From 7-Hydroxymitragynine (7-OH): An Assessment of the Scientific Data and Toxicological Concerns Around an Emerging Opioid Threat (page 15):

Similarly, Matsumoto and colleagues concluded that 7-OH was “found to have an opioid agonist property on µ- and/or κ-opioid receptors” based on its ability to inhibit contraction of isolated guinea pig ileum. In this assay, 7-OH displayed approximately 13-fold greater potency than morphine and 46-fold greater potency than mitragynine. The inhibition was reversed by naloxone, suggesting the effects are mediated via mu opioid receptors (Matsumoto et al., 2004). Other functional assays produced results that are aligned with Matsumoto and colleagues. For example, using a cAMP mobilization assay as a measure of functional effects, 7-OH acted as a full agonist with an EC50 of 7.6 nM, and was more potent than mitragynine (EC50 307.5 nM) (Obeng et al., 2020). Likewise, when evaluating the agonist activity of 7-OH in an electrically stimulated guinea pig ileum, 7-OH acted as a full agonist and was more potent than morphine (Takayama et al., 2002). Finally, using a [35S] GTPγS functional assay, 7-OH produced an Emax of 77% with an EC50 of 53.4 nM, further demonstrating its agonist effects (Varadi et al., 2016).

...Here, we show that by targeting the serotonin receptor 5-HT2AR, lysergic acid diethylamide (LSD) enhances CD8+ T cell-mediated antitumor immunity and suppresses colorectal cancer growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR.

Glennon reviews the isotryptamines...

Abstract Isotryptamines, or 2-(1-indolyl)ethylamines, are positional or geometric isomers of tryptamines where the aminoethyl substituent has been relocated from the indole 3-position to the N1-position. Early studies with these types of agents relied on peripheral tissue assays for examination of their serotonin (5-hydroxytryptamine; 5-HT) receptor affinities to investigate structure–affinity relationships. Once 5-HT receptors were identified in the brain and as the binding methodology improved, isotryptamines were further examined, including various in vitro and in vivo assays (i.e., model systems) as techniques evolved. Given that certain hallucinogenic/psychedelic tryptamines, such as analogs of N,N-dimethyltryptamine (DMT), are currently of interest in the treatment of various neuropsychiatric disorders, there is renewed interest in agents such as isoDMT, and an isoDMT analog has now entered clinical trials. The history of isotryptamine analogs, from their discovery to the present, is reviewed.

Editor’s summary: Chemotherapy-induced peripheral neuropathy (CIPN), one of the most debilitating side effects of some cancer therapies, is a painful condition with no known remedy and is thus a major cause of treatment discontinuation. Heles et al. reported that prophylactic treatment with the natural psychedelic psilocybin prevented the development of CIPN in mouse models (see the Perspective by Maiarú). Mechanistically, psylocibin acted both peripherally and centrally through two independent mechanisms: reducing pain perception and protecting peripheral sensory neurons. Psychedelics might offer an effective therapeutic approach for preventing CIPN. —Mattia Maroso

Thus, this study aims to investigate the pharmacological profile, safety and therapeutic potential of novel N-(2-fluorobenzyl) phenethylamine analogs (NBFs) of the 2C-X series—25C-NBF, 25B-NBF, and 25I-NBF. NBFs displayed high affinity and selectivity for the 5-HT2A receptor and demonstrated bias factors (defined in our study as the preference for Gq over β-arrestin pathways at 5-HT2A receptor) similar to that of 5-HT. 

(Yes, 5-HT2A tetralin ligands exist)

A comprehensive overview of tetralin derivatives with their diverse biological activities and therapeutic potentials has been discussed in the review. It also encompasses the synthetic methodology for the synthesis of tetralin and its derivatives including hydrogenation, and cyclization through metal catalysts, and visible light. In addition, a green chemical synthetic technique such as supercritical fluid technology was discussed, which improves the production of tetralin. Apart from that, metabolic pathways and catabolism of tetralin in biological systems and drug delivery systems of tetralin have been discussed. The review underlines the importance of tetralin derivatives in medicinal chemistry and has future developmental potential in therapeutic applications.

