Classic psychedelics, such as psilocybin and LSD, have been shown to promote structural and functional plasticity in the brain, offering hope for durable relief from depression, PTSD, and other refractory brain disorders. These compounds typically activate the serotonin 5-hydroxytryptamine 2A (5-HT₂A) receptor, inducing a cascade of molecular events that include immediate early gene (IEG) activation and transient bursts of glutamate neurotransmission within cortical circuits. These neurochemical phenomena were considered essential precursors to the long-term remodeling of synapses and dendritic spines that underlie neuroplasticity. However, their association with powerful hallucinogenic effects raised significant challenges for clinical translation and wide-scale therapeutic use.

The study led by Aarrestad et al. confronts these challenges head-on by investigating whether TBG, a novel psychoplastogen structurally related to ibogaine but modified to be nonhallucinogenic, can stimulate cortical neuroplasticity through pathways similar to those activated by classical psychedelics but without triggering the immediate neurochemical cascades previously thought indispensable. Employing a sophisticated set of pharmacological interventions combined with genetic tools in rodent models, the researchers provide compelling evidence that TBG enhances dendritic spine density and promotes synaptogenesis through engagement of the 5-HT₂A receptor. This activation sets off downstream signaling pathways involving TrkB, the receptor for brain-derived neurotrophic factor (BDNF), as well as the mammalian target of rapamycin (mTOR) and AMPA-type glutamate receptors, all pivotal regulators of synaptic growth and plasticity.

Perhaps most strikingly, despite utilizing the canonical neuroplasticity pathway shared by classical psychedelics, TBG does not induce immediate bursts of glutamate or activate immediate early genes—transcriptional markers that have long been considered hallmarks and possibly prerequisites of psychedelic-induced neural remodeling. This dissociation between neuroplasticity and IEG activation challenges prevailing dogma and suggests that the brain can be coaxed into structural reorganization absent the overt neural excitation patterns linked to perceptual alterations. The implications for developing safer, scalable, and more widely acceptable therapeutics for mental health disorders are profound.

The authors meticulously mapped the temporal and spatial dynamics of TBG-induced cortical spinogenesis, using high-resolution imaging to demonstrate enhanced dendritic spine formation specifically in prefrontal cortical neurons. The prefrontal cortex is a key hub for executive function and emotional regulation, often disrupted in psychiatric illnesses. The enhancement of spinogenesis in this region was shown to be dependent on 5-HT₂A receptor signaling, as pharmacological blockade of this receptor abolished TBG’s effects. Further, genetic knockdown of TrkB similarly prevented the neuroplastic changes, underscoring the critical role of neurotrophic signaling downstream of serotonin receptor engagement.

Critically, the behavioral assays presented in the study link these cellular mechanisms to antidepressant-like effects in rodent models of chronic stress. TBG administration resulted in sustained improvements in behavioral paradigms reflective of mood and affect regulation, effects that were abrogated when cortical spinogenesis was pharmacologically inhibited. This finding firmly connects the promotion of cortical neuroplasticity by TBG with functional amelioration of depressive phenotypes, highlighting therapeutic relevance beyond molecular and cellular observations.

Contrasted with classical psychedelics, TBG’s lack of an immediate glutamate surge and IEG activation suggests a separation between the acute hallucinogenic or excitotoxic effects and the longer-term neuroplastic adaptations that underpin therapeutic benefits. This dissociation raises intriguing questions about the necessity of these immediate neurochemical events for clinical efficacy, potentially shifting the focus toward designing compounds that sidestep such side effects while preserving or even enhancing plasticity-promoting capacities.

The absence of IEG activation after TBG treatment also calls for a re-evaluation of the molecular signatures conventionally used to identify neuroplastic responses. Immediate early genes, such as c-Fos and Arc, have been widely exploited as markers of neuronal activation and plasticity, but this research suggests they may not be universally requisite or indicative of all forms of adaptive neural remodeling. Instead, more nuanced and context-dependent frameworks will be needed to catalog the molecular orchestration of plasticity.

