Psychedelics Revamped Effect on Mortality12

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News & views which dietary protein, and BCAAs in par- is premature to recommend adoption by the Nature 493, 338–345 (2013). ticular, enhance evolutionarily conserved general population. This is especially true for 4. Le Couteur, D. G. et al. Ageing Res. Rev. 64, 101198 (2020). pro-longevity mechanisms. A clear picture those above the age of 65 or those who already 5. Chantranupong, L. et al. Cell Rep. 9, 1–8 (2014). is emerging of how specific amino acids are have a healthy, active lifestyle. 6. Solon-Biet, S. M. et al. Nature Metab. 1, 532–545 sensed by sestrin to regulate mTOR signalling (2019). 7. Selvarani, R., Mohammed, S. & Richardson, A. and autophagy and so preserve the function of Cristal M. Hill is in the Pennington Biomedical GeroScience https://doi.org/10.1007/s11357-020-00274-1 intestinal stem cells during ageing. Although Research Center, Baton Rouge, Louisiana (2020). many details remain to be elucidated, and 70808, USA. Matt Kaeberlein is in the 8. Newman, J. C. et al. Cell Metab. 26, 547–557 (2017). 9. Roberts, M. N. et al. Cell Metab. 26, 539–546 (2017). other downstream targets of mTOR are Department of Laboratory Medicine and 10. Hill, C. M., Berthoud, H.-R., Münzberg, H. & Morrison, C. D. likely to be involved in mammalian ageing, Pathology, Healthy Aging and Longevity Front. Neuroendocrinol. 51, 125–131 (2018). these studies represent a key step forward. Research Institute, University of Washington, 11. Fontana, L. et al. Cell Rep. 16, 520–530 (2016). 12. Yan, B., Su, X., Xu, B., Qiao, X. & Wang, L. PLoS ONE 13, The past decade has seen a growing trend Seattle, Washington 98195, USA. e0206134 (2018). in popular culture towards the idea that nutri- e-mail: [email protected] 13. Liao, C.-Y., Rikke, B. A., Johnson, T. E., Diaz, V. & tional strategies that delay ageing in rodents Nelson, J. F. Aging Cell 9, 92–95 (2010). 14. Jin, K. et al. PLoS Genet. 16, e1008835 (2020). should be adopted by people. Should we con- 1. Lu, J. et al. Nature Aging https://doi.org/10.1038/s43587- 15. Lipman, R. D., Smith, D. E., Bronson, R. T. & Blumberg, J. sider protein or BCAA restriction as a healthy 020-00001-7 (2020). Aging Clin. Exp. Res. 7, 136–139 (1995). 2. Richardson, N. E. et al. Nature Aging http://doi.org/ 16. Levine, M. E. et al. Cell Metab. 19, 407–417 (2014). lifestyle choice? Support for the idea that 10.1038/s43587-020-00006-2 (2021). excessive protein intake is associated with 3. Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. This article was published online on 14 January 2021. poorer health outcomes and increased mortality in humans can be found in epidemiological Drug discovery data11. But even in people who have chronic kidney disease — for whom protein restriction is a favoured clinical intervention — it is unclear whether protein restriction has an Psychedelics revamped effect on mortality12. It is also of note that most of the human evidence that points to the nega- Gabriela Manzano-Nieves & Conor Liston tive health impacts of high protein comes from populations that are probably eating too much An analogue of the psychedelic drug ibogaine has been altogether. Activity level is another factor that developed. The analogue mirrors ibogaine’s ability to treat has not been addressed in animal studies. addiction and depression in animal models, has fewer side Although speculative, it seems plausible that effects and is much simpler to synthesize. See p.474 protein or BCAA restriction could have quite different effects in people who have a seden- tary lifestyle than in those who are active and exercise regularly. The discovery in the 1940s and 1950s that cause dangerous irregularities in heartbeat There are other considerations, too. Genetic the drugs lysergic acid diethylamide (LSD) and neurotoxicity. Second, the drug produces background is crucial in the response to diet and psilocybin had psychoactive properties long-lasting hallucinations at therapeutic ary restriction, with an identical low-calorie ignited intense interest in whether psyche- doses. Third, ibogaine is technically compli- regimen increasing lifespan in some mouse delic compounds could be useful in the clinic1. cated to synthesize, limiting its production. strains but shortening it in others13. It is not yet But in the 1970s, increasing concerns about Cameron et al. set out to engineer an ibo- known how genetic variability might alter the safety and the drugs’ potential for abuse led gaine analogue that retained its therapeutic effects of dietary protein or BCAA restriction to research becoming increasingly restricted. potential but had less-severe side effects. The in mice, although a study published last year In the past decade, there has been a renewed authors first systematically deleted key struc- found that protein restriction has detrimen- interest in the therapeutic potential of psyche- tural elements of the molecule, and found that tal effects in about one-quarter of the genetic delic compounds, with preliminary findings ibogaine’s tetrahydroazepine ring is crucial for backgrounds tested in fruit flies14. indicating promise for drugs including LSD, promoting growth and branching of neurons There is also evidence that dietary restric- psilocybin and ibogaine in combating treat- in culture, as well as in the brains of mice. The tion initiated later in life might have reduced ment-resistant depression2, post-traumatic group subsequently synthesized ibogaine ana- benefits in rodents and, in some cases, result in stress disorder3 and anxiety in people who logues that retained their tetrahydroazepine premature death15. Interestingly, there seems have terminal cancer4. On page 474, Cameron ring and growth-promoting effects, but had to be a hint of this in the data from Richardson et al.5 report the synthesis of a non-hallucino- more favourable toxicity profiles. and colleagues, who found that starting BCAA genic analogue of ibogaine that could have the These efforts produced one particularly restriction at 16 months of age (perhaps equiv- potential to treat addiction and depression. promising candidate for further study — alent to 50 years of age in humans) seems to Ibogaine is a naturally occurring alkaloid a new compound called tabernanthalog cause about one-quarter of the female mice found in the West African rainforest shrub (TBG), which can be easily synthesized in to die early. Perhaps of relevance, dietary pro- Tabernanthe iboga (Fig. 1). Preclinical data a single step from readily available starting tein intake in young people is associated with and small-scale studies indicate that ibogaine materials. Cameron and colleagues used higher all-cause death rates, but this relation- might be useful for reducing drug cravings, established assays in rodents and zebrafish ship inverts at around the age of 65, such that withdrawal symptoms and the risk of relapse to compare TBG and ibogaine. They showed higher protein intake is associated with lower in opioid and alcohol addictions. This might be that TBG had lower hallucinogenic potential death rates in older adults16. because of ibogaine’s ability to modulate neu- than ibogaine, as measured by its propensity Taken together, these observations suggest ronal growth and maintenance and to alter the to elicit head-twitching behaviour in mice. It that although protein- and BCAA-restricted strength of the connections between neurons also showed less cardiac and developmental diets are a powerful research tool for explor- (synaptic plasticity)6–9. However, ibogaine has toxicity in zebrafish, especially at low doses. ing the fundamental mechanisms of ageing, it several undesirable properties10. First, it can Together, these data indicate that TBG is

