The psychedelic ibogaine has built a reputation as an anti-addiction magic bullet. By now even have the Wolf of Wallstreet vouching for it. Drug manufacturers who fuelled the opioid crisis are forced to blow billions on lawsuit settlements. The state of Kentucky recently announced they might use double-digit millions for ibogaine research. Maybe you’ve heard of the promising effects of psychedelic psilocybin.
The clinical development of psychedelics is not as rosy as you might expect. There is an increasing number of case reports with severe and even deadly adverse events at high doses. Thus, scientists pursue next-generation molecules that unify life-changing efficacy with superior safety.
Join me on a journey to learn the biochemistry, therapeutic promise, and chemical synthesis of ibogaine and psychedelics-inspired medicines. How can we even know if these drugs might help, let’s say, heroin addiction?
Let’s start with the basics. What is ibogaine? Iboga comes from the bitter root bark of the Tabernanthe Iboga rainforest shrub native to West-Central Africa. Beyond traditional medicine, iboga also has a long-rooted – pun intended – importance to spiritual practices. From a Western perspective, its ritual use was first documented by French and Belgian explorers in the 19th century. Early on, high iboga doses were shown to induce powerful states of mind but also have toxic side effects. On the other hand, tribal hunters used much smaller quantities as mild stimulants. These guys were already microdosing before it was cool.
History of ibogaine and context:
Its recent history is reminiscent of other substances as it also meets what you could call the “20th century psychedelics starter pack”. Was iboga once sold commercially as a dubious extract, just like psilocybin or heroin? Check. Did the CIA run unsettling experiments as we’ve seen with LSD, in search of agents for warfare or mind control? You bet. And did the FDA classify ibogaine as a devilish Schedule 1 drug – to the dismay of people like Howard Lotsof who started to report anecdotal evidence of potent anti-addictive effects? Check. Although it was indeed abused by athletes as a doping agent, this classification dealt a blow to ibogaine investigations. While some early clinical studies were funded in the 1990s, many were terminated, and progress was quite sluggish.
Before we can understand medicinal effects, we need to take step back again from history. Iboga bark is not a pill, so it contains numerous natural products. This table from a mass spec study just shows ones over 1% – so the full list is long. Like we’ve mentioned for psilocybin, it could be that some of these phytochemicals support some sort of entourage effect of iboga. As the major alkaloid present with 2% of total bark weight, ibogaine is our primary molecule of interest. Here’s a fun fact some of you might find interesting: iboga even contains yohimbine, an alkaloid used as a dietary fat burning supplement.
Biochemical Effects of Ibogaine
In the body, ibogaine has a half life of roughly 7 hours. After ingestion, metabolization through a demethylation kicks in, catalysed by several cytochrome P450 enzymes. The resulting noribogaine with the free phenol group is more persistent. With an even longer half-life, it’s quite evident why ibogaine usually results in psychoactive effects over 24 hours, longer than most other psychedelics. Despite intensive research, we still do not understand these molecule’s mechanisms properly.
I mean, just look at this table – I’m you will agree that it seems complex! Unlike psilocybin or LSD, ibogaine does not get its hallucinogenic properties due to serotonin 2A receptor activation. This sets ibogaine apart from classical psychedelics.
Noribogaine displays sub-micromolar agonistic affinity to the kappa opiod receptor. This profile is reminiscent of the hallucinogenic natural product Salvinorin A, present in the leaves of the Mexican Salvia plant.
Noribogaine is also a strong partial agonist of the related mu opiod receptor – this is the target of classic opiod analgesics such as morphine and fentanyl, commonly used as sedatives or to treat severe pain. These agents are usually very dangerous, highly addictive substances – they are behind the extensive opioid overuse in the US. But as we will see, due to the breadth of molecular mechanisms implicated, ibogaine-derived substances could be helpful in overcoming opioid dependency.
Another key mechanism is the inhibition of NMDA-receptors, similar to drugs like ketamine and even alcohol. This might explain the dissociative effects of ibogaine shared with these other agents. NMDA receptors are glutamate-gated ion channels which drive neural processes like learning, memory, and neuroplasticity. I’m not saying that randomly taking drugs can help neurodegenerative diseases like Alzheimer’s. It’s probably counterproductive, but there is a molecular link here.
