. However, TBG did not have as long of a lasting effect on locomotion 24 hours following treatment, which makes it seemingly less durable compared to a drug that does have lasting effects such as ketamine. Additionally, short-term treatment of TBG reduced alcohol- and heroin-seeking behaviors in mice, which matches binge-drinking behaviors and opioid usage in humans, respectively. TBG also reduced cue-induced relapse after a single treatment, which is a rare effect that is not observed in other drugs that have anti-addictive properties such as ketamine, which requires multiple treatment sessions before showing a reduction in relapse (Ezquerra-Romano, et al. 2018). While TBG also reduced sucrose-seeking behavior, an indicator of depression in mice, it did not have any effect on reinstatement. This leads to the possibility that TBG is modulating behaviors rather than drug use itself.

Conclusions

Cameron et al. concluded that TBG can be a potentially non-toxic, non-hallucinogenic, safe analogue of ibogaine in treating addiction and depression in animal models. Although Cameron, et al.’s research is breaking ground in creating safe psychoplastogens for therapeutic use in humans, more studies in different animals as well as humans must be done to determine effective dosages and to evaluate potential side effects. Cameron, et al.’s research is only a stepping stone in the psychedelics field and may provide a future in synthesizing therapeutic analogues of other drugs like psilocybin, whose therapeutic effects are often attributed to the psychedelic experience.

Figure created with BioRender. Brain diagram obtained from neuroscientificallychallenged.com.

[+] References

[+] Other Work By Nicholas Le