A step towards psychedelics with none of the undesirable side effects/symptoms

Good news! Amazing stuff!

"Psychedelic drugs hold great promise for treating mental health conditions like depression and anxiety. But beyond their otherworldly hallucinogenic manifestations, many of these drugs also come with all-too-familiar side effects like nausea, vomiting, and gastrointestinal discomfort.

This occurs because the psychedelic compounds activate several off-target pathways as well as the intended serotonin receptors in the brain.

Reducing these unwanted interactions and the unpleasant symptoms that come with them is an important step for demonstrating the safety of psychedelics.

In a new study ... researchers pushed closer to this reality by re-engineering the synthetic psychedelic drug quipazine to activate only the desired receptors .

The pharmacologists began by examining quipazine atom-by-atom to identify how the drug could bind to both the target 5-HT2AR receptor and the 5-HT3R receptor that causes nausea and other gastrointestinal symptoms.

After singling out the nitrogen atom responsible, they replaced it and rearranged the whole molecule. The resultant drug could still bind to the desired 5-HT2AR receptor, but it bounced off 5-HT3R receptors.

To test the new psychedelic’s effectiveness, the researchers gave the drug to mice with symptoms of depression and anxiety. Once the hallucinogenic effects subsided, the mice exhibited fewer symptoms and showed no apparent discomfort. When they examined the animals’ brains, the researchers found an increased density of neuron structures called dendritic spines, a telltale sign that the psychedelic had restored some of the brain activity lost to depression. ..."

From the editor's summary and abstract:

"Editor’s summary

The clinical use of serotonergic psychedelics is limited by their side effects. Younkin et al. generated a derivative (called VCU-1012) of the psychedelic quipazine with greater activity at the serotonin receptor subtype that mediates the clinically desirable effects (5-HT2AR) than at the serotonin receptor subtype responsible for the undesirable ones.

Similar to quipazine, VCU-1012 exerted antidepressant and antianxiolytic effects in mice but without the gastrointestinal side effects of quipazine. Moreover, like other psychedelics, VCU-1012 increased dendritic spine density in the frontal cortex in a 5-HT2AR–dependent manner.

Thus, VCU-1012 shows promise as a 5-HT2AR agonist with a more favorable side effect profile than those of typical psychedelics. ...

Abstract

Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects.

Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR agonist devoid of 5-HT3R activity.

VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT2AR activation with structure-activity relationship studies to minimize 5-HT3R agonism.

We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT2AR without activating 5-HT3R, thereby avoiding the gastrointestinal side effects of quipazine.

In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT2AR.

Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits."

ScienceAdviser

Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects (no public access)

Design and Synthesis of Quipazine Analogs for Programmable Control of Psychedelic Effects (A PhD thesis covering a similar topic. The author was not part of the team authoring the above research article.)

VCU-1012 (Wikipedia page indicating this psychedelic drug was already developed in 2024)

VCU-1012 2D chemical structure

Engineered in One Plant, Three Kingdoms, Five natural psychedelics

Good news!

"... Researchers ... have now managed to bring together in a single organism five psychedelic substances that in nature are scattered across the tree of life.

After uncovering how plants naturally produce one of the best-known psychedelic compounds, DMT, they were able to reengineer that process step by step inside a model plant – along with four other psychedelics. The result is what amounts to a biological factory that could, in the future, be used to simultaneously produce multiple psychedelic molecules, including some that do not naturally occur in plants. ..."

From the abstract:

"Psychedelic indolethylamines with therapeutic potential are naturally produced in plants, fungi, and animals.

Here, we elucidated the complete N,N-dimethyltryptamine (DMT) biosynthetic pathway in hallucinogenic plant species traditionally used in shamanic rituals for spiritual healing.

Leveraging the similarities in their chemical structures, we reconstructed in one plant assay the full biosynthetic pathways of five renowned natural psychedelics; psilocin and psilocybin found in mushrooms, DMT from plants, and bufotenin and 5-methoxy-DMT secreted by the Sonoran Desert toad. 

We further engineered halogenated analogs of these molecules, which do not naturally occur in plants and exhibit prospective therapeutic potential for psychiatric conditions.

Blending catalytic functions across the tree of life, coupled with metabolic engineering guided by rational protein design of mutant enzymes, enabled substantially more efficient in planta production of the indolethylamine components.

