Psychedelics are a panacea for drug addiction (PART II)

Brain

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Does ibogaine have potential against addiction?
Ibogaine is the main alkaloid of the shrub Tabernanthe iboga. Low doses are used by some equatorial African tribes as a stimulant to prevent fatigue, hunger, and thirst on the hunt, and high doses in religious rituals (Figure 7).

However, ibogaine also has negative side effects such as tachycardia, hypotension, nausea, vomiting, and even death. Some authors suggest that noribogaine, the main metabolite, may be behind the fatalities in humans because ibogaine has a half-life of 4-7 hours, and death occurs ≥8 hours and 24-48 hours after ingestion.
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The adherents of the bwiti movement (although it is not the only one in Africa associated with this plant) use ibogaine voluntarily (without subsequent regret or remorse; mostly for ritual or medical purposes), so one can hardly speak of "addiction" here. Ethnobotanists who have studied bwiti have been led to think about the use of the terms "addiction," "withdrawal" and "breakdown. The development of bwiti was also influenced by French colonialism-though, of course, ibogaine was used before that. But the French not only forced Africans to work hard and imposed crippling taxes, but also interfered with cultural patterns. The natives experienced despair, exile, and foreignness to their own land.
Male sexual activity on plantations or in forest camps also greatly increased venereal disease, reducing the fertility of both men and sick women. The dramatic decline in fertility questioned the possibility of maintaining generations over time. Religious leaders promised, among other things, that iboga would restore lost contact with ancestors, women's fertility, and the emergence of the next generations. Desperate natives found solace in bwiti - as ibogain allows one to feel a connection with ancestors through time and space, which constitutes one of the fundamental ideas of the movement.
Tabernanthe iboga was brought to France in the mid-19th century, and its psychoactive component was isolated in 1901 from the root bark. Between 1939 and 1970, ibogaine was marketed as a neuromuscular stimulant under the trade name Lambarene, recommended for the treatment of fatigue, depression and recovery from infectious diseases. Much of ibogaine's popularity, however, stems from the plant's anti-addictive effects, which had been known before, but gained particular popularity thanks to Howard Lotsoff.
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The young man with a group of friends in the 1960s studied the effects of ibogaine on the psyche - we can assume that at that time, such gatherings with friends were not surprising. In addition, these events took place a few years before ibogaine was no longer legal and the sale of Lambarene was stopped.

Among the unexpected effects was a lack of desire to use heroin, although before that G. Lotsof had an opioid addiction. During the trip, which lasted about a day, he was visited by visions, and at the end there was an insight: "If before I saw heroin as a drug that gave me a feeling of comfort, now this view has changed - heroin was something that brings death. The next thing I knew: I preferred life to death".

Twenty years after his psychedelic experience and intensive work, G. Lotsof founded the Dora Weiner Foundation, a non-profit organization whose goal was to promote ibogaine therapy.

During the same period, G. Lotsof
received a patent for the use of ibogaine as a withdrawal aid. Later patents were obtained for the treatment of cocaine, alcohol, nicotine, and poly-dependence, and a French patent was obtained by psychiatrist Claudio Naranjo for the psychotherapeutic use of ibogaine. In 1991, the National Institute on Abuse (NIDA) began a project to toxicologically evaluate ibogaine and create a research protocol on volunteers. Although meetings were held to develop Phase 1 and Phase 2 clinical trials, NIDA closed the project due to criticism from members of the pharmacological industry.