I wanted to highlight two other mechanisms – firstly, inhibition of serotonin and dopamine transporters. The 2 micro-molar Ki value for ibogaine and Noribogaine essentially match the affinity of amphetamines. Ibogaine differs from these notorious drugs of abuse as the serotonin uptake inhibition is non-competitive. This and other reasons are why ibogaine has a lower abuse potential than cocaine, another inhibitor of this class. This mechanism might drive ibogaine’s effect on mood and psychological performance.
Finally, the nicotinic acetylcholine receptor activity is perhaps most likely accounting for the anti-addictive property of ibogaine. Ibogaine is a non-competitive antagonist at several receptor subtypes, most notably the alpha 3 beta 4. This receptor is an important part of reward pathways. Blocking it can dampen dopaminergic activity and reduce self-administration of various drugs.
Beyond this, ibogaine also induces upregulation of GDNF. This is a crucial neurotrophic factor that promotes survival and plasticity of neurons, amongst others. This effect likely drives the attenuation of drug craving and use by ibogaine.
What is the Evidence for Ibogaine?
Now we’ve seen that ibogaine bridges several different classes of psychoactive substances. This translates into promising clinical efficacy, particularly in substance-use disorder. Most ibogaine studies lack rigorous clinical study design – however, there are good data in opioid and cocaine craving.
Let’s briefly check out the largest study, comparing self-reported mood and drug craving measures of opiod or cocaine dependent patients. Strikingly, after an oral dose of ibogaine, patients reported significantly lower levels of drug craving. This is measured through a questionnaire which tests patients’ confidence in ability to quit, emotionality and other factors. In addition, depressive symptoms got better as well. These improvements continued to grow after one month follow-up, indicating potentially quite durable benefits. Many other conditions have preliminary data but we will not talk about them here.
In any case, the upsides look quite promising. What about the downsides?
Ibogaine’s complex pharmacology leads to considerable potential to generate adverse effects. In rats, high doses led to degeneration of neurons. They did not replicate this in primates, so it might be species dependent and less worrisome. High doses have also led to tremors and convulsions in rats.
Much more importantly, ibogaine can also negatively affect the cardiovascular system by prolonging the QT interval of the heart. This comes from strong inhibition of hERG potassium ion channels. These channels coordinate the heart’s beating through repolarization of cardiac neuromuscular junctions. Abnormally QT intervals increase risk of developing heart rhythms problems and even sudden cardiac death.
That’s why alarming reports of life-threatening complications associated with ibogaine have been accumulating. As you can see here, even young people with no other substance use are at risk. Due to the longevity of the metabolite Noribogaine we mentioned, cardiac adverse events may also occur several days. In some cases it can even be weeks after intake of a single dose of ibogaine.
The goal is not to test ibogaine mindlessly in dozens of conditions, potentially giving patients sudden cardiac arrests. Instead, we should explore safer, ibogaine-related molecules to unlock its therapeutic potential. This research needs to elucidate the underlying mechanisms of actions. If promising, the drugs should be translated into robust, objective clinical trials in humans.
So how can we shift the balance towards better safety at similar or even better efficacy?
Ibogaine Variants: 18-Methoxy-Coronaridine
The first attempt at this is an investigational molecule is 18-MC. 18-Methoxy-coronaridine is a modified ibogaine with an additional methoxy and methyl ester group. It is synthesized differently than ibogaine, so stay tuned for the last chemistry section.
These new functionalities impact the pharmacological profile a lot. For instance, low activity at sigma sites reduces risks of neurotoxicity, while lack of activity on serotonin transporters means that 18-MC is not hallucinogenic. Interestingly, the activity at the alpha 3 beta 4 nicotinic receptor is much lower, but 18-MC is much more selective for this sub receptor than ibogaine. So, we can see that in some cases, a lower affinity is not bad if it is more targeted.
