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.
Science
February 16, 2023
Maxemiliano V. Vargas, Lee E. Dunlap, Chunyang Dong et al.
467 citations
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
Cell
April 28, 2021
Chunyang Dong, Calvin Ly, Lee E. Dunlap et al.
207 citations
A genetically encoded fluorescent sensor called psychLight, based on the 5-HT2A receptor structure, detects behaviorally relevant serotonin release and correctly predicts whether structurally similar 5-HT2AR ligands will cause hallucinogenic behavioral effects. Using psychLight, a non-hallucinogenic psychedelic analog was identified that produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The sensor enables in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and development of non-hallucinogenic therapeutics targeting the 5-HT2AR.
ACS Chemical Neuroscience
April 17, 2018
Lindsay P. Cameron, Charlie J. Benson, Lee E. Dunlap et al.
168 citations
Depression and anxiety impose large economic costs, and many patients do not respond to traditional antidepressants. A single dose of DMT, the main psychoactive compound in ayahuasca, initially increased anxiety-like behaviors in adult male rats but later reduced anxiety by speeding the extinction of conditioned fear memories. DMT also decreased immobility in the forced swim test, a standard measure of antidepressant-like effect. These results indicate that DMT produces both antidepressant and anxiety-reducing behavioral effects in rodents, supporting further research into ayahuasca and similar psychedelics as potential treatments for depression and PTSD.
ACS Chemical Neuroscience
July 12, 2018
Lee E. Dunlap, Anne M. Andrews, David E. Olson
105 citations
MDMA, known as ecstasy, is a small molecule that shapes youth culture similarly to LSD in the 1960s. Structurally related to amphetamine and mescaline, it produces unique subjective effects distinct from psychostimulants or hallucinogens and reliably induces prosocial states. This review covers MDMA's synthesis, pharmacology, metabolism, adverse effects, and potential medical uses. The authors argue MDMA may be the most important compound for the future of psychedelic science, capable of either advancing new research or triggering a second Dark Age for the field.
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.
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.
ACS Omega
May 7, 2018
Lee E. Dunlap, David E. Olson
15 citations
The quaternary ammonium salt byproduct forms at an exceedingly slow rate when DMT is exposed to dichloromethane (DCM), only accumulating significantly after prolonged contact. The byproduct is readily extracted into water. DMT can be exposed to DCM for less than 30 minutes with minimal risk of degradation, and the byproduct is not observed after aqueous extraction. Alternative solvents should be used for longer contact times. These findings have implications for preparing pharmaceuticals with the DMT structural core in high yields and purities.
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.
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.