18-methoxycoronaridine
Like any psychedelic known today, ibogaine was eventually placed on the Schedule of Category 1 drugs in the United States and several other countries. However, Lotsof did not give up in his attempts to use ibogaine as an addiction treatment and convinced pharmacologist Stanley Glick to test the substance on morphine-dependent rats. The pilot study showed that ibogaine reduced morphine self-administration (at least for the next day). Through further collaboration by S. Glick,
M. Kühne and J. Bandaraj, the researchers synthesized the compound 18-methoxycoronaridine (Figure 9), which was effective in treating morphine and cocaine addiction in rats, being both less neurotoxic and non-tremor-inducing, compared to ibogaine.
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18-MC is currently being tested on healthy volunteers for safety assessment and, in the future, for the treatment of opioid addiction. Most of the synthesized analogues of 18-MC inhibited the nyctonic acetylcholine receptor α3β4 (located mainly in the medullary-medullary pathway), operating as a second reward system - separate from the mesolimbic one. It is assumed that they are reciprocally linked and can inhibit each other's activity. Glick et al. suggested that 18-MC, while in the medullary-cerebellar pathway, may attenuate mesolimbic activity, thereby reducing euphoria from drug use.

Molecular perversions
At this point there is no clear understanding of whether ibogaine has a "favorite receptor" because it binds to many with different affinities. Ibogaine, noribogaine, and 18-MC bind to μ-opioid receptors (MOR) in the micromolar range. On its own, ibogaine does not exhibit the classic MOR-mediated effect of analgesia, but enhances it in the presence of morphine. Noribogaine binds more to κ-receptors than to MOP.

Ibogaine inhibits the binding of the radioligand-labeled disocilpine (MK-801) in rats, which is a noncompetitive NMDA antagonist. NMDA antagonists block the effects of "reward" (in which environmental stimuli induce a desire to use) and reinforcement (in which certain stimuli reinforce this desire) from drugs such as morphine and cocaine. It can be assumed that NMDA receptor inhibition plays a role in the treatment of addiction.

Non-competitive antagonists are molecules that irreversibly bind to a receptor with any amount of an agonist (a substance that causes a physiological response when it binds to the receptor).
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Ibogaine stabilizes the inward-open conformation of the dopamine (DAT) and serotonin (SERT) transporters in vitro, acting opposite to amphetamines. The latter, by binding to DAT, causes dopamine to flow out of the cell into the synaptic cleft, whereas ibogaine, in contrast, reduces dopamine release.

Blockade of serotonin reuptake leads to its increased amount in the synaptic cleft; its antidepressant effect, as well as the effect of many stimulants, may be related to this. In rats, ibogaine has been shown to block the increase in extracellular dopamine concentration caused by cocaine, morphine and nicotine, which may be the mechanism that inhibits use.

Ibogaine and its analogues also demonstrate the unusual property of serving as "pharmacoshaperones" of DAT: when added to mutant transporters, ibogaine transformed immature proteins into mature ones, and mutant ones into working ones again. French chemist
Robert Gutarel hypothesized that ibogaine therapy induces a state functionally similar to the REM phase of sleep. During this phase, reconsolidation of learned information occurs: everything that happened during the day is recomposed in the brain, and new associations emerge. Gutarel suggested that this corresponds to a period of increased plasticity, during which pathological connections between key stimuli associated with, among other things, consumption can be weakened.

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Howard Lotsof about the tabernantalogue
However, what is the mystery of ibogaine's pharmacological properties?
Researchers in David Olson's laboratory wanted to understand what pharmacophore was needed to exhibit psychoplastic properties (Figure 12). An intermediate analogue that lacked isoquinuclidine was called ibogainalog (hereafter, IBG). It acted like ibogaine, but had a simplified chemical structure. The chosen molecule also had lower lipophilicity, which means (and was shown in in vitro tests) lower cardiotoxicity. The final variant was a molecule called tabernanthalog (TBG). It was synthesized in the likeness of 6-MeO-DMT, an analogue of the strong hallucinogen dimethyltryptamine, a molecule supposedly devoid of hallucinogenic effects (according to animal tests, it did not cause head jerking in rats).