From a therapeutic innovation perspective, the advent of nonhallucinogenic psychoplastogens represents a paradigm shift with ramifications far beyond clinical neurology and psychiatry. Compounds like TBG could pave the way for treatments that are more easily integrated into primary care settings, reduce stigma associated with psychedelic therapy, and mitigate regulatory hurdles linked to hallucinogenic properties. Moreover, the clearer mechanistic understanding elucidated by this work facilitates rational drug design strategies aimed at selectively targeting beneficial neuroplastic pathways without engaging side-effect-inducing circuits.

Looking forward, this research opens multiple avenues for further exploration. Determining whether other nonhallucinogenic psychoplastogens engage the same biochemical pathways, or if alternative circuits can be harnessed to promote neuroplasticity, remains an active area of investigation. Additionally, dissecting how the temporal dynamics of receptor activation and downstream signaling differ between classical psychedelics and TBG-like compounds could yield insights into optimizing dosing regimens to maximize efficacy and durability of therapeutic outcomes.

An important consideration will be the translatability of these findings to human clinical populations. While rodent cortical circuits share many conserved features with humans, the complexity of human neuropsychiatric disorders demands rigorous trials to assess safety, tolerability, and efficacy. The apparent decoupling of hallucinogenic side effects from plasticity induction offers a hopeful prospect for more acceptable treatments, but the nuances of human neurophysiology and subjective experience must be carefully evaluated.

Furthermore, the study provides a critical biochemical framework that might illuminate how certain pathologies characterized by impaired neuroplasticity could be ameliorated. Conditions such as major depressive disorder, post-traumatic stress disorder, and even neurodegenerative diseases like Alzheimer’s could potentially benefit from therapies that restore synaptic connectivity and plastic potential without inducing adverse neuropsychiatric symptoms.

Beyond therapeutic applications, the demonstration that neuroplasticity can be pharmacologically induced independently of immediate early gene activation raises fundamental questions about the cellular and molecular underpinnings of brain adaptability. It suggests there may be multiple molecular routes to achieve synaptic remodeling, each with distinct regulatory checkpoints and contextual dependencies. This realization could spur new experimental designs aimed at uncovering the diversity of plasticity mechanisms tailored to specific neuronal populations or brain states.

In summary, the findings by Aarrestad and colleagues mark a pivotal advance in our understanding of psychoplastogens and their mode of action. By demonstrating that TBG induces robust cortical neuroplasticity through 5-HT₂A-, TrkB-, mTOR-, and AMPA receptor-mediated pathways—yet without triggering immediate glutamate bursts or immediate early gene activation—the study challenges long-held assumptions about the neurobiology of psychedelics and opens promising doors for therapeutic innovation. The ability to achieve neuronal growth and synaptic remodeling without hallucinogenic effects could revolutionize how we approach the treatment of complex brain disorders, making neuroplasticity-based therapies safer, more scalable, and broadly accessible.

As neuroscience continues to unravel the intricate dance of receptors, signaling cascades, and gene expression that shape the brain’s plastic capacity, the distinction between neural excitation and structural adaptation becomes increasingly nuanced. TBG and related nonhallucinogenic psychoplastogens may well represent the vanguard of a new class of brain therapeutics that harness the power of plasticity in unprecedented, refined ways—potentially transforming mental health care and offering renewed hope to millions worldwide.

Subject of Research:
Neuroplasticity mechanisms induced by nonhallucinogenic psychoplastogens and their behavioral effects.

Article Title:
The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.

Article References:
Aarrestad, I.K., Cameron, L.P., Fenton, E.M. et al. The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nat Neurosci (2025). https://doi.org/10.1038/s41593-025-02021-1

Image Credits:
AI Generated

Neural tissue is exceptionally energy-hungry. The brain’s primary energy currency, adenosine triphosphate (ATP), is produced predominantly through mitochondrial oxidative phosphorylation and glycolysis. Neurons, glial cells, and their supporting vasculature form a sophisticated metabolic network that ensures an uninterrupted flow of glucose and oxygen, facilitating ATP synthesis. Alterations in any segment of this supply chain—be it glucose uptake, glycolytic processing, or mitochondrial function—can exert profound effects on neural signaling and plasticity. Thus, understanding the biochemical pathways of cerebral energy metabolism offers a lens through which to interpret brain health and disease.