A more complicated point is also that this table only shows binding affinity – but sometimes, an equally strong affinity expressed as Ki can have a much higher IC50 value, which reflects true inhibition. Unlike ibogaine however, 18-MC does not increase GDNF expression, the additional factor believed to be critical for neuroplasticity, so their mechanisms of action are potentially distinct. Overall, 18-MC seems to have a much narrower spectrum of actions. In theory, this drives a greater therapeutic index – meaning the effective dose is much lower than a potentially harmful dose.
Regarding cardiotoxicity, 18-MC inhibits hERG channels roughly 3- to 4-times weaker than ibogaine. It’s not fully clear whether this is enough to abolish the arrythmia and cardiac adverse events – just shortly, we will check out another analog which is even better.
The clinical fate of 18-MC is not clear either. The biotech MindMed – don’t confuse it with Mind Cure – completed a Phase 1 trial last year with a solid number of patients dosed. Initial data was positive with good tolerability and no serious adverse events. They also planned a larger proof of concept trial. However, they paused it due to financial reasons with new financing and partnering required to advance the program.
Instead, the company is focusing their efforts on the development of LSD in phase 2 for anxiety and ADHD, and MDMA pre-clinically for autism spectrum disorder. As we have seen in previous videos on this channel, these drugs might be very promising in these conditions. So, who knows – strong data could resurrect MC-18. Drop me a comment if you want an update on these programs in future!
Ibogaine Variants: Tabernanthalog
In any case, fortunately there has been a promising addition to the analog roster. A 2021 paper in Nature reported the results of another quest into ibogaine analogs. Instead of throwing more groups on ibogaine like MC-18, the logic here was to simplify ibogaine’s structure, thereby improving accessibility and elucidating which features are most important for activity. In case of the ibogaine skeleton, you can envision two different simplified ring systems – one in light green and one in blue.
Out of many compounds, the most promising is “tabernanthalog“, featuring a shifted methoxy group compared to ibogaine. Before we check out why this molecule seemed to hit the sweet spot of safety and therapeutic effect – do you have an idea how to synthesize TBG?
Even though it’s quite sizeable, it requires only one step, a Fischer indole synthesis. This reaction links this substituted phenyl hydrazine with the seven-membered ketone, creating the tricyclic TBG. The mechanism is part of many undergrad courses. The initial condensation reaction forms a phenyl hydrazone which isomerizes to the enamine form, drawn here. Upon protonation, we have a sigmatropic rearrangement which creates the C-C bond. After re-aromatization, the nucleophilic amine drives C-N bond formation via the aminal – which eliminates ammonia under acidic catalysis. We will review full syntheses of ibogaine in the final section of this video – but you can already guess that making TBG in a single step with 55% yield is infinitely easier than synthesizing ibogaine from scratch.
What are Effects Of Tabernanthalog?
First up is hallucinogenicity. While appreciated by some folks, pharmaceuticals should not elicit hallucinations. Seasoned channel viewers will recognize the classic head-twitch response assay to test for hallucinogenic potential of molecules. As a positive control, we have 5-methoxy DMT which is strongly hallucinogenic, reflected in the frequent head-banging of mice. In red is IBG – this is not ibogaine but rather the simplified version with the methoxy at a constant position. Even lower than IBG was TBG in blue with essentially no hallucinogenic potential. So, these were quite some sleepy mice instead of the energetic headbangers for 5-MeO-DMT.
Remember ibogaine’s adverse cardiac effects, mediated by the hERG channel? Both simplified analogs have much weaker inhibitors than ibogaine. The simple shift of the methoxy position between IBG to TBG comes with an additional 7-fold reduction in IC50 value. The overall 150-fold weaker binding gives TBG its promise as a quote unquote “safer ibogaine”. Obviously, this is much better than the 3-4-fold difference between ibogaine and 18-MC, the first analog we talked about.
So, safety is just one part of the equation – but does TBG also bring similar positive effects? Here is where we want to review a few interesting experiments, starting with neural plasticity.