Head twitch response (HTR) is a behavioral pattern of hallucinogen action manifested by rapid side-to-side head movements in mice and rats after activation of the serotonin 5-HT2A receptor. However, some compounds (e.g., lysuride) do not induce HTR, although they most likely bind to the same receptors.
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Hope for the future
David Olson, one of the co-authors of the article discussed here, is also the co-founder of Delix Therapeutics with the inspiring slogan - Rewiring the brain to heal the mind. They want to create a world-class company based on the therapeutic potential of psychoplastogens. And they see their mission as increasing patient access to safe, fast-acting, long-lasting medications. Maybe they will succeed, because they have a lot of investors willing to give money for promising and breakthrough research.

Recent work by Delix Therapeutics focuses on the development of a biosensor to determine the hallucinatory effects of compounds. PsychLight, a biosensor based on a chimeric serotonin receptor, allows recording conformational changes when serotoninergic hallucinogens bind to it. This technology will allow the development of therapeutic agents that target 5-HT2A receptors but do not cause hallucinations.

And the work discussed in this chapter was published in 2020 with support from the U.S. National Institutes of Health (NIH) and the U.S. National Institute on Drug Abuse (NIDA), as well as numerous other foundations. And in December 2021, Delix Therapeutics announced a partnership with these institutes to test one of the leading developments: a non-hallucinogenic and non-toxic analog of ibogaine, tabernanthalol.

In preclinical studies to investigate a potential drug, we need to determine how safe it is, how carcinogenic it is, how it affects fertility, and a host of other health-related factors. This work does not look like a full-fledged preclinical study (which may be just around the corner, given the partnerships with National Institutes), but it does borrow some elements from there.

Receptor mechanism
As we have seen before, ibogaine and noribogaine bind to many different receptors. We studied the binding of their analogues IBG and TBG only to serotonin and opioid receptors, and while there was almost no activity on the latter, these molecules acted just fine on human and murine serotonin 5-HT2A receptors. With respect to the 5-HT2B receptors, TBG and IBG behave as antagonists, which reduces the likelihood of heart failure.

Despite the promising results, another important question remains: isn't TBG addictive? Although it is known that psychedelic substances are (seemingly) not addictive, the authors conducted a conditionally-reflexive place selection test. This test can be used to show whether an animal spends more or less time in the compartment of the cage in which the experimental manipulation (in this case, administering TBG) was performed compared to the other compartment. In other words, how pleasant or unpleasant it was, and whether it was addictive. It turned out that at low doses, TBG did not induce a preference in the animals, and at high doses it even led to avoidance of that compartment. In this case, it helped answer the question: is tabernanthaline addictive?
The answer: it does not.
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Assessment of neuronal plasticity
As discussed above, one of the signs of neuroplasticity is a change in the structure of dendritic branches. Injection of TBG into cortical neurons of rat embryos increased the complexity of dendritic branches (Figure 14), but the effect was blocked by the serotonin receptor agonist ketansirin, indicating the involvement of 5-HT2A receptors in the process. In addition to the complexity of branching, we looked at the density of dendritic spines in cortical cultures - and it increased to the same extent as when neurons were treated with ibogaine. Such changes could potentially be useful in the treatment of psychiatric diseases because it stimulates plasticity, which can reconnect those neural circuits that lead to disease in new ways.
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As readers may recall, a peculiarity of psychoplastogens is that the changes that have occurred persist rather than being a temporary effect. This was confirmed by transcranial two-photon imaging, which showed that the formed spicules did not disappear for at least 24 hours after IBG and DOI administration (Figure 15).
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Porsolt forced swimming test
It is assumed that increased structural plasticity in the anterior brain regions (e.g., prefrontal cortex) mediates the sustained (>24 h) antidepressant-like effects of ketamine in rodents, and ketamine is a psychoplasticogen. From previous tests, we can see that TBG affects plasticity changes as well, but does it manifest itself at the behavioral level? Could it be that TBG also has an antidepressant effect?

