#5ht2a — Public Fediverse posts
Live and recent posts from across the Fediverse tagged #5ht2a, aggregated by home.social.
-
DATE: August 16, 2026 at 07:00AM
SOURCE: PSYPOST.ORG** Research quality varies widely from fantastic to small exploratory studies. Please check research methods when conclusions are very important to you. **
-------------------------------------------------TITLE: Psychedelic drug calms hyperactive brain cells linked to chronic pain
URL: https://www.psypost.org/a-single-dose-of-psilocybin-relieves-chronic-pain-and-depression-in-mice/
A single dose of the psychedelic compound psilocybin can rapidly relieve both chronic pain and the symptoms of anxiety and depression that often accompany it. The drug achieves this dual effect by calming hyperactive brain circuits associated with these linked conditions. The research was published in Nature Neuroscience.
Chronic pain rarely exists in isolation. People who suffer from persistent physical pain often develop mood disorders like anxiety and depression. These conditions can feed into one another, making the pain feel worse and making the depression harder to treat. Standard medical treatments usually address the physical pain and the mood symptoms separately, often with limited success.
Researchers suspect these conditions share an underlying physical root in the brain. Brain scans of individuals with chronic pain and depression often show abnormal activity in the anterior cingulate cortex. This region of the brain helps process emotions and the unpleasantness of pain.
Psilocybin is the primary psychoactive ingredient found in magic mushrooms. Once ingested, the body converts it into an active molecule called psilocin. Psilocin binds to serotonin receptors in the brain, which are the same receptors targeted by many standard antidepressant medications.
Recent clinical trials have shown that psilocybin can provide lasting relief for severe depression. Separate observations suggest it might also help with chronic nerve pain. University of Pennsylvania researchers Joseph Cichon, Ahmad Hammo, and Stephen Wisser wanted to see if a single treatment could target the shared brain circuits of both conditions at the same time.
To study this, the research team first established chronic pain in laboratory mice using two different methods. One group of mice received a minor surgical nerve injury to simulate long-lasting nerve pain. Another group received a specialized injection in their paw to create persistent inflammatory pain.
After a few weeks, both groups of mice displayed severe sensitivity to a light physical touch. They also began to show behaviors that researchers use to gauge anxiety and depression in rodents. For example, they spent less time exploring open, exposed areas, and they showed less motivation to keep moving when placed in water.
The researchers then gave the mice a single systemic injection of psilocybin. The next day, the mice showed a complete reversal of their physical pain sensitivity. Their mood-related behaviors also returned to normal baseline levels. This restorative effect lasted for at least twelve days, which was the end of the testing period.
To verify that the psilocybin was actually relieving the negative experience of pain, the team used a behavioral test involving two connected rooms. The mice were given psilocybin in one specific room and a plain saline solution in the other.
When given the freedom to choose, the mice with chronic pain strongly preferred to spend time in the room where they had received psilocybin. Healthy mice without pain did not show this preference. This indicates that the mice associated the environment with the relief of their discomfort.
Pain signals travel from the body, up the spinal cord, and into the brain. The researchers needed to find out exactly where the drug was acting to provide relief. They injected psilocin directly into the lower spinal cords of a group of mice with nerve pain. This local spinal treatment did not improve the animals’ pain or mood behaviors.
Next, they injected the psilocin directly into the anterior cingulate cortex of the brain. This direct brain application rapidly reversed both the physical pain sensitivity and the signs of depressed mood. This result suggests that the drug works by altering networks in the higher brain centers rather than blocking pain signals at the spinal level.
To observe this brain activity in real time, the team used a technique called two-photon calcium imaging. This allowed them to look at individual brain cells in the anterior cingulate cortex of awake mice.
They found that mice with chronic pain had abnormally high levels of spontaneous cellular activity in this brain region. When the researchers applied psilocin to the area, it rapidly suppressed this erratic hyperactivity. The overactive cells quieted down to match the activity levels seen in healthy mice.
Psilocin interacts with several types of serotonin receptors, specifically ones known as 5-HT2A and 5-HT1A. To figure out which receptors were responsible for the healing effect, the team gave the mice drugs that block these specific receptors before administering the psilocybin.
Blocking either the 5-HT2A receptor or the 5-HT1A receptor completely stopped the psilocybin from working. The mice remained in pain and continued to show depressed behaviors. This demonstrates that psilocybin requires access to both of these serotonin receptor types simultaneously to initiate its healing effects.