This is the ability of neural networks to change through growth or reorganization. One way to look at it is the growth of dendrites – these are a nerve cell’s extensions which propagate electrical stimuli. Exposure of rat neurons to ibogaine, IBG or TBG all lead to more dense dendritic spines.
We can distinguish if dendritic growth is due to slower break-down of spines, or instead by a higher rate of formation. Both DOI and TBG drive growth in the same manner – they accelerate the formation of new dendritic spines.
Do these psychoplastogenic effects translate into behavioral or anti-addictive effects for TBG as well? We pointed out, there are anecdotal and initial clinical reports that ibogaine can reduce alcohol or opioid use. For this analysis, you unfortunately must make mice alcoholic by giving them the option of binge drinking. After a standard 7-weeks protocol, they compared alcohol consumption between two groups. Mice who proceeded as usual (blank) and mice who received TBG prior to the drinking session. The latter group had much lower alcohol intake both during the initial part of the consumption test, as well as acutely over the following days.
The team observed similar effects when looking at heroin as another substance with high abuse potential. Here, TBG administration also led to a much lower heroin intake – seen on the left graph – and also seeking behavior – as seen on the right graph in terms of number of lever presses during their experiment.
As a last notable effect, we look at TBG’s impact on depression. We can investigate this through a “forced swim test”. “Less depressed” mice will spend more time in motion, somewhat reflecting their drive and will to live. Even though also quite controversial, all marketed antidepressants increase swimming time in the FST – so the test is legit. The researchers performed two tests – one 24 hours after administration of TBG, and a second after one week of rest. This time, the blank positive control bar is ketamine, an effective anti-depressant. During the first test, both ketamine and TBG reduced immobility. Adding ketanserin once again abolished the effect as you can see in red. Interestingly, ketamine’s effects seemed more durable, as it still led to significant lower immobility one week after administration. TBG on the other hand looked more like the vehicle control.
We discussed previously that ibogaine and its metabolite noribogaine interact with numerous biological targets. Unlike Noribogaine, TBG or IBG showed no activity at opioid receptors. Perhaps, the higher selectivity could lead to a better drug profile down the line. On the other hand, the control experiments which ketanserin already showed us that serotonin receptors are vital for TBG’s activity. A more detailed screening revealed that TBG is both an agonist of the serotonin 2A receptor – but also an antagonist to the serotonin 2B receptor. Drop a comment if you need some more explanations on how to read these charts. The interesting thing here is that many 2A agonists are also 2B agonists, which can lead to side effects like heart valve disease. 5-methoxy DMT is a key example – as you can see in the orange plot, it inhibits both receptors in a similar manner.
Outlook on Tabernanthalog
This case study was rather simple on the synthetic design part of things. Still, I think it’s really fascinating that TBG looks like ibogaine but seems to behave differently mechanistically. Although much work on translational science into humans and dosing optimization is required, TBG might be able to overcome ibogaine’s safety limitations and unlock the potential of this class of drugs.
And last, a brief note on Mindcure. This biotech company was pursuing the development of ibogaine, garnering some attention from professional and private investors such as the chap we saw during the intro. They supposedly were on track to have fully synthetic GLP supply of ibogaine ready by end of last year – but ironically, just two weeks after, reported the result of a strategic review – the discontinuation of all activities. The psychedelic pharmaceutical market can be quite volatile, and funding challenges in recent years have definitely not helped these companies either.
As a random side note, their website was dubious from the start as they didn’t get the molecular structure of ibogaine right – unless they were showing some other analog which I missed.
So – all in all, there are some promising evolutions, but progress is sluggish. I expect that we are still far away from regulatory approvals. Instead, emerging clinics in countries where ibogaine is legal will continue to draw visits from abroad. They might be helpful for some individuals as a last resort but come at a risk of sketchy medical practices and questionable patient safety.
On the positive side, we do see increased state and federal interest in ibogaine due to the opioid problem, and psychedelics more broadly. For instance, the state of Kentucky is currently considering the allocation of 42 million dollars for ibogaine research. Out of a much bigger pocket of almost a billion in settlement funds, this looks like money well spent on larger and broader clinical trials.