In neuropsychiatric disorders such as depression, schizophrenia, bipolar disorder, and autism spectrum disorders, a recurring theme emerges: bioenergetic dysregulation. Research over the past several decades has revealed mitochondrial dysfunction, impaired glucose metabolism, and altered lactate dynamics in afflicted individuals. These anomalies manifest in diminished ATP production, increased oxidative stress, and compromised cellular homeostasis. Brain imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) have supported these biochemical findings, demonstrating region-specific metabolic deficits correlated with clinical symptoms.

Mitochondria, colloquially dubbed the “powerhouses” of the cell, have garnered heightened attention in psychiatry. These organelles are central hubs for energy conversion and reactive oxygen species management. Dysfunctional mitochondria not only falter in ATP generation but also contribute to excessive oxidative damage, triggering apoptosis or cell death. The neurobiological sequelae include synaptic weakening, impaired neurotransmitter release, and altered neural circuitry — all hallmarks observed in psychiatric conditions. Intriguingly, genetic studies have pointed to the involvement of nuclear and mitochondrial DNA variants influencing mitochondrial efficacy, suggesting a heritable component underpinning bioenergetic vulnerability.

On a systemic scale, the bidirectional communication between brain metabolism and peripheral energy states is increasingly recognized. The concept of the “brain-body metabolic axis” posits that disruptions in systemic energy balance—such as insulin resistance, obesity, or metabolic syndrome—can exacerbate or even precipitate neuropsychiatric symptoms. Peripheral metabolic disorders often mirror or potentiate central bioenergetic impairments, creating a vicious cycle that complicates treatment outcomes. This interconnectedness hints that psychiatric disorders might benefit from interventions traditionally reserved for metabolic diseases.

Therapeutic strategies targeting bioenergetic abnormalities are burgeoning. Pharmacological agents aimed at enhancing mitochondrial function, reducing oxidative stress, or modulating glucose metabolism have entered clinical trials with varying degrees of success. For example, compounds like coenzyme Q10, creatine, and nicotinamide adenine dinucleotide (NAD+) precursors have shown potential in restoring mitochondrial efficiency. Additionally, metabolic modulators such as ketone bodies and insulin sensitizers offer alternative fuel sources or improve glucose utilization respectively, yielding symptomatic improvements in some patients.

Lifestyle interventions also represent a pivotal front in remediating bioenergetic deficiencies. Nutritional approaches that optimize glucose availability or promote ketogenesis have demonstrated cognitive and mood benefits. Exercise, known to enhance mitochondrial biogenesis and efficiency, is regularly advocated as an adjunctive treatment. Moreover, novel neuromodulation techniques, including transcranial magnetic stimulation (TMS) and photobiomodulation, are being explored for their capacity to influence cerebral metabolism and ameliorate psychiatric symptoms indirectly.

The challenges that remain are formidable. The heterogeneity of psychiatric disorders complicates the identification of universal bioenergetic biomarkers. Moreover, temporal dynamics—understanding whether energetic deficits are causes or consequences of psychiatric pathology—require longitudinal and mechanistic studies. Advanced imaging technologies combined with molecular profiling promise to unravel these complexities. Precision medicine approaches integrating metabolic signatures could potentially stratify patients for targeted metabolic therapies.

Given the expanding corpus of evidence, future research agendas must emphasize multidimensional integration. Bridging neuroscience, mitochondrial biology, endocrinology, and psychiatry will be paramount. Deep phenotyping of patients coupled with metabolic profiling may facilitate early diagnosis or prognostic evaluation. Additionally, interdisciplinary collaborations can accelerate the development of novel agents that penetrate the blood-brain barrier and selectively enhance cerebral energy production without systemic side effects.

On a molecular level, advancements in single-cell metabolomics and proteomics provide tools to dissect cell-type-specific bioenergetic pathways. This granularity can elucidate how distinct neuronal populations or glial subtypes contribute to overall brain energy homeostasis and vulnerability. Unraveling the interplay between neuron and astrocyte metabolism, particularly the astrocyte-neuron lactate shuttle hypothesis, may reveal therapeutic targets that optimize substrate delivery and utilization.