In pharmacology, a full agonist is a drug that turns a receptor on completely. A partial agonist, like psilocin, only turns it on partially. The researchers tested what would happen if they used different drugs to fully activate the 5-HT2A and 5-HT1A receptors in the mice.
Activating these receptors fully, even at the same time, failed to replicate the broad therapeutic effects of psilocybin. The mice did not experience the same comprehensive relief from pain and mood issues. The researchers suspect that the partial activation provided by psilocin creates a specific, balanced modulation of brain cells that full activation cannot achieve.
While these animal studies offer a detailed look at brain circuitry, mice are not humans. Brain structures and the subjective experience of pain differ between species. It is not yet known if the specific dosage that provided relief in mice will translate safely and effectively to human patients.
The researchers tracked the mice for twelve days after the single dose. It remains unseen exactly how long the pain relief might last beyond that window.
Future studies will need to explore how this brief chemical intervention translates into long-term physical changes in the brain. The authors suggest that calming the hyperactive brain cells might allow the brain to physically rewire itself, breaking the cycle of chronic pain and depression over time.
The study, “Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain,” was authored by Ahmad Hammo, Stephen Wisser, and Joseph Cichon.
URL: https://www.psypost.org/a-single-dose-of-psilocybin-relieves-chronic-pain-and-depression-in-mice/
-------------------------------------------------
Private, vetted email list for mental health professionals: https://www.clinicians-exchange.org
Unofficial Psychology Today Xitter to toot feed at Psych Today Unofficial Bot @PTUnofficialBot
-------------------------------------------------
#psychology #counseling #socialwork #psychotherapy @psychotherapist @psychotherapists @psychology @socialpsych @socialwork @psychiatry #mentalhealth #psychiatry #healthcare #depression #psychotherapist #psilocybin #chronicpain #anxiodepressive #serotoninreceptors #5HT2A #5HT1A #neuroscience #NatureNeuroscience #painrelief #psychedelictherapy
-
DATE: August 12, 2026 at 10:00AM
SOURCE: PSYPOST.ORG** Research quality varies widely from fantastic to small exploratory studies. Please check research methods when conclusions are very important to you. **
-------------------------------------------------TITLE: Newly engineered psychedelic shows therapeutic promise without gastrointestinal distress
A recent study published in Science Signaling provides evidence that a newly engineered psychedelic compound can produce antidepressant and anti-anxiety effects in mice without causing gastrointestinal side effects. By altering the chemical structure of an existing psychedelic drug, researchers created a variant that targets specific brain receptors linked to mental health benefits but avoids receptors associated with nausea and physical discomfort.
“Psychedelics such as psilocybin and LSD are showing therapeutic potential for individuals with severe psychiatric conditions, including depression, anxiety and PTSD,” explained study co-authors Javier González-Maeso, a professor of pharmacology and toxicology at the Virginia Commonwealth University School of Medicine, and Malgorzata Dukat, a professor of medicinal chemistry at the Virginia Commonwealth University School of Pharmacy. “However, like most therapeutic drugs, psychedelics can also produce unwanted side effects.”
“Another interesting aspect of this field is that essentially all psychedelics currently being studied clinically belong to three major chemical classes: phenethylamines, such as mescaline; tryptamines, such as psilocybin; and ergolines, such as LSD,” the authors noted. “Despite their chemical differences, many of their hallucinogenic and potentially therapeutic effects are mediated through the serotonin 2A receptor (or 5-HT2A receptor) in the brain, as first proposed by Prof. Richard A. Glennon (coauthor of the manuscript) in 1984.”
The serotonin 2A receptor mediates positive mood and neural adaptability, but the drugs that target it often lack specificity. “We became interested in quipazine, a serotonergic compound first described in the 1960s and originally investigated as a potential antidepressant,” the authors explained. “Quipazine was never developed for routine medical use, in part because it also activates another serotonin receptor, the 5-HT3 receptor, which is highly expressed in the gastrointestinal system and can produce significant gastrointestinal side effects.”
To separate the therapeutic benefits from adverse physical reactions, the authors sought to chemically redesign quipazine. “Our goal was to combine medicinal chemistry in Dr. Dukat’s laboratory with molecular and behavioral pharmacology in Dr. Maeso’s laboratory to design, synthesize and test new compounds derived from quipazine,” the researchers said.