This work establishes a versatile platform for concurrent biosynthesis and diversification of psychoactive indolethylamines, paving the way for their production in plants."

One Plant, Three Kingdoms, Five Trips - Environment | Weizmann Wonder Wander - News, Features and Discoveries "... scientists decipher how a well-known psychedelic substance is created, then engineer a plant to produce several psychedelics at once"

Complete biosynthesis of psychedelic tryptamines from three kingdoms in plants (open access)

Fig. 3. Reconstruction of the N,N-dimethyl-tryptamine biosynthetic pathway.

Fig. 5. Metabolic engineering strategy for complete reconstruction of psychedelic indolethylamine biosynthetic pathways in N. benthamiana.

In der Schweiz wird immer öfter mit Psychedelika behandelt

Gute Nachrichten!

Wirken die Psychedelika dauerhaft oder müssen die Psychedelika ständig eingenommen werden über Jahre etc.?

"... Stand der Forschung: Nach einem Hype in den 1960er Jahren wurde die Forschung an Psychedelika aufgrund des amerikanischen «War on Drugs» komplett eingestellt und erst in den 2000er Jahren wieder aufgegriffen. Heute gehört die Schweiz zu den Vorreitern in der Forschung.

• In Ausnahmefällen erlaubt: In der Schweiz können Patienten seit 2014 eine Bewilligung für die Therapie mit Psychedelika bekommen. In Deutschland ist 2025 eine ähnliche Regelung in Kraft getreten. Bedingung: Andere Therapien blieben erfolglos.
• Das zeigen Studien: Vor kurzem wurden die Ergebnisse einer der bisher grössten Studien publiziert. Die Forscher untersuchten 144 Probanden. Wer Psychedelika erhielt, war sechs Wochen später signifikant weniger depressiv als die Probanden in der Kontrollgruppe.
• Mehr als nur Depressionen: Es gibt Hinweise darauf, dass Psychedelika auch gegen Sucht, posttraumatische Belastungsstörung und Ängste am Lebensende wirken können.

..."

Glücklicher dank Psychedelika

Trump expedites review of psychedelics to treat mental health disorders funded with $50 million

Good news! A nation of junkies by executive order? Just kidding!

We ought to find better cures than administering psychedelic drugs!

"President Trump has signed an executive order to make certain psychedelic drugs more available to treat mental health conditions, such as depression and anxiety. He directed $50 million in federal funds to make them more accessible, and ordered the Food and Drug Administration to fast track a review of such drugs as psilocybin and ibogaine.

"Can I have some, please?" Trump joked to a laughing audience in the Oval Office. ..."

Trump expedites review of psychedelics to treat mental health disorders : NPR

Engineered tobacco plant can produce five psychedelics, including psilocybin and DMT

Amazing stuff! What are you smoking? What's growing in your flower pot or garden? 😊

"... The new study focused on engineering plants to produce five major natural psychedelics: DMT, psilocin, psilocybin, bufotenin, and 5-MeO-DMT. They first had to identify and characterize the key biosynthetic enzymes from certain plants, fungi, and the Sonoran Desert toad and combine enzymes from different species to reconstruct entire biosynthetic pathways. They then used genetic engineering to introduce these enzymes into a type of tobacco plant (Nicotiana benthamiana), which was chosen because it is easily cultivated and produces tryptophan.

After the genes required for production of the compounds were identified, they were introduced to the plant by a process called agroinfiltration, where plant leaves are injected with a suspension of bacterium to induce the expression of genes. The team used AlphaFold3, an AI model that predicts 3D structures and interactions of molecules, to guide their design of a mutant protein that substantially enhanced indolethylamine production by improving efficiency of the enzymes needed to produce it. ..."

Engineered tobacco plant can produce five psychedelics, including psilocybin and DMT

Trippy tobacco? Plants engineered to make five psychedelics at once

Complete biosynthesis of psychedelic tryptamines from three kingdoms in plants (open access)

Fig. 5. Metabolic engineering strategy for complete reconstruction of psychedelic indolethylamine biosynthetic pathways in N. benthamiana.