The depressiveness of mice is assessed by the amount of time they spend trying to get out of a cylinder filled with water. The effect of TBH on behavior was assessed by forced immersion after a week of stress, during which the mice could not predict which stressor they would be exposed to today (Figure 16).
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As a result of this exposure (rather inhumane), the time that the mice were immobile after they stopped trying to get out significantly increased. And after a dose of TBG, it decreased again, i.e., the mice made more effort to stay afloat! Perhaps this also speaks to the antidepressant potential of TBG.

Effects of TBH on alcohol and heroin intake
An experiment simulating inebriation in humans was conducted using the "two-bottle test": when mice have access to drinkers with alcohol or water (Figure 17). The mice were subjected to repeated cycles of binge drinking and withdrawal for 7 weeks, resulting in high ethanol intake and blood levels equivalent to those in humans who regularly drink alcohol.
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Will we see a decrease in the amount of alcohol we use if we give TBG injections to the mice beforehand? Yes, we do! Injecting TBG three hours before accessing the drinkers reduced alcohol intake for the first four hours without affecting water intake. Again, the question is, what if TBG basically reduces the intake of another substance?
It turns out that no - neither sucrose nor water preferences changed, indicating a selective reduction in alcohol intake.

All his life Lotsof wanted recognition of ibogaine therapy as a treatment for addiction to psychoactive substances, and, of course, heroin. Thanks to his persistence and the desire of the academic community to help people with addiction, the experiments continue: rats were trained to associate light and sound with a dose of heroin (Figure 18) to see: Will TBG help this time, too?
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Under all three conditions, administration of TBG compared to controls dramatically reduced heroin-seeking behavior. However, administration of TBG also strongly reduced sucrose self-administration in a similar experiment, suggesting that the operant response in response to the TBG dose may be nonselectively impaired.

It was also shown that the response to the conditioned stimulus on presentation after extinction was less in the groups that received TBG beforehand. However, TBG had no effect on sucrose-seeking behavior. Thus, a single administration of TBG induced an anti-addictive effect lasting up to 12-14 days.

It seems that Howard Lotsof has not wasted so much effort, and now scientists can move on, with new questions and a scientific methodology to answer the boldest questions.

Conclusion
Cases from clinical practice, human and animal studies show the potential of psychoplastic compounds both in the treatment of problematic substance use and in psychiatric diseases. Their main advantage is to provide a sustained therapeutic effect through neuroplasticity within a day and after a single administration compared to the long-term effects of pharmacotherapies and psychotherapies.

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The simplification of ibogaine structure to obtain TBG made the compound not only safer but also synthesizable in one step, unlike 18-MC, which requires 13 steps for synthesis. In addition, it is unknown whether 18-MC has a psychoplastic effect compared to the demonstrated effect on the neuroplasticity of TBG.

We traced the amazing story beginning with the use of the African plant Tabernanthe iboga by the Bwiti religious movement, its sale in France as a cure for a variety of ailments, the obtaining of patents, the banning and the beginning of years of research on ibogaine through the incredible tenacity of passionate Lotsof and other scientists, and arrived at the point where this research reached a new level - scientists are no longer interested only in phenomenological experience, but in how this experience can be taken apart and see if it will work.

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And returning to the questions posed at the beginning of the paper - they can be tentatively answered positively: yes, the structure of psychedelics can be changed so as to retain their therapeutic effect but remove their hallucinatory one; yes, it is also possible that the therapeutic effects of psychedelics are due to their effect on neuroplasticity, not to a profound mystical experience.

The work associated with the identification of pharmacophores within mystical experience compounds certainly adds to, if not reverses, our understanding of their effects on brain function. There is little doubt that other compounds with the potential to treat a wide range of psychiatric disorders will follow, and will be more effective than currently available therapies.
 
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HerrHaber

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Nice work!
 

AnnaliseWilliamson

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Ibogaine is definitely a fascinating substance with a complex history and potential uses.
 

MsContingency

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I want to try Ibogaine to see if I can slowly decrease my meth use but I wouldn't even know how or how much to even take
 
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