African Psychedelic Plant Inspires Two New Depression Drugs
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Modeling the pharmacological properties of the African psychedelic plant medicine ibogaine, researchers have developed two novel drug candidates for treating addiction and depression. The research is published in Cell.
Ibogaine – a psychoactive compound derived from an African shrub
A revived interest in the use of psychedelic compounds for the treatment of psychiatric conditions has seen drugs such as LSD enter clinical trials and hit the headlines. A perhaps lesser-known molecule is the psychoactive indole alkaloid ibogaine, which is derived from the root bark of the native African shrub Tabernanthe iboga, also known as the iboga plant. In small doses it acts as a stimulant, reducing appetite and counteracting fatigue, but in large doses it can lead to intense hallucinogenic visions that have been likened to the effects of LSD.
Traditionally ibogaine has been adopted for medicinal and ritualistic purposes. In the mid-1900s purified ibogaine hydrochloride was marketed under the trade name Lambarène in France, where it was prescribed as a stimulant. Later in 1962, the American scientist Howard Lotsof advocated for the use of ibogaine as a treatment for opioid dependence to be explored based on his personal experience. Several studies have demonstrated encouraging results for this application.
A 2018 trial led by chemist Dr. Thomas Kingsley Brown, and funded by the Multidisciplinary Association on Psychedelic Studies (MAPS), found that ibogaine was associated with “substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful.” Brown suggests that ibogaine’s anti-addictive effects are achieved via two processes: a biochemical reaction in the brain and body followed by a psychoactive effect. In tandem, these processes appear to “eliminate opioid desire and withdrawal symptoms.”
However, ibogaine is a scheduled 1 substance, declared as unsafe for use and lacking medical application by the US Food and Drug Administration (FDA). This classification has limited its clinical development as a drug for treating addiction in the United States, but in other areas of the world, ibogaine is unregulated – it isn’t illegal, but it also isn’t approved for use. Successfully navigating this “grey area” in legal status, several alternative medicine centers have opened their doors to offer ibogaine treatment for addiction, sometimes for a substantial financial cost.
“Some people swear by ibogaine for treating addiction, but it isn’t a very good drug. It has bad side effects, and it’s not approved for use in the United States,” says Dr. Brian Shoichet, professor in the University of California San Francisco (UCSF) School of Pharmacy. Schoichet is referring to ibogaine’s complex pharmacology which, alongside the stigma associated with hallucinogens, contributed to its classification as a schedule 1 substance.
A “dirty” drug from pharmacology’s perspective
Beyond its effects on the brain, ibogaine can adversely impact the cardiovascular system, an effect that has been associated with several fatalities over the last few decades. According to Shoichet, ibogaine is what’s known as a “dirty” drug in pharmacological terms – it interacts with several processes, receptors and transporters in the human body, creating a myriad of side effects. This list of targets includes the serotonin transporter (SERT) – to which it is a non-competitive inhibitor – and the human voltage-sensitive potassium channel hERG, which plays a key role in the cardiac action potential. “Ibogaine binds to hERG, which can cause heart arrhythmias,” says Shoichet.
Shoichet’s lab harnesses computational docking methods to identify drug candidates that could treat depression and pain. Docking enables researchers to simultaneously test whether a variety of “virtual” chemical structures bind to specific proteins that could be drug targets. It’s a process that can be likened to searching for the correct key for a lock. Using computers, however, the scientists are not required to synthesize hundreds or thousands of keys (or drugs) to find one that fits – it’s all virtual work.
After Professor Gary Rudnick – an expert on SERT at Yale School of Medicine – spent some time in his lab, Shoichet too became interested in SERT, which is also the target through which selective serotonin reuptake inhibitor (SSRI) antidepressant drugs elicit their effects. In the new study, Shoichet and collaborators at UCSF, Yale and Duke University screened 200 million molecular structures to identify any that could block SERT in the way that ibogaine does, without a “spill over” effect.
Two molecules inhibit SERT and alleviate anxiety and depression symptoms
In the first round of docking, the list of 200 million molecules was reduced to 49, 36 of which could be synthesized in the lab and 13 that inhibited SERT. Virtual “docking parties” were then held by the team to aid Dr. Isha Singh – then a post-doctoral student in Shoichet’s lab – to prioritize specific molecules for further optimization. Singh, who is co-first author of the paper, says she was eager to transform the “buzz” surrounding ibogaine into a more comprehensive understanding of SERT.
The two most potent candidates were handed over to Professor Allan Basbaum at UCSF and Professor William “Bill” Wetsel who were tasked with exploring their safety and efficacy in pre-clinical models of depression, addiction and anxiety. At low doses, the compounds alleviated the symptoms in mice. “All of a sudden, they popped – that's when these drugs looked a lot more potent than even paroxetine,” Shoichet says. Paroxetine is an SSRI used to treat depression.
Cryo-electron microscopy (cryo-EM) was used to confirm that one of the two molecules, named 8090, indeed fit into SERT at the atomic level as Shoichet and Singh’s computational models had predicted. While 8090 inhibited SERT like ibogaine, it was more selective in its targeting and more potent in its effects. A major advantage is that it also lacked “spill over” effects when tested on a panel comprising hundreds of other transporters and receptors. “With this sort of potency, we hope to have a better therapeutic window without side effects,” Basbaum says. “Dropping the dose almost 200-fold could make a big difference for patients.”
Using computational methods to identify synthetic drugs capable of mimicking plant-based medicines without adverse side effects is becoming increasingly popular in drug discovery. In cases where the plant is used traditionally by Indigenous populations, synthetic alternatives could mitigate the effects of plant poaching that depletes the reserves available for Native groups.
The structures of the two molecules identified in this research have been shared with a chemical manufacturing company, a move that Shoichet hopes will increase their availability for further testing by other researchers. Meanwhile, he will continue to hunt for even more precise molecular structures.
“This is really the way science should be done,” Basbaum concludes. “We took a group with expertise in disparate fields and came up with something that might really make a difference.”
Reference: Singh I, Seth A, Billesbølle CB, et al. Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Cell. 2023. doi: 10.1016/j.cell.2023.04.010