Journal of NeurotraumaOctober 19, 2026Hoda K AbouEich, Ali Izadi, Jonathan Lifshitz et al.
There are currently no available effective pharmacological therapies for treating chronic cognitive deficits after traumatic brain injury (TBI). Psychoplastogens, including atypical psychedelics, classical serotonergic psychedelics, and neuroplastogens, are a class of small molecule drugs that can enhance neuroplasticity by inducing rapid and sustained effects on neuronal architecture and...
Of the classic psychedelics, lysergic acid diethylamide (LSD) is perhaps the best-known, but its complex chemical architecture has limited synthetic investigations aimed at generating analogues with improved safety and efficacy profiles. Here, we systematically deconstruct the tetracyclic ergoline core of LSD to create 9 simplified ergoline analogues (i.e., ergologs) and evaluate them in...
Neuroplastogens, small molecules that induce beneficial neuronal growth and plasticity, are a class of compounds emerging as new drugs for treating a range of central nervous system conditions. Clausenamide is a plasticity-promoting natural product isolated from the leaves of Clausena lansium, an evergreen native to Southeast Asia and southern China. Herein, we report an efficient synthesis of...
Recent clinical evidence suggests that racemic 3,4-methylenedioxymethamphetamine (MDMA) might be useful for treating a range of neuropsychiatric diseases including post-traumatic stress disorder (PTSD) and depression. However, concerns about its abuse potential stemming from its monoamine releasing properties have hampered its clinical development. Thus, safer analogues of racemic MDMA with...
Exogenously administered psychedelics produce both rapid and long-lasting effects on neuroplasticity and behavior, but it is currently unclear if endogenously produced psychedelics can elicit similar effects. There have been relatively few studies on the role of endogenous psychedelics in health and disease, perhaps owing to the difficulty in quantifying their levels and manipulating their...
ACS Chemical NeuroscienceOctober 13, 2025Rajiv Agrawal, Daniel J. Gillie, Alison E. Mungenast et al.8 citations
Many neuropsychiatric conditions, including depression, involve synaptic loss and atrophy of the prefrontal cortex. The rapid regrowth of cortical neurons has been hypothesized to explain the rapid and enduring therapeutic effects of psychedelics and the dissociative anesthetic ketamine. However, safety concerns related to hallucinogenic/dissociative properties have limited the addressable...
Abstract Psilocybin increases social connectedness and has strong clinical transdiagnostic efficacy for mental illness, making it a candidate treatment to reduce maternal disconnect, anxiety, and blunted affect seen in peripartum mood disorders. However, the efficacy and safety of psilocybin in peripartum mood disorders has not been investigated. We used a social stress model to examine the...
Tropane alkaloids and their derivatives represent a diverse class of small molecules with a broad range of therapeutic applications. Many tropanes regulate synaptic levels of neuromodulators by interacting with monoamine transporters such as dopamine (DAT) and serotonin (SERT) transporters. While DAT inhibition plays an important role in the addictive potential of tropanes such as cocaine,...
Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of...
Abstract Background Peripartum mood disorders (PMDs) are a major public health concern; they present in 20% of birthing parents and are responsible for 1 in 4 maternal deaths in the United States. The psychedelic antidepressant psilocybin (PSI) increases social connectedness, self-compassion, and has strong clinical transdiagnostic efficacy for mental illness – making it a candidate treatment...
The serotonin 2A receptor (5-HT2AR) modulates various neurotransmitter systems and is implicated in psychiatric disorders, including depression and schizophrenia. Despite progress, the detailed mechanisms of signaling at the 5-HT2AR and its therapeutic implications remain unclear, warranting further exploration. Overcoming the limitations of conventional pharmacology, photopharmacology...
Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the...
Anecdotal reports and preliminary clinical trials suggest that the psychoactive alkaloid ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder. Here we report a gram-scale,...
Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit...
Numerous preclinical studies have demonstrated that psychedelics promote the growth of cortical neurons in the prefrontal cortex. However, measuring psychedelic-induced structural plasticity in humans has remained a challenge. New advances in positron emission tomography imaging could facilitate the measurement of synaptic proteins in humans following psychedelic administration. Identifying a...
Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in...
There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical...
Abstract Intracellular calcium (Ca 2+ ) is ubiquitous to cell signaling across biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca 2+ levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and...
Tropane-containing small molecules like scopolamine are a promising class of psychoplastogens. However, their potent antagonism of all muscarinic receptor subtypes presents the potential for undesirable anticholinergic side effects. In an effort to decouple their neuroplasticity-promoting effects from their muscarinic activity, we performed phenotypic structure-activity relationship studies...
Psychedelics are quite unique among drugs that impact the central nervous system, as a single administration of a psychedelic can both rapidly alter subjective experience in profound ways and produce sustained effects on circuits relevant to mood, fear, reward, and cognitive flexibility. These remarkable properties are a direct result of psychedelics interacting with several key neuroreceptors...
Lysergic acid diethylamide (LSD), a semisynthetic ergoline alkaloid analogue and hallucinogen, is a potent psychoplastogen with promising therapeutic potential. While a variety of synthetic strategies for accessing ergoline alkaloids have emerged, the complexity of the tetracyclic ring system results in distinct challenges in preparing analogues with novel substitution patterns. Methods of...
Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or...
Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively...
The potential use of psychedelic drugs as therapeutics for neuropsychiatric disorders has been limited by their hallucinogenic properties. To overcome this limitation, we developed and characterized tabernanthalog (TBG), a novel analogue of the indole alkaloids ibogaine and 5-methoxy-N,N-dimethyltryptamine with reduced cardiac arrhythmogenic risk and a lack of classical psychedelic...
In recent years, psychedelics have garnered significant interest as therapeutic agents for treating diverse neuropsychiatric disorders. However, the potential for these compounds to produce developmental neurotoxicity has not been rigorously assessed, and much of the available safety data is based on epidemiological studies with limited experimental testing in laboratory animal models....