probably a much safer alternative to ibogaine, although more studies will be needed to fully understand TBG’s toxicity across a range of doses and in acute or chronic dosing regimens. Next, the group evaluated TBG’s potential therapeutic properties. First, they assessed its antidepressant potential. They exposed mice to seven days of unpredictable, mild stressors, and then tested the animals on the forced-swim test — a commonly used assay for antidepressant compounds, in which mice alternate between periods of swimming and immobility. Compounds that reduce immobility in this test tend to have antidepressant properties in humans. TBG had rapid anti depressant-like effects on immobility behaviour just one day after treatment, to a degree comparable to ketamine, a rapidly acting antidepressant. However, TBG’s effects were not as durable as those of ketamine one week later. Future studies should assess whether TBG’s antidepressant-like effects could be extended

by modifying the dosing regimen or combin- SAZY LAURENT ing it with other interventions. Figure 1 | The drug ibogaine is derived from the roots and bark of the shrub Tabernanthe iboga. Ibogaine Second, Cameron et al. tested whether is a psychedelic compound that has shown promise for treating depression and addiction, but has several TBG could modify opioid and alcohol use undesirable properties. Cameron et al.5 have developed a safer analogue of ibogaine. in two rodent models of addiction. In a binge-drinking model, mice were offered drug’s antidepressant-like properties. The effective dosing regimens in humans; and, the choice between drinking water and 20% growth-promoting effects of TBG on neu- ultimately, to confirm its clinical efficacy. ethanol, then subjected to withdrawal of the rons were likewise blocked by ketanserin. Indeed, Cameron et al. are careful to empha- ethanol, in cycles over seven weeks, to pro- These findings raise the intriguing possibil- size that this report is just a first step in that

