Nature
January 1, 2021
Lindsay P Cameron, Robert J Tombari, Ju Lu et al.
468 citations
Ibogaine, a psychedelic alkaloid, shows anti-addictive effects in humans and animals but has safety issues including toxicity and heart arrhythmias. Researchers engineered tabernanthalog, a water-soluble, non-hallucinogenic, non-toxic analogue made in a single step. In rodents, tabernanthalog promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects. This demonstrates that careful chemical design can create safer, non-hallucinogenic variants of psychedelic compounds with therapeutic potential.
ACS chemical neuroscience
February 1, 2023
Lindsay P Cameron, Seona D Patel, Maxemiliano V Vargas et al.
113 citations
Activation of serotonin 2A receptors (5-HT2ARs) is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. While hallucinogenic properties are generally attributed to 5-HT2AR activation, it was unclear whether these receptors also mediate antidepressant effects, especially because some nonhallucinogenic analogues show antidepressant-like properties. Using pharmacological and genetic tools, the authors demonstrate that 5-HT2AR activation is required for the antidepressant-like effects of tryptamine psychedelics, suggesting that hallucinogenic and therapeutic effects can arise through the same receptor.
Journal of neurochemistry
July 1, 2022
Hannah N Saeger, David E Olson
59 citations
Psychedelics show promise for treating depression, PTSD, and substance use disorder, potentially by reversing cortical atrophy through effects on neurotrophic factors, neuronal growth, and immune modulation. This review argues that similar approaches could benefit neurodegenerative disorders like Alzheimer's disease, where the primary psychedelic target, the 5-HT2A receptor, is dysregulated. Evidence also suggests psychedelics might help manage behavioral and psychological symptoms of dementia (BPSD). The authors call for more research in neurodegenerative models, emphasizing that the compounds' robust effects on neuroplasticity and inflammation warrant further investigation.
Neuroscience insights
January 1, 2021
Jamie Peters, David E Olson
38 citations
Addiction arises from maladaptive neuroplasticity that strengthens reward pathways driving compulsive drug seeking while weakening circuits for executive control. Psychedelics show promise for treating addiction, often attributed to insights gained during hallucinations, but they are also potent psychoplastogens that rapidly rewire the adult brain. Non-hallucinogenic psychoplastogens, such as tabernanthalog (TBG), have anti-addictive properties in preclinical models for alcohol and opioid addiction, suggesting hallucinations may not be necessary for therapeutic effects if pathological neural circuitry is repaired. This review discusses implications for addiction treatments and next steps for advancing TBG and related compounds.
Proceedings of the National Academy of Sciences
April 14, 2025
Jeremy R Tuck, Lee E Dunlap, Yara A Khatib et al.
32 citations
A newly designed compound, (+)-JRT, structurally similar to LSD but with reduced hallucinogenic effects, promotes the growth of dendritic spines in the cortex—a process that is diminished in neuropsychiatric diseases such as depression, addiction, and schizophrenia. In behavioral tests, (+)-JRT showed antidepressant-like and cognition-enhancing effects without worsening signs related to psychosis. This suggests that nonhallucinogenic compounds that promote neuroplasticity could be safer alternatives to psychedelics for treating conditions where psychedelics pose risks.
Neuron
February 5, 2025
Marc Duque, Alex B Chen, Eric Hsu et al.
27 citations
A brief exposure to ketamine can produce lasting changes in behavior and mood. In larval zebrafish, a short ketamine treatment suppressed the passive "giving-up" response that normally occurs when swimming fails to produce forward movement. Whole-brain imaging showed that ketamine initially hyperactivates a circuit involving norepinephrine and astrocytes, which controls this passivity. After ketamine is removed, the same circuit becomes less sensitive to futility, resulting in long-term increased perseverance. Experiments using pharmacology, chemogenetics, and optogenetics confirmed that norepinephrine and astrocytes are both necessary and sufficient for this effect. In adult mice, astrocytes in the cortex were similarly activated during a futility test, and ketamine also caused astrocyte hyperactivation. The cross-species conservation of this mechanism suggests new strategies for treating affective disorders.
Psychedelic medicine (New Rochelle, N.Y.)
June 1, 2023
Jasper A Heinsbroek, Giuseppe Giannotti, Joel Bonilla et al.
26 citations
Tabernanthalog (TBG), a novel analogue of ibogaine and 5-methoxy-N,N-dimethyltryptamine, lacks classical psychedelic effects and cardiac arrhythmogenic risk. In a polydrug model of heroin and alcohol co-use in rats, TBG reduced motivation for both substances in a progressive ratio test, where the number of lever presses required for a reward increased exponentially. The study used a two-bottle binge protocol for alcohol exposure, followed by self-administration training for intravenous heroin or oral alcohol, and then sessions with both substances. TBG's efficacy was preserved in animals with a history of heroin and alcohol polydrug use.
Nature chemistry
March 1, 2025
Rishab N Iyer, David Favela, Andras Domokos et al.
22 citations
A new chemical method produces ibogaine in seven steps from pyridine, enabling gram-scale synthesis. This approach also creates three additional iboga alkaloids, the unnatural enantiomer (+)-ibogaine, and four analogues. Biological tests show that (+)-ibogaine does not affect cortical neuron growth like natural ibogaine, while (-)-10-fluoroibogamine strongly promotes neuron growth and potently modulates the serotonin transporter. The work provides a platform for making iboga alkaloids and related compounds for further study, supporting research into their therapeutic potential for addiction and other neuropsychiatric conditions.
ACS chemical neuroscience
March 1, 2023
Robert J Tombari, Paige C Mundy, Kelly M Morales et al.