“The Dukat team had already investigated 5-HT2 and 5-HT3 structure-activity relationships and found that quinazolines bind at, but are devoid of, 5-HT3 receptor activation,” the authors told PsyPost. “We wanted compounds that retained activity at the 5-HT2A receptor while minimizing activity at the 5-HT3 receptor; hence, investigation of quipazine/quinazoline hybrid molecules. That effort led us to design VCU-1012, a novel quinazoline compound that activates the 5-HT2A receptor while showing minimal activity at the 5-HT3 receptor.”
The authors synthesized several variations of the quipazine molecule and tested these new compounds on human embryonic kidney cells. When the scientists screened VCU-1012 against a panel of over 40 other receptors, it showed minimal off-target activity. VCU-1012 completely failed to activate the serotonin 3 receptor, indicating it might bypass the physical distress seen with the original drug.
This broad testing approach relied on multiple areas of scientific specialty. “This study was a highly collaborative effort,” González-Maeso and Dukat noted. “It brought together the medicinal chemistry expertise of Dr. Dukat’s laboratory and the molecular and behavioral pharmacology expertise of the Maeso laboratory, along with important contributions from other teams at VCU. These included the laboratory of Scott Ramsey, which helped characterize effects at the 5-HT3 receptor; the laboratory of Imad Damaj, which contributed expertise in mouse behavioral models, and the laboratory of Hamid Akbarali, which evaluated gastrointestinal motility.”
To test the physical side effects in a living organism, the researchers evaluated gastrointestinal function in male mice, using six to eight animals per group. They fed the mice a harmless charcoal solution and measured how far the charcoal traveled through the small intestine over a 30-minute period. Mice injected with the original quipazine drug at a dose of 5 milligrams per kilogram of body weight experienced a severe slowdown in digestion. In contrast, mice given VCU-1012 at 1 milligram per kilogram showed normal intestinal movement that was indistinguishable from mice given a plain saline vehicle injection.
Next, the team evaluated behavioral effects by measuring a specific head-twitch behavior in groups of six mice. This rapid side-to-side head movement is a standard animal proxy for hallucinogenic effects. VCU-1012 prompted a robust increase in head twitches within the first 15 minutes of administration, which was completely blocked when mice were pretreated with a drug that selectively prevents serotonin 2A receptor activation.
To evaluate potential antidepressant properties, the researchers used a forced-swim test. Mice were placed in a beaker of water for a short time to induce a passive coping state, which is characterized by floating rather than swimming. Twenty-four hours after receiving VCU-1012, the classical psychedelic psilocybin, or a saline vehicle, the mice were retested. The researchers also performed this test on a separate group of eight to ten genetically modified mice lacking the serotonin 2A receptor.
Both psilocybin and VCU-1012 reduced floating time in normal mice, which suggests an antidepressant-like effect lasting well beyond the drug’s immediate hallucinogenic window. In the genetically modified mice lacking the serotonin 2A receptor, VCU-1012 had no behavioral effect. Psilocybin still reduced floating time in the modified mice, which indicates psilocybin relies on additional biological pathways that VCU-1012 does not engage.
The researchers also explored whether the compound could alleviate anxiety caused by medical treatments. They repeatedly administered the chemotherapy drug paclitaxel to groups of seven or eight mice to induce a prolonged state of anxiety. Anxiety was measured by observing how much time the mice spent in the brightly lit section of a specialized testing box.
Paclitaxel noticeably reduced the time mice spent in the light area. A single dose of VCU-1012 given 24 hours prior restored normal exploratory behavior, countering the chemotherapy-induced anxiety without altering the animals’ general movement levels.
To understand how the drug alters the brain on a microscopic level, the scientists examined dendritic spines. These are tiny protrusions on the branches of brain cells that help form synapses, or connections, with other neurons. The team used a fluorescent virus to visually highlight neurons in the frontal cortex, analyzing 40 to 106 neurons from three or four mice per group.
Both psilocybin and VCU-1012 increased the density of mature, mushroom-shaped dendritic spines 24 hours after a single dose. This change indicates enhanced brain plasticity and stronger neural connections. Just as in the behavioral tests, this structural brain plasticity did not occur in mice lacking the serotonin 2A receptor.