Organic Chemistry: Retrosynthesis of Ibogaine
Now we will discuss not one or two, but three different approaches towards the ibogaine framework – as well as the synthesis of 18-MC.
From a retrosynthetic perspective, given the high complexity of the ibogaine scaffold, there are various disconnections that lead to sensible synthetic approaches. A quite straight-forward option uses a Fischer indole synthesis with a simpler ketone. However, most approaches include the indole from the start to guide the synthesis. One method we will review uses transition metal catalysis, while others harness the electrophilic reactivity of the indole. The gram-scale synthesis we will look at uses yet another approach based on nucleophilic substitution at the aliphatic nitrogen. Note that these syntheses focus on ibogamine – which is ibogaine lacking the methoxy group – because it is not a controlled substance.
First total synthesis of ibogamine (Büchi)
Let’s start with the pioneering first total synthesis of ibogamine, published by Büchi in 1965. It started from this pyridinium salt, which was reduced to the diene. This prepared the Diels-Alder reaction with methyl vinyl ketone which nicely builds the iso-quinuclidine core of ibogamine. Next, some redox and functional group interconversions produce the following intermediate. There are quite a few things going on, so we won’t go into it in detail – but this is a nice exercise for motivated viewers. Now, hydrogenation of the benzyl protecting group released the nucleophilic amine, which was coupled to this indole, bearing an acyl chloride.
The next task was to create the central C-C bond to connect the rings. This was achieved in two steps – under acidic conditions, the indole electrophilically attacks the adjacent ketone, and the resulting adduct was reduced with Zinc and acid. A few more steps were needed to get all ducks in order. First, a reduction removed the acetate protecting group and partially reduced the amide. To get to the fully aliphatic amine, they had to take a detour due to the reactivity of the system. Elimination of the hydroxy group with base temporarily cleaved the isoquinuclidine ring.
The link was regenerated by reduction with Zinc, which is mediated through the unsaturated ketone. Finally, a Wolff-Kishner reduction with hydrazine removed the ketone and gave ibogamine. All in all, not bad for 1965, but can we make this more efficient?
Modern Synthesis of Ibogaine
That’s exactly what the second synthesis is about. It starts off with a Palladium-catalysed heteroannulation to forge a highly functionalized indole. You will note that the ring contains a methoxy group, so this is indeed a synthesis of proper ibogaine. Next, two iodide groups were introduced – first at the indole by treatment with electrophilic NIS, and second at the aliphatic position by deprotection and SN2.
This reactive iodide should remind you of the acyl chloride we saw in the 1965 synthesis – again, it allows the introduction of the isoquinuclidine through another substitution. This can be made in a similar fashion as we saw in the 1965 synthesis as well – so these syntheses have some parallels. Interestingly, the authors noted that when using potassium carbonate as a base, there was a significant degree of intramolecular cyclization to the cyclopropane. This could be suppressed by using caesium carbonate instead. Finally, the indole and isoquinuclidine were bridged through a reductive Heck coupling, which after elimination already gave our product ibogaine. This synthesis is definitely more efficient and direct – but is there anything cooler?
Large-Scale Synthesis of Ibogaine
Three time’s a charm today. Quite recently, a paper described the gram-scale synthesis of ibogamine in just nine steps and an impressive 24% overall yield. Most notably, this approach would provide ample material to pursue even more synthetic analogs, particularly ones than are more complex than TBG.
The synthesis started from this vinylogous ester. First, a simple silylation protected the primary alcohol. Then, a Stork-Danheiser transposition with the Grignard reagent formed an enone, now bearing the ethyl group present in ibogamine. Through a Mitsunobu coupling, this fragment was linked to an indole bearing an amine. So, this contrasts with the previous syntheses where we had an electrophilic indole partner, this one is nucleophilic.