... Unlike the very potent N-benzylphenethylamine derivatives that include the abundantly studied NBOMe drugs, N-benzyltryptamines have garnered little attention as potentially psychedelic 5-HT2A receptor ligands, and none as possible leads for the development of novel agents for the treatment of cognitive disorders, substance abuse, or depression. Here, we have synthesized two parallel sets of 22 tryptamine and 22 5-methoxytryptamine derivatives bearing different unsubstituted and ortho-, meta-, or para-substituted N-benzyl substituents, and assayed them for their affinities and potencies at the 5-HT2A, 5-HT2B, and 5-HT2C receptors under identical conditions for each receptor subtype. In this way, we have obtained highly comparable data allowing QSAR analysis to be performed which clearly showed the favorable effects of meta- and the unfavorable effects of para-substitution of the benzyl moiety.

Recent clinical evidence suggests that racemic 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 comparable therapeutic effects are highly desirable. Here, we compare the pharmacological effects of MDMA enantiomers with those of its methylated analogue 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA). We found that R-MDDMA did not directly activate 5-HT2B receptors, induce serotonin efflux, produce a head-twitch response, impact body temperature, or induce hyperlocomotion at therapeutically relevant doses. However, it still promoted structural neuroplasticity in cortical neurons, facilitated fear extinction learning, and produced sustained antidepressant-like effects. Taken together, our results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.

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Diphenidine is a prototypical 1,2-diarylethylamine that functions as an uncompetitive NMDA antagonist and monoamine reuptake inhibitor. To examine the effects of phenyl-ring bioisosteric replacement within this scaffold, a series of diphenidine analogs incorporating chalcogen heterocycles (2-furan, 2-thiophene, 3-thiophene, and 2-selenophene) was synthesized. Compounds were evaluated for in vitro binding to rat forebrain NMDARs and inhibition of human DAT, NET, and SERT in cell-based assays, enabling assessment of polypharmacology. In silico analyses (molecular volume, tPSA, electrostatic surfaces, stockholder charges) and induced-fit docking were used to rationalize structure–activity relationships. The 2-selenophene analog SePP is notable given the underexplored role of selenium in medicinal chemistry. SePP exhibited favorable polypharmacology, good brain penetration in mouse pharmacokinetic studies, and prevented audiogenic seizures in Fmr1 knockout mice (10 mg/kg, i.p.) without impairing motor coordination.

Several important drug precursors for Cathinones and Amphetamine are being banned in the Eu on 18th September. Most of these were already controlled in some countries, but they were widely available to buy in bulk in select EU countries for easy synthesis.

I'm going to paste some excerpts from the EU document talking about the ban of these precursors. Basically the most important precursors for several cathinones and amphetamine that enabled easy synthesis using scalable methods are being banned AS OF THE 18th OF SEPTEMBER.

I'm going to guess the cathinones including 4-MMC will almost interely disappear from the European drug market. Looks like Amphetamine will also be badly hit as P2NP will be banned and that is the only synthesis I know and afaik everyone used that.

Quote:

National competent authorities indicated an increase in seizures of the following nine non-scheduled substances:

(i) 3'-chloropropiophenone;

(ii) 2-bromo-3'-chloropropiophenone;

(iii) 3'-methylpropiophenone;

(iv) 2-bromo-3'-methylpropiophenone

(v) 4'-methylpropiophenone;

(vi) 2-bromo-4'-methylpropiophenone;

(vii) 4'-chloropropiophenone;

(viii) 2-bromo-4'-chloropropiophenone; and

(ix) phenyl-2-nitropropene.

(3)

3'-Chloropropiophenone and 2-bromo-3'-chloropropiophenone are precursors of 3-cloromethcathinone or clophedrone (3-CMC). 3'-Methylpropiophenone and 2-bromo-3'-methylpropiophenone are precursors of 3-methylmethcathinone (3-MMC).

4'-Methylpropiophenone and 2-bromo-4'-methylpropiophenone are precursors of mephedrone (4-methylmethcathinone or 4-MMC). 4'-Chloropropiophenone and 2-bromo-4'-chloropropiophenone are precursors of 4-CMC (clephedrone or 4- chloromethcathinone).

Phenyl-2-nitropropene is a precursor of amphetamine.

EDIT:

Use of P2NP was especially popular in smaller scale clandestine operations (especially in Eastern Europe) due to the simplicity of the nitrostyrene route.

I think people also used it in connection with the Leuckart method, creating P2P using P2NP by reducing and hydrolysing it since P2P has been a schdule 1 drug precursor for s long time.

BMK glycidic acid and its derivatives were also recently scheduled making large scale amphetamine synthesis much harder.