15 citations
Thirteen psychoactive compounds from different chemical classes were screened in larval zebrafish for developmental toxicity. Psychedelic tryptamines and ketamine were less neurotoxic than LSD and psychostimulants. The results provide a reference database for comparing neurotoxicity profiles of novel psychedelics being developed as therapeutics.
Frontiers in cellular neuroscience
January 1, 2022
Charles Sutton, Erin Q Williams, Hoomam Homsi et al.
13 citations
Mutations in the dopamine transporter gene cause Dopamine Transporter Deficiency Syndrome (DTDS), a fatal infantile parkinsonism-dystonia with no current treatment. Pharmacological chaperones can rescue some disease-causing variants. This study examined structure-activity relationships for two known chaperones, bupropion and ibogaine. The isoquinuclidine substituent of ibogaine and its analogs is important for chaperone efficacy. For bupropion, the secondary amine group is essential. Additional analogs with varying chemical modifications showed variable chaperone efficacies, contributing to the design of improved dopamine transporter pharmacological chaperones.
The Journal of organic chemistry
October 6, 2023
Jeremy R Tuck, Lee E Dunlap, David E Olson
7 citations
A novel seven-step formal synthesis of LSD has been developed, focusing on connecting the A- and D-rings first and then bridging the B- and D-rings last. The synthesis uses cross-coupling, intramolecular α-arylation, borrowing hydrogen alkylation, and rhodium-catalyzed C-H insertion to form the tetracyclic ergoline core. The methods enable the first introduction of substitutions on the C-ring, though each strategy faces unique challenges when elaborating to ergoline natural products. These findings provide insights that will guide future synthetic strategies toward ergolines and related compounds.
bioRxiv : the preprint server for biology
May 14, 2024
Run Zhang, Maribel Anguiano, Isak K Aarrestad et al.
5 citations
preprint
A new enzyme-based method called CaST (Ca2+-activated Split-TurboID) biochemically tags cells with elevated calcium levels in living animals within 10 minutes, without requiring implants or light delivery. The signal increases with calcium concentration and labeling time, acting as a time-gated integrator of calcium activity. Unlike transcriptional reporters that take hours, CaST allows immediate read-out after activity labeling. The approach was used to tag prefrontal cortex neurons activated by psilocybin in untethered mice, and the CaST signal correlated with psilocybin-induced head-twitch responses.
ACS chemical neuroscience
September 3, 2025
Arabo A Avanes, Hunter T Warren, Abinaya Senthil et al.
2 citations
Tropane alkaloids and their derivatives are a diverse group of small molecules with many therapeutic uses. Many tropanes affect dopamine and serotonin transporters in the brain. While blocking the dopamine transporter contributes to the addictive potential of tropanes like cocaine, modulating the serotonin transporter may counteract those effects. Serotonin transporter modulators such as MDMA, ibogaine, and SSRIs show promise for treating depression, addiction, and PTSD. This work profiled various tropane subclasses and identified compounds, notably UCD0168 and UCD0820, that potently modulate the serotonin transporter similarly to fluoxetine, MDMA, or noribogaine. UCD0168 acts as a full serotonin releasing agent, and UCD0820 as a partial one. The tropane scaffold can serve as a starting point for developing new serotonin transporter modulators.
Journal of medicinal chemistry
June 18, 2025
Alexandra Sink, Eline Pottie, Samuel J Carter et al.
2 citations
A photoswitchable ligand for the serotonin 2A receptor (5-HT2AR) was designed to independently study G protein- and β-arrestin2-dependent signaling pathways. The cis-photoisomer binds the receptor with greater affinity than the trans-isomer, at nanomolar concentrations. In functional assays, this ligand showed a preference for recruiting β-arrestin2 over mini-Gαq relative to LSD, offering a tool to investigate β-arrestin2's role in 5-HT2AR signaling and its potential involvement in psychedelic effects.
ACS chemical neuroscience
May 6, 2026
Maxemiliano V Vargas, Cassandra J Hatzipantelis, Lee E Dunlap et al.
A safer analogue of MDMA, called R-MDDMA, shows promise for treating PTSD and depression without the abuse potential of MDMA. Unlike MDMA, R-MDDMA does not activate 5-HT2B receptors, induce serotonin release, cause head-twitch responses, affect body temperature, or increase locomotion at therapeutic doses. However, it still promotes structural neuroplasticity in cortical neurons, facilitates fear extinction learning, and produces sustained antidepressant-like effects. These results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.
ACS chemical neuroscience
October 15, 2025
Cassandra J Hatzipantelis, Lindsay P Cameron, Min Liu et al.
A new genetic mouse model lacking the enzyme indolethylamine N-methyltransferase (INMT) shows that INMT is not required for the production of endogenous psychedelics, suggesting alternative biosynthetic pathways exist in rodents. INMT knockout mice had no major abnormalities in reproduction or growth but did exhibit altered behaviors across several domains. The study also describes highly sensitive mass spectrometry methods for quantifying endogenous psychedelics in mice. These findings challenge the assumption that INMT is the primary enzyme for endogenous psychedelic production and open new questions about the role of these compounds in health and disease.
Natural product reports
March 4, 2021
Rishab N Iyer, David Favela, Guoliang Zhang et al.
Iboga alkaloids, a family of natural products including the anti-addictive compound ibogaine and the chemotherapeutic precursor catharanthine, have inspired chemists and biologists for over 120 years. This review covers advances from 2000 to 2020 in their biosynthesis and chemical synthesis, as well as their development as next-generation neurotherapeutics for mental illness. The authors provide historical context for recent discoveries and highlight unresolved questions. Although significant progress in chemistry and pharmacology has occurred since the 1960s, the iboga alkaloids continue to drive scientific innovation.