The ketone was then selectively reduced under Luche conditions and acetylated to create an activated allylic system. This set the stage for pivotal Friedel-Crafts reaction – which as we’ve seen can be mediated by Bronsted or Lewis acids. After some screening, the chemists found decent conditions with catalytic camphorsulfuric acid and lithium perchlorate at a 5M concentration. This meant that the scale-up would require massive amounts of perchlorate. Initial optimization attempts were not fruitful, as they either had to keep the quantity of perchlorate or dilute the mixture to unpractical 0.001M. Ultimately, after trying enough conditions, they got good conditions employing only 2 equivalents of magnesium perchlorate.
Finally, the only thing left was the formation of the C-N bond on the isoquinuclidine – you might remember that we highlighted this as a key retrosynthetic disconnection at the start. First, the double bond which remained from the enone was hydroborated and activated as a mesylate. And last, the nitrogen was deprotected which triggered the intramolecular SN2 reaction to give ibogamine. The whole exercise delivered 1.1g of pure ibogamine in one go.
Synthesis of 18-Methoxycoronaridine
To conclude our journey, let’s check out the initial synthesis of 18-MC starting from tryptamine – as you can imagine, it will be more complex than the ibogaine syntheses given the two additional functional groups.
The route starts off with a condensation of tryptamine to the ketone of this fragment. If you are still awake, you will notice that this ester group ultimately ends up in 18-MC. Due to the alpha-chloro group, the product can undergo an intramolecular substitution, creating a transient aziridine, and rearrange to the expanded 7-membered ring. Then, the double bond can be reduced, and the nitrogen protected.
The unique thing about this system is that upon heating, a retro 1-4 addition can fragment the ring, liberating the free amine and the alpha, beta unsaturated ester. Why is this helpful? Well, by condensing the amine with this aldehyde, a dearomative Diels-Alder reaction can be triggered. As a side note – that it really matters down the line – note that because the intermediary (e)-enamine was preferred, the product has the substituents in trans positions. Also, the newly introduced piece features the methoxy group we want to have in 18-MC.
So now, it’s all about linking up the rings properly. First, a conjugate reduction regenerates the aromatic indole and releases the quaternary carbon. Next, a hydrogenation unveils the amine, which upon deprotection of the aldehyde forms yet another cyclic enamine.
Redrawing this structure, we realize that just a final ring closure is needed to create 18-MC. This was achieved by simply heating in toluene because the additional ester group proved quite handy. It’s likely that an intramolecular proton shift facilitates formation of an anion and iminium, which can react to create the quaternary centre and deliver 18-MC. This first synthesis from 2001 did seem a bit random – and there are more efficient routes that are more analogous to ibogamine – but I thought it was nice that they used the additional ester to guide the approach.
This concludes our ibogaine journey. I hope you learned several new interdisciplinary science facts today!
References on Ibogaine, Ibogamine, Tabernanthalog & 18-MC
- DARK Classics in Chemical Neuroscience: Ibogaine | ACS Chem. Neurosci. 2018, 9, 2475
- Phytochemical characterization of Tabernanthe iboga root bark and its effects on dysfunctional metabolism and cognitive performance in high-fat-fed C57BL/6J mice
- A systematic literature review of clinical trials and therapeutic applications of ibogaine | Journal of Substance Abuse Treatment 2022, 138, 108717
- Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes| Front. Pharmacol., Sec. Neuropharmacology 2018, 9: 00529
- The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation | Molecules 2015, 20, 2208
- 18-Methoxycoronaridine (18-MC) and Ibogaine: Comparison of Antiaddictive Efficacy, Toxicity, and Mechanisms of Action Annals of New York Academy of Sciences 2000, 914, 369
- A non-hallucinogenic psychedelic analogue with therapeutic potential | Nature 2021, 589, 474
- The Total Synthesis of (±)-Ibogamine and of (±)-Epiibogamine | JACS 1965, 87, 2073
- Total synthesis of ibogaine, epiibogaine and their analogues | Tetrahedron 2012, 68, 7155
- Gram-Scale Total Synthesis of (±)-Ibogamine | Org Lett 2023, 25, 4567
- Chemical Synthesis and Biological Evaluation of 18-Methoxycoronaridine (18-MC) as a Potential Anti-addictive Agent | Current Med Chem CNS Agents 2001, 1, 113