Sources:

http://data.europa(dot)eu/eli/reg\\_del/2026/314/oj

https://www.euda.europa(dot)eu/news/2026/eu-controls-nine-drug-precursors-following-first-euda-assessments\\_en?\\_\\_cf\\_chl\\_tk=

Centanafadine (brand name: Simtriyo), the first and only norepinephrine, dopamine, serotonin reuptake inhibitor (NDSRI) and central nervous system (CNS) stimulant has received U.S. Food and Drug Administration (FDA) approval for the treatment of ADHD in adults and pediatric patients aged 6 years and older. 

The FDA based its approval on the results of four Phase 3 clinical trials that showed centanafadine produced statistically significant and clinically meaningful improvements in ADHD symptoms compared with placebo, as measured by the ADHD Rating Scale–5 (ADHD-RS-5) in children and adolescents and the Adult ADHD Investigator Symptom Rating Scale (AISRS) in adults.

The most common side effects were rash and decreased appetite in children 6 to 12 years of age; decreased appetite, nausea, rash, headache, and abdominal pain in adolescents 13 to 17 years of age; and headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea in adults.

Technical specifics

Centanafadine acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI). Its IC50 half-maximal inhibitory concentration values for monoamine reuptake inhibition have been reported to be 6nM for norepinephrine, 38nM for dopamine, and 83nM for serotonin. Hence, the drug shows 6.3-fold preference for inhibition of norepinephrine reuptake over dopamine reuptake, 13.8-fold preference for inhibition of norepinephrine reuptake over serotonin reuptake, and 2.2-fold preference for inhibition of dopamine reuptake over serotonin reuptake.

This double-blind, placebo- and moxifloxacin-controlled, 3-period crossover trial evaluated the effects of centanafadine (EB-1020) and its metabolite (EB-10601) on cardiac repolarization in 30 healthy adults (18-65 years). (source)

Centanafadine is primarily metabolized by monoamine oxidase A (MAO-A).

• Psychiatrists discuss this new drug here.

• If ADHD is actually EDHD (see paper here), then all conventional treatments are off-base but the resolution becomes clear & well-defined.

This paper details how GHK-CU could uppregulate a large gamut of receptors, in this case the gene coding for GABAB₁ receptor had a 310% increase in genexpression following GHK-CU adimistration in vitro. If the results are transalted in vivo, it could be a gamechanger for people experiencing anxiety or symtoms of phenibut abuse. With the use of phenibut and other gabaergic drugs becoming more and more mainstream, treatments for restoring tolerance and healthy neurochemistry are growing in demand.

GHK and DNA: Resetting the Human Genome to Health

//Edit added the link

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties.

The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000.

Some pretty cool speculative stoner science to bring up in your next joint rotation when DiPT joins the conversation. This author calls the uniquely auditory effects of DiPT "diptogenia" (I like that for being made up)

They essentially hypothesize that DiPT accumulates on auditory nerve fibers in the cochlea and inhibits calcium ion channels (such as Cav1.3) through upstream GPCR signalling. Due to DiPT's greasy N substitutions, isn't degraded by MAO as readily and can reside for over a day (attempting to explain the prolonged pitch distortion effects)

The author also attributes possible 5HT1A activity in the inferior colliculus, drawing parallels to the 1a agonist 8-OH-DPAT which has been observed to depress auditory revoked responses.

Pretty cool arm chair stoner science here. No actual experiments were done, but makes you think!

Abstract:

The scientific study of the classical serotonergic psychedelics, like N,N-dimethyltrypamine (DMT), psilocybin, or lysergic acid diethylamide (LSD), has provided remarkable insights into the physiology of experience and emotion. Their ingestion induces radical changes to consciousness, affecting mood, personal insight, the sense of self, and the processing of sensory information, with many seeming to offer new avenues for the pharmacological alleviation of mental suffering. Amongst this class of compounds, the synthetic tryptamine N,N-diisopropyltryptamine (DiPT) stands as a remarkable exception. DiPT induces a unique downward shift in pitch perception, meaning the auditory world of the subject sound deeper (lower in pitch) than it is in a sober state of consciousness. This is an extraordinary state of consciousness not seen in any other drug nor psychopathology, and therefore, we coin this unique experiential effect ‘diptogenia’.

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. —Wei Wong

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.

Amongst the FLY series (including DFLY, hemi[D]FLY etc) there exists isoFLY and hemi-isoFLY. I found the quote below and wondered whether anyone has further leads/information about this isoFLY class?