Furthermore, the epigenetic modulation of metabolic genes introduces another layer of complexity and opportunity. Environmental stress, inflammation, and early life adversity can induce lasting changes in metabolic gene expression, influencing susceptibility to psychiatric conditions. Therapies aimed at reversing these epigenetic marks or enhancing metabolic resilience could reshape the future of mental health treatment.

In light of these insights, it is evident that the brain’s energy metabolism is not a peripheral player but a central determinant of psychiatric health. Disentangling the metabolic underpinnings of mental illness offers hope for innovative treatments that move beyond symptom management toward root cause remediation. The integration of metabolic diagnostics and therapeutics into clinical psychiatry holds promise not only for improved outcomes but also for a paradigm shift in understanding mental disorders.

To capitalize on the burgeoning knowledge, researchers and clinicians must pursue comprehensive, mechanistic studies coupled with translational efforts. The prospect of tailoring interventions based on individual metabolic profiles is an exciting horizon. As neuropsychiatry continues to embrace metabolic perspectives, the potential exists to unveil novel biomarkers, optimize pharmacological regimens, and ultimately enhance patient quality of life.

The marriage of brain bioenergetics with psychiatric research symbolizes a pivotal chapter in neuroscience. Advancements here may answer longstanding questions about the biological substrates of mental illness and drive the development of metabolically informed therapies. As we stand on the cusp of this new frontier, the urgency to fund and focus research efforts on brain-body energy interactions has never been greater.

This evolving understanding underscores a simple yet profound truth: to heal the mind, we must first understand and support the engine that powers it. With continued exploration into brain and body energy metabolism, the prospect for revolutionizing treatment paradigms for psychiatric disorders is within reach, illuminating a path toward more effective and enduring mental health interventions.

Subject of Research: Brain and body energy metabolism’s role in the pathophysiology and treatment potential for psychiatric disorders.

Article Title: Brain and body energy metabolism and potential for treatment of psychiatric disorders

Article References:
Andreazza, A.C., Barros, L.F., Behnke, A. et al. Brain and body energy metabolism and potential for treatment of psychiatric disorders. Nat. Mental Health (2025). https://doi.org/10.1038/s44220-025-00422-6

Image Credits: AI Generated

The newly identified fungus, named Periglandula clandestina, was found living within morning glory plants (Ipomoea tricolor), a species celebrated not only for its ornamental beauty but also for its biochemical complexity. Morning glories have been known to carry intricate chemical defenses, particularly ergot alkaloids, protective compounds produced by fungal symbionts. These alkaloids share structural similarities to the synthetic modifications found in LSD, a drug historically explored for its psychoactive and therapeutic properties. Hazel’s keen observation of subtle fuzz on the seed coats of morning glory plants led to the first hints that this elusive fungal partner was finally within reach of scientific characterization.

Under the auspices of a WVU Davis College Student Enhancement Grant, Hazel undertook the preparation of fungal DNA isolates, initiating genome sequencing efforts that ultimately substantiated the presence of a new fungal species. The molecular data, now cataloged in public genomic repositories, validate the classification of Periglandula clandestina and lay the foundation for future biochemical and pharmacological studies. “Sequencing a genome of this caliber is no small feat,” commented Professor Panaccione. “It’s extraordinary that a student could shepherd a project from discovery to genetic characterization.”

The genus Periglandula is a group of endophytic fungi known for their mutualistic relationship with morning glories. These fungi inhabit specialized structures on the plant’s seeds and tissues, synthesizing ergot alkaloids that contribute to the plants’ defense mechanisms against herbivory and disease. Ergoline alkaloids, produced exclusively by fungi, have a storied history — notably in the 20th century, when Swiss chemist Albert Hofmann synthesized LSD by modifying similar natural products derived from ergot fungi found in rye. Hofmann speculated decades ago that fungi colonizing morning glories might be sources of these LSD-like compounds, but despite intensive research, the responsible fungal species remained unidentified—until now.