Finally, the researchers used computer modeling and mutated receptor cells to see exactly how VCU-1012 fits into the serotonin 2A receptor. “One particularly interesting finding came from examining how VCU-1012 interacts with the 5-HT2A receptor,” the authors observed. “You can think of the receptor’s binding pocket as a small three-dimensional lock. A drug with the right shape and chemical properties can fit into that lock and change how the receptor behaves.”
“We found that VCU-1012 occupies this binding pocket in a different three-dimensional orientation from serotonin, the neurotransmitter that naturally activates the receptor,” they continued. “That finding suggests that there may be additional ways to chemically engage the 5-HT2A receptor beyond those used by classical psychedelics. This opens new possibilities for designing chemically distinct classes of psychedelic compounds and investigating how different interactions with the same receptor influence their biological and behavioral effects.”
The data suggests that VCU-1012 fits into the receptor’s primary binding pocket in a slightly different orientation than the body’s natural serotonin, relying on a specific network of hydrogen bonds. “Our study shows that it is possible to design a psychedelic-like compound from a new chemical class that produces potentially beneficial behavioral and brain-plasticity effects in mice while avoiding an important receptor associated with gastrointestinal side effects,” the researchers said.
Animal models of anxiety and depression, such as the forced-swim test and the light-dark box, cannot fully capture the complexity of human psychiatric disorders. A mouse’s physical responses do not perfectly translate to the subjective emotional experiences or hallucinogenic trips reported by humans. The therapeutic efficacy observed in these experiments might not completely predict actual clinical outcomes in human patients.
“These findings are preclinical, and VCU-1012 is not ready for use in humans,” the authors noted. “Although we were able to greatly reduce its activity at the 5-HT3 receptor, VCU-1012 still interacts with other receptors, including the 5-HT2B receptor. Activation of this receptor can be associated with peripheral side effects, including cardiac valvulopathy.”
Because cardiac valvulopathy involves damage to the heart’s valves, avoiding this off-target receptor is an important safety consideration. “Therefore, additional medicinal chemistry will be necessary to improve the selectivity and safety profile of this new class of compounds before considering clinical development,” they added. All behavioral and neurological tests in this study were conducted exclusively on male mice. Because biological sex often influences how bodies process drugs, future research will need to include female animals to determine if these effects apply universally.
“One major goal is to conduct additional structure-activity relationship studies to design compounds with greater selectivity for the 5-HT2A receptor and fewer off-target effects,” the authors explained. They also hope to answer fundamental questions about how these drugs work. “A broader question we hope to address is whether the hallucinogenic effects produced by classical psychedelics, and by compounds such as VCU-1012, are necessary for their potentially beneficial effects on behavior and brain plasticity.”
“Understanding whether these properties can be separated could help guide the development of the next generation of psychedelic-inspired therapeutics,” they concluded. “The study illustrates how combining medicinal chemistry, molecular pharmacology and animal models can help us understand how psychedelic drugs work and, ultimately, guide the design of compounds with improved therapeutic and safety profiles.”
The study, “Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects,” was authored by Jason Younkin, Ajay H. Bansode, Somdatta Saha, Archana Paymode, Jessica L. Maltman, Charles B. Jones, Justin M. Silverman, Belle Buzzi, Alaina M. Jaster, Michael Fiorillo, Jeremy Rolquin, George D. Miller, Roya Abedi, Minho Kang, Maya Gaines-Smith, Enrique I. Valenzuela Lesme, Mattias Embretsen, Jennifer T. Wolstenholme, Richard A. Glennon, Hamid I. Akbarali, M. Imad Damaj, I. Scott Ramsey, Małgorzata Dukat, and Javier González-Maeso.
-------------------------------------------------
Private, vetted email list for mental health professionals: https://www.clinicians-exchange.org
Unofficial Psychology Today Xitter to toot feed at Psych Today Unofficial Bot @PTUnofficialBot
-------------------------------------------------
#psychology #counseling #socialwork #psychotherapy @psychotherapist @psychotherapists @psychology @socialpsych @socialwork @psychiatry #mentalhealth #psychiatry #healthcare #depression #psychotherapist #psychedelics #VCU1012 #5HT2A #mentalhealthresearch #antidepressant #anxietytherapy #drugdesign #serotoninreceptors #brainplasticity #quipazine