Mushrooms’ magic evolved twice through different pathways

There must be something magic about the evolution of hallucinogens/psychedelics! 😊

"Psychoactive compounds in certain mushrooms can provoke profound psychedelic experiences, but researchers don’t fully understand why the hallucinogenic fungi evolved in the first place. Now a new analysis has added to that confusion.

Two distinct genera of magic mushroom produce the same psychoactive compound through entirely different chemical pathways, suggesting they evolved independently.

The researchers made the discovery after examining the genes and proteins involved in psilocybin production in fungi from the genus Inocybe, commonly known as fiber cap mushrooms. They assumed that these mushrooms would synthesize the compound in much the same way as the better studied fungi in the genus Psilocybe, such as Psilocybe cubensis. But to the researchers’ surprise, the fiber cap mushrooms produced psilocybin through a totally different set of biochemical steps.

Like the pathway in Psilocybe mushrooms, the process in fiber caps can result in two different compounds: either psilocybin or a related molecule known as baeocystin. However, the two syntheses follow completely different logics. Psilocybe mushrooms proceed sequentially and make psilocybin out of baeocystin.

Fiber caps, by contrast, make both compounds side by side, using none of the same enzymes. ..."

From the abstract:

"Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, 1) is the main indolethyl-amine natural product of psychotropic (so-called “magic”) mushrooms. The majority of 1-producing species belongs to the eponymous genus Psilocybe, for which the biosynthetic events, beginning from l-tryptophan (2), and the involved enzymes have thoroughly been characterized.

Some Inocybe (fiber cap) species, among them Inocybe corydalina, produce 1 as well. In product formation assays, we characterized four recombinantly produced biosynthesis enzymes of this species in vitro: IpsD, a pyridoxal-5′-phosphate-dependent l-tryptophan decarboxylase, the kinase IpsK, and two near-identical methyltransferases, IpsM1 and IpsM2. The fifth enzyme, the insoluble monooxygenase IpsH, was analyzed in silico.

Surprisingly, none of the reactions intrinsic to the 1 pathway in Psilocybe species takes place in I. corydalina.

Contrasting the situation in Psilocybe, the Inocybe pathway is branched and leads to baeocystin (4-phosphoryloxy-N-methyltryptamine, 3) as a second end product. Our results demonstrate that mushrooms recruited distantly or entirely unrelated enzymes to evolve the metabolic capacity for 1 biosynthesis twice independently."

ScienceAdviser

In mind-bending twist, ‘magic’ mushrooms evolved twice independently

Dissimilar Reactions and Enzymes for Psilocybin Biosynthesis in Inocybe and Psilocybe Mushrooms (open access)

Graphical Abstract

Mushrooms have learned twice independently how to make the iconic magic mushroom natural product psilocybin. This article introduces the enzymes of the second pathway, found in a fiber cap mushroom. Curiously, the two pathways do not share any reaction, nor do the enzymes show a close relationship, but both pathways proceed via 4-hydroxytryptamine as a common intermediate.

What was The Beatles Magical Mystery Tour of 1967 all about? 😊

Can psychedelics treat mental health disorders?

Recommendable!

LSD microdosing for ADHD: Does it work? Not really!

Recommendable! At least the study confirmed that treatment with LSD microdosing is safe! 😊

What is microdosing anyway? If the dose is small enough it may not have an effect at all. It becomes a placebo.

"A landmark clinical trial testing the effect of microdosing LSD on symptoms of attention-deficit hyperactive disorder (ADHD) recently delivered its first data readout and the results have been surprising, to say the least, raising questions over the efficacy of this popular trend. ...

Despite this massive wealth of anecdotal evidence, robust clinical research into microdosing has been minimal. The very few placebo-controlled examinations conducted on the practice have pretty consistently struggled to find any effect at all.

The latest clinical trial to test the practice has focused on the effect of microdosing LSD for symptoms of ADHD. The trial is the first to test microdosing in a cohort of patients suffering from a specific condition. Prior trials have mostly focused on mood effects in healthy cohorts or groups with sub-clinical mental health problems. The new trial is also one of the longest and most robust investigations into the popular phenomenon ever conducted. ...

The trial recruited 53 participants, all fitting the diagnostic criteria for moderate to severe ADHD. Half were given LSD microdoses of 20 micrograms, and the other half were given a placebo. All were administered doses twice a week for six weeks.