duce binge-drinking behaviour. TBG treat- ity that TBG acts rapidly through a 5-HT2AR direction, not an invitation to immediately ment reduced alcohol consumption rapidly, signalling pathway to produce therapeutic begin using TBG, ibogaine or related com- with sustained effects lasting at least two days, behavioural effects, which might then be pounds in the clinic or in unsupervised set- comparable to effects often observed with sustained through effects on neuron growth tings. Instead, their work presents a highly other anti-addiction drugs. and plasticity, as has been observed in stud- compelling case for pursuing this fundamen- In an opioid-seeking model, rats learnt to ies of ketamine. Studies will be needed to tally new class of therapeutic compound. It press a lever to receive an intravenous infusion evaluate whether and how synaptic plas- also provides a road map for future efforts to of heroin. In this setting, TBG caused a rapid ticity is required, and how synaptic plasticity engineer new analogues of psychedelic com-

reduction in heroin consumption. Perhaps and 5-HT2AR signalling together influence pounds that retain their potential therapeutic most compellingly, Cameron and colleagues behaviour and neuronal function through benefits while minimizing adverse side effects found that TBG effectively eliminated relapse and other unwanted properties. in rats that had been subjected to heroin with- “The work presents a highly drawal for 12–14 days after TBG treatment. This Gabriela Manzano-Nieves and Conor Liston remarkably durable protection from relapse is compelling case for pursuing are in the Department of Psychiatry, Sackler rarely observed after a single treatment with this fundamentally new class Institute for Developmental Psychobiology, other drugs, and suggests that TBG might be of therapeutic compound.” and Feil Family Brain and Mind Research especially useful for reducing relapse behav- Institute, Weill Cornell Medicine, New York, iour in people recovering from drug addiction. New York 10021, USA. Of note, TBG treatment also rapidly reduced effects on specific cell types and circuits. e-mail: [email protected] sucrose-seeking behaviour in rats. This finding Cameron and colleagues’ work builds a foun- 1. Vollenweider, F. X. & Kometer, M. Nature Rev. Neurosci. 11, suggests that TBG could be acting acutely, not dation for future investigations into whether 642–651 (2010). to diminish the rewarding properties of drug TBG and other ibogaine analogues can be 2. Carhart-Harris, R. L. et al. Lancet Psychiatry 3, 619–627 abuse, but instead to modulate learnt behav- used to treat addictions and depression. Ani- (2016). 3. Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L. iours more generally. This is an equally inter- mal models of psychiatrically relevant behav- & Doblin, R. J. Psychopharmacol. 25, 439–452 (2011). esting alternative explanation that suggests iours are notoriously complex, and no single 4. Ross, S. et al. J. Psychopharmacol. 30, 1165–1180 (2016). TBG could be useful for modifying a variety model faithfully recapitulates all aspects of a 5. Cameron, L. P. et al. Nature 589, 474–479 (2021). 11 6. He, D.-Y. et al. J. Neurosci. 25, 619–628 (2005). of habitual behaviours, and remains to be psychiatric disorder . Not all compounds that 7. Noller, G. E., Frampton, C. M. & Yazar-Klosinski, B. Am. J. explored. have promising behavioural effects in rodents Drug Alcohol Abuse 44, 37–46 (2018). How does TBG work? The authors showed turn out to be therapeutically useful. Exten- 8. Ly, C. et al. Cell Rep. 23, 3170–3182 (2018). 9. Glick, S. D. et al. Brain Res. 657, 14–22 (1994). that it potently activates the serotonin 2A sive studies in other animal models, and later 10. Iyer, R. N., Favela, D., Zhang, G. & Olson, D. E. Nat. Prod. receptor (5-HT2AR) protein. Co-treatment in clinical trials, will be needed to elucidate Rep. https://doi.org/10.1039/D0NP00033G (2020). 11. Nestler, E. J. & Hyman, S. E. Nature Neurosci. 13, 1161–1169 with ketanserin, a 5-HT2AR inhibitor, blocked how TBG works; to understand the relation- (2010). TBG’s effects on immobility in the forced-swim ship between drug dosing, therapeutic effects test, implicating this signalling pathway in the and adverse side effects; to establish safe and This article was published online on 9 December 2020.