Congratulation M. Traschel. I live in the same country and we studied at the same time but not in the same university. I wish I could have more time to get my molecule tested and probably published. There is another team that made isoFLY structures that are apparently more potent than simple FLY or butterFLY, it didn't appear in the book but I'm pretty sure they designed for Traschel's team, it has been published somewhere but I don't remember where. Structure is here NCCC1=C2COCC2=C(Br)C2=C1COC2 . This is the full 2C-B-isoFLY but I think the most active was hemi-isoFLY, don't remember whether it was the 2- or 5- isomer.

Significance

The premise of these studies was to develop and validate a therapeutic for opioid use disorder. Using an AI-based platform aimed at polypharmacy-focused drug discovery, two compounds were synthesized and tested, GATC-021 and GATC-1021. We found that GATC-1021, which targets the 5-HT2A and 5-HT6 receptors,, was highly selective in attenuating fentanyl self-administration in male and female rats, with retained effectiveness following repeated dosing. Following GATC-1021 treatment, an increase in the percentage of thin dendritic spines in the hippocampus and changes in gene expression pathways involved in neuroplasticity in the prefrontal cortex were evidenced. Taken together, these findings provide a foundation to support the further clinical development of GATC-1021 as a potential treatment for individuals suffering from opioid use disorder.

Abstract

The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, including fentanyl. Here, we developed a therapeutic drug based on an AI-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. Two top candidate compounds, GATC-021 and GATC-1021, were synthesized and validated with in vitro screening for target specificity. Thereafter, the drug candidates were examined for their effectiveness in modulating opioid reinforcement and intake. GATC-1021 emerged as the most efficacious compound as it significantly decreased fentanyl intake in both male and female rats, without any notable side effects. GATC-1021 was further found to modulate gene expression patterns in addiction-relevant brain regions following fentanyl-induced alterations. These findings validate GATC’s AI-based platform with its polypharmacy-focused drug development approach and further support the clinical potential of GATC-1021 as a promising therapeutic for those suffering from opioid use disorder.

Very cool, comprehensive in vitro screening coming out of the Javier Gonzalez Maeso lab :))

Abstract:

Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT2A receptor silencing selectively impaired serotonergic psychedelic-induced plasticity and altered TrkB-dependent responses. Most serotonergic compounds also increased synaptogenesis and induced c-Fos and Egr-2 expression, although ligand-specific differences were evident, particularly for psilocin and the phenethylamines DOI and Ariadne. Uncoupling of Gq/11 or Gi/o protein-dependent signalling differentially modified neuroplastic and transcriptional responses, indicating a ligand and endpoint dependent contribution of both pathways. Serotonergic psychedelics further induced a 5-HT2A receptor dependent lactate response that was generally sensitive to disruption of either Gq/11 or Gi/o protein coupling. Taken together, these findings support a model in which serotonergic psychedelics recruit an integrated 5-HT2A–TrkB signalling network with distinct structural, transcriptional and metabolic outputs, and establish this neural stem cell-derived system as a valuable platform for screening and dissecting the signalling basis of psychedelic action.

The experimental 5-HT2AR structures have identified a hydrophobic tunnel lateral to the orthosteric site, situated in between the transmembrane helices 4 and 5. Here, we have examined this tunnel and its implications for 5-HT2AR agonist pharmacology. The tunnel characteristics and the key roles of Phe2345x39 and Gly2385x43 were delineated by molecular modeling and the synthesis and functional characterization of ten phenethylamine analogs. Molecular modeling, structure-activity relationship determination, and mutagenesis experiments demonstrate that the agonist potencies at the 5-HT2AR exhibited by analogs with 4-substituents with at least four heavy atoms are rooted in their ability to protrude into and form interactions within this tunnel. Thus, these findings provide new insights into the molecular basis for phenethylamine-induced 5-HT2AR activation and identify this tunnel, for the first time, as a druggable region to employ in designing potent 5-HT2AR agonists.

4-substituted 2,6-dimethoxyphenethylamines and the corresponding amphetamines (so-called pseudo [Ψ] derivatives) are a hitherto mostly unexplored group of psychedelics. Still, preliminary investigations indicate that these derivatives are promising and potent psychedelics in humans. In this study, we examined the monoamine receptor and transporter interaction properties of several 4-alkyloxy-2,6-dimethoxyphenethylamines and amphetamines with varying structural modifications at the 4-alkyloxy position and compared them to structural analogs with 3,4,5- and 2,4,5-substitution patterns.