Periglandula clandestina’s efficiency in producing large quantities of ergot alkaloids positions it as a compelling candidate for drug development pipelines. Ergot alkaloids have diverse and potent biological activities, ranging from vasoconstrictive to neurotropic effects. While ergot derivatives have traditionally been used to manage migraines, uterine hemorrhaging, and Parkinson’s disease symptoms, their clinical application often comes with significant side effects. Contemporary research aims to harness these compounds’ beneficial pharmacodynamics while minimizing toxicity, an endeavor Periglandula clandestina may substantially accelerate.

The discovery holds further intrigue because it solves a decades-old mystery in ethnobotany and fungal biology: how morning glories attain their psychedelic properties. The high concentrations of lysergic acid derivatives found in these plants had long suggested fungal involvement, but the actual fungus remained “clandestine,” evading detection. Corinne Hazel’s meticulous lab work and innovative application of genomic tools now bring clarity to this biological enigma. “The name fits perfectly,” said Panaccione. “‘Clandestina’ reflects the fungus’s elusive nature and the achievement in finally identifying it.”

Beyond its biochemical significance, this finding highlights the value of student-led research and the integration of molecular biology with classical mycology and plant sciences. Hazel’s journey—from noticing faint fungal growth on seed coats to contributing to a peer-reviewed Mycologia publication—epitomizes the potential for talent and opportunity to revolutionize scientific understanding. Her ongoing investigations aim to refine culturing techniques for this slow-growing fungus, an important step toward large-scale biochemical extraction and analysis.

More broadly, the discovery invites questions about the diversity of Periglandula fungi among other morning glory species and their respective alkaloid profiles. The possibility of undiscovered fungal symbionts with unique alkaloid biosynthesis pathways could transform both agricultural biotechnology and pharmacology. Since ergot alkaloids can have toxic effects on humans and livestock in unregulated forms, understanding and harnessing fungal metabolism presents dual imperatives: enhancing medication safety profiles and mitigating risks in crop production.

The symbiotic relationship between morning glories and Periglandula clandestina exemplifies a sophisticated evolutionary mechanism. The fungus benefits from protected niches within the plant, while the host gains chemical defenses and potentially enhanced survival. This mutualism underscores the broader interactive complexity of plant-fungal ecosystems and their unexplored potential for natural product discovery.

As research progresses, Periglandula clandestina may play a pivotal role in the development of novel psychedelics and pharmaceuticals aimed at treating an array of psychiatric disorders including depression, post-traumatic stress disorder, and addiction—areas where current therapeutic strategies remain limited. By delving into the fungus’s genetic blueprint and biochemical output, scientists hope to isolate compounds that maintain therapeutic efficacy with reduced adverse effects, a critical advancement amid growing interest in psychedelic-assisted therapies.

In summary, the identification and genomic characterization of Periglandula clandestina represent a landmark in fungal biology with promising implications for neuroscience and medicine. This discovery not only validates historical hypotheses about the origins of psychoactive compounds in morning glories but also opens a new frontier for biotechnological exploration of ergot alkaloids. Corinne Hazel’s groundbreaking contribution reflects the power of curiosity-driven research and may well inspire a renaissance in natural product drug discovery derived from plant-fungal symbioses.

Subject of Research: A newly discovered species of fungus, Periglandula clandestina, symbiotic with morning glory plants producing ergot alkaloids similar to LSD.

Article Title: A new species of Periglandula symbiotic with the morning glory Ipomoea tricolor

News Publication Date: 22-Apr-2025

Web References:
http://dx.doi.org/10.1080/00275514.2025.2483634

References:
Hazel, C., & Panaccione, D. (2025). A new species of Periglandula symbiotic with the morning glory Ipomoea tricolor. Mycologia. DOI: 10.1080/00275514.2025.2483634

Image Credits: WVU Photo/Brian Persinger

Keywords: Drug studies, Pharmacology, Research programs, Drug research, Affective disorders, Psychiatric disorders, Mental health, Cognitive disorders, Depression, Substance related disorders, Drug addiction, Cocaine addiction, Alcoholism, Narcotics addiction, Withdrawal symptoms, Illicit drugs, Mycology