At the end of the study period all participants showed statistically significant reductions in their ADHD symptoms, regardless of placebo or LSD. In fact, the placebo group displayed marginally greater symptomatic improvements, although that difference was considered statistically insignificant. ..."

From the key points and abstract:

"Key Points

Question

Does twice-weekly low-dose (20 μg) lysergic acid diethylamide (LSD) over 6 weeks reduce symptoms of attention-deficit/hyperactivity disorder (ADHD) in adults with moderate to severe ADHD compared with placebo?

Findings

In this multicenter, double-blind, placebo-controlled randomized clinical trial in 53 individuals, both the LSD and placebo groups exhibited a significant reduction of ADHD symptoms. However, there was no difference in symptom reduction between the 2 groups.

Meaning

LSD was not efficacious in reducing ADHD symptoms compared with placebo; these results question the anecdotal practice and highlight the importance of placebo-controlled trials in low-dose psychedelic research.

Abstract

Importance

Microdosing psychedelics, including lysergic acid diethylamide (LSD), has gained attention for its potential benefits in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, LSD’s efficacy in reducing ADHD symptoms remains unknown.

Objective

To determine the safety and efficacy of repeated low doses of LSD in reducing ADHD symptoms compared with placebo.

Design, Setting, and Participants

This was a 6-week, multicenter, double-blind, placebo-controlled, parallel-group phase 2A randomized clinical trial conducted between December 17, 2021, and December 4, 2023. Data were analyzed from March 22, 2024, to August 19, 2024. Outpatient treatment was provided at 2 centers: University Hospital in Basel, Switzerland, and Maastricht University in the Netherlands. Adults aged 18 to 65 years with a prior ADHD diagnosis who presented with moderate to severe symptoms (Adult Investigator Symptom Rating Scale [AISRS] score ≥26 and Clinical Global Impression Severity score ≥4) were eligible for inclusion. Key exclusion criteria included selected current major psychiatric or somatic disorders and the use of potentially interacting medications.

Intervention  Participants received either LSD (20 μg) or placebo twice weekly for 6 weeks (total of 12 doses).

Main Outcome and Measures  The primary outcome was the change in ADHD symptoms from baseline to week 6, assessed by the AISRS and analyzed with a mixed-effects model for repeated measures.

Results

A total of 53 participants were randomized to LSD (n = 27) or placebo (n = 26). Mean (SD) participant age was 37 (12) years, and 22 participants (42%) were female.

The LSD group presented a mean AISRS improvement of −7.1 points (95% CI, −10.1 to −4.0).

The placebo group presented a mean AISRS improvement of −8.9 points (95% CI, −12.0 to −5.8), with no difference between groups. LSD was physically safe and psychologically well tolerated overall.

Conclusions and Relevance 

In this randomized clinical trial, repeated low-dose LSD administration was safe in an outpatient setting, but it was not more efficacious than placebo in reducing ADHD symptoms."

LSD microdosing for ADHD: new trial shows surprising results

Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults/A Randomized Clinical Trial

LSD analogue synthesised by swapping just two atoms less likely to cause hallucinations and it exhibited strong neuroplastic effects

Good news! Amazing stuff! Flipping just two atoms!

"An analogue of the psychedelic drug LSD has been found to offer the same therapeutic effects as LSD but is less likely to cause the hallucinogenic trips associated with the drug. The researchers say that their work highlights the potential of rationally designed, non-hallucinogenic psychedelic analogues in the treatment of neuropsychiatric diseases such as schizophrenia, where the use of psychedelics is not recommended. ...

Using tests, such as the mouse head twitch response assay, which, ... correlates well with human hallucinogenic potency, they found that JRT did not produce hallucinogenic-like behaviours in mice dosed with LSD. ... in contrast to LSD, JRT does not bind the 5-HT2A receptor for very long. ..."

"... researchers have developed a new, neuroplasticity-promoting drug closely related to LSD that harnesses the psychedelic’s therapeutic power with reduced hallucinogenic potential. ..."

To design the drug, dubbed JRT, researchers flipped the position of just two atoms in LSD’s molecular structure. The chemical flip reduced JRT’s hallucinogenic potential while maintaining its neurotherapeutic properties, including its ability to spur neuronal growth and repair damaged neuronal connections that are often observed in the brains of those with neuropsychiatric and neurodegenerative diseases. ...

JRT exhibited powerful neuroplastic effects and improved measures in mice relevant to the negative and cognitive symptoms of schizophrenia, without exacerbating behaviors and gene expression associated with psychosis. ..."

From the significance and abstract:

"Significance

Psychedelic compounds, such as lysergic acid diethylamide (LSD), can promote the growth of atrophied cortical neurons, which is relevant to the treatment of numerous brain conditions.

However, their hallucinogenic properties have limited their adoption as medicines and preclude their use in certain patient populations, such as those with schizophrenia or a family history of psychosis.

By transposing only two atoms, we have created JRT, an exceptionally potent analogue of LSD with lower hallucinogenic potential, improved pharmacological selectivity, and the ability to produce a wide range of therapeutic effects.

Our work highlights the potential of rationally designed, nonhallucinogenic analogues of psychedelics for treating diseases where the use of psychedelics is contraindicated.

Abstract

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 molecular design and de novo total synthesis of (+)-JRT, a structural analogue of lysergic acid diethylamide (LSD) with lower hallucinogenic potential and potent neuroplasticity-promoting properties.

In addition to promoting spinogenesis in the cortex, (+)-JRT produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating behavioral and gene expression signatures relevant to psychosis.

This work underscores the potential of nonhallucinogenic psychoplastogens for treating diseases where the use of psychedelics presents significant safety concerns."

LSD analogue synthesised by swapping just two atoms less likely to cause hallucinations | Research | Chemistry World

Researchers Develop an LSD Analogue with Potential for Treating Schizophrenia (original news release)

Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential (open access)

JRT differs from LSD in the positioning of two atoms. An N and C in the ergoline structure of LSD have been swapped to make the less hallucinogenic JRT

Fig. 2 Total synthesis of JRT.

Imaging reveals psilocybin's neurological mechanisms in the brain that enable the psychedelic compound’s long-lasting effects

Good news! When will we finally be able to separate pain killing and other beneficial effects from becoming addicted and/or to hallucinate!

"... researchers have identified a pair of key neurological mechanisms in the brain – a cell type and receptor – that enable the psychedelic compound’s long-lasting effects.

Targeting the pyramidal tract neurons and their specific serotonin 5-HT2A receptor in the medial frontal cortex could enable pharmaceuticals to deliver psilocybin’s mood-altering benefits while suppressing the perceptual hallucinatory trip. ...

Using two-photon microscopy on transgenic mice, the researchers targeted the two largest populations of primary cells in the brain: 

pyramidal tract (PT) neurons and 

intratelencephalic (IT) neurons.

Inactivating the IT neurons, which are responsible for high-order cortical-cortical communication, did not change the behavioral effects of the psilocybin. ...

silenced the PT neurons, the drug was essentially ineffective – proof that this cell type and its pathway, which extends from the frontal cortex down into the midbrain and brainstem – is essential to psilocybin’s effects.

Equally important is the PT neurons’ 5-HT2A receptor, which has previously been shown to play an important role in humans experiencing acute, short-term hallucinatory trips. When the researchers knocked out the receptors, psilocybin’s positive behavioral effects disappeared. None of their manipulations affected the acute effects. ..."

From the abstract:

"Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses. At the cellular level, psychedelics induce structural neural plasticity, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells.

A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioral actions.

Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex.

We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types.

Behaviorally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration.

Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action."

Hitting the target: Imaging reveals psilocybin’s neural odyssey | Cornell Chronicle

The neurons that mediate a psychedelic’s long-term antidepressive effects (research briefing; no public access) "Psilocybin, a classic psychedelic, has therapeutic potential for psychiatric disorders. A specific brain circuit and receptor have now been found to be required for psilocybin’s long-term effects on neural plasticity and depression-related behaviour."

Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors (no public access)

Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action (preprint, open access)

Fig. 1 Psilocybin induces structural plasticity in both PT and IT types of frontal cortical pyramidal neurons

FDA rejects MDMA-assisted therapy for PTSD

I might be wrong, but PTSD is one of those more ambiguous and controversial  diagnoses like gender dysphoria!

The usual placebo testing is very difficult or impossible with psychedelic drugs.

On the other hand, there is e.g. the Right to Try issue and government paternalism.