Abstract:

It is unclear how serotonin 2A receptors (5-HT2ARs) in cortical layer 5 pyramidal neurons differentially contribute to psilocybin-induced hallucinations versus neuroplasticity. Here we show that psilocybin promotes synapse formation and maturation while accelerating the elimination of pre-existing synapses. Cell type-specific manipulation further demonstrated that 5-HT2AR signaling in cortical layer 5 pyramidal neurons is necessary and sufficient for psilocybin-induced synaptic remodeling but dispensable for the head-twitch response, a rodent proxy of hallucination.

Disclaimer: A friend asked if they could publish their research through my account as they do not have an account. But I have heard them out, and I do think it is worthwhile to publish. Hopefully that's alright.
-----

Definition of Tolerance: Reduced ability of a drug to elicit a particular effect (e.g., analgesia) following repeated administration.

On Reddit drug tolerance is often thought of as a relatively long-lasting alteration in function of the central nervous system and brain as a result of the drugs interactions with bodily systems. For instance, on Reddit it is commonly said that an individual becomes tolerant to the effects of morphine due to morphine interacting with the MOR protein causing its extracellular component to retract into the cell membrane preventing ligands from interacting with it to maintain balance (Negative Feedback). Although this phenomena does in fact occur it holds little relevance for most recreational drug users as they often do not maintain consistent drug levels and instead have levels of the drug that fluctuate greatly throughout the day. When a consistent level of a drug is not maintained, tolerance will mainly develop through the body learning to suppress the drug effect. After administration of the drug the body will analyze the chemical characteristics of the drug and which bodily processes it disturbs and respond accordingly to compensate for the disturbing effect of the drug. After several more drug administrations the environmental and interoceptive cues that precede the administration of the drug will be identified and will determine when the compensatory response will be generated and it’s magnitude.

The effect that environment has on drug tolerance has been confirmed experimentally thanks to rat mortality experiments which demonstrated rats with a history of intravenous injections to ethanol, pentobarbital, and heroin lost their tolerance when the drug was administered in an environment not associated with previous injections of the drug (Fig 2. Source 1). The mortality rate of the rats approached that of the control group which had no experience with the drug. Further experiments highlighted the effect of interoceptive cues on the magnitude of the compensatory response. The effects of small dosages of morphine administered to rats tolerant to a much higher dosage demonstrate that counterintuitively small dosages produce greater withdrawal symptoms than when an inactive ingredient is injected (Table 1. 4).

Several more experiments confirmed that drug tolerance is a learned response. Early experiments of drug tolerance identified that biological agents that impair learning also impair development of tolerance to morphine. Concurrent administration of Actinomycin D with morphine prevents the development of analgesic tolerance to morphine in the same way that it prevents acquisition of other learned responses (2 and 3). Interestingly Actinomycin D did not reverse tolerance and only inhibited it from developing further. The conclusion that the authors drew was

“Actinomycin D did not overcome established tolerance in animals that had been previously exposed to morphine, and thus appeared to affect a process which occurred only while tolerance was developing” (2).

The same effect was observed for other manipulations that impair learning as early tolerance experiments demonstrated that electroshock and fronto-cortical stimulation also impair tolerance development to morphine (3).

The neural circuitry that produces the compensatory response to counteract the analgesic effects of morphine was identified in 2023 by ablating neurons in brain regions using a genetically modified rabies virus and seeing if ablation of these neuron types prevented the compensatory response to the analgesic effects of the drug (6). The ventral hippocampus dorsomedial prefrontal cortex and basolateral amygdala were determined to be needed for the development of intermittent tolerance. Upon further experimentation it was determined that the ventral hippocampus and dorsomedial prefrontal cortex coordinated together to identify drug cues and then relayed a signal to the basolateral amygdala to secrete the neuropeptide cholecystokinin. Cholecystokinin was then demonstrated to counteract the effects of the opioid agonist DAMGO confirming that cholecystokinin is responsible for associative morphine tolerance.

This study builds upon a series of studies in the 2000’s where it was discovered that the CCK-B receptor antagonist L365260 eliminated tolerance in rats given intermittent injections of morphine but not in those implanted with morphine pellets. A dose response curve to the associative tolerance blocking effect of increasing levels of L365260 in the basolateral amygdala was then identified (Fig. 7l 5).

This observation seems to align with the computational model of tolerance described by Abraham Peper where tolerance is modeled using a fast and slow regulator (7). The fast regulator is responsible for generating a compensatory response and the slow regulator is used for developing long term adaptations to drug use. Explaining how tolerance is calculated is beyond the scope of this post. The gist of it is that after several drug administrations the compensatory response generated is calculated from the average dosage of previous drug administrations minus an arbitrary number to replicate the phenomena that most often the effects of the drug are only partially blocked. The slow regulator then takes into account the amount of time and the level that the drug is active to determine the strength of the long term adaptations that will develop. As stated by the author “A permanent drug administration is no different from any other permanent change in the environment”. In this case the adaptation to the cold comes in two parts shivering (the compensatory response) and growth of fur (negative feedback). To echo the start of this post when there is as large interval between drug administrations negative feedback plays a smaller role in drug tolerance than when the interval between administrations is high. For this reason, internalization of receptors plays a small role in drug users not maintaining a stable level of the drug and the compensatory responses generated is the main form of compensation the body employs. This carries a heavy question what effect does misrepresentation of tolerance have on drug forums. There are many subreddits where the users recognize the development of permatolerance however, they do not have the right words to describe it because it goes against their standard theory of tolerance. The existence of subreddits such as r/thisaintadderall resort to conspiracy theories instead of recognizing that they developed permatolerance. If you search “permatolerance” on r/thisaintadderall you will find several posts talking about going into withdrawal after taking a small dose of amphetamine after a long break mirroring the model in source 7. I will not write anymore.

1. https://www.appstate.edu/~steelekm/classes/psy5150/Documents/Siegel2002.pdf

2. https://pmc.ncbi.nlm.nih.gov/articles/PMC1570218/pdf/bripharmchem00005-0025.pdf

3. http://private.luisaranguren.com/lectures/Siegel%20%20(2000).%20Pavlovian%20psychopharmacology%20The%20associative%20basis%20of%20tolerance.%20Experimental%20and%20Clinical%20Psy.pdf.%20Pavlovian%20psychopharmacology%20The%20associative%20basis%20of%20tolerance.%20Experimental%20and%20Clinical%20Psy.pdf)

4. http://private.luisaranguren.com/lectures/Siegel%20%20(2000).%20Pavlovian%20psychopharmacology%20The%20associative%20basis%20of%20tolerance.%20Experimental%20and%20Clinical%20Psy.pdf.%20Pavlovian%20psychopharmacology%20The%20associative%20basis%20of%20tolerance.%20Experimental%20and%20Clinical%20Psy.pdf)

5. https://www.science.org/doi/epdf/10.1126/sciadv.abo5627

6. https://www.science.org/doi/10.1126/sciadv.adg6086

7. https://extras.springer.com/?query=978-1-4614-0750-8

I’m posting this because I think an important development has gone almost unnoticed, even within communities following SR-17018.

**The UK government has formally proposed making SR-17018 a Class A controlled drug. The legislation is currently awaiting parliamentary approval.**

This is not speculation. The draft *Misuse of Drugs Act 1971 (Amendment) Order 2026* was laid before both Houses of Parliament on **14 September 2026**. It explicitly names SR-17018 (5,6-dichloro desmethylchlorphine) for permanent Class A control.

SR-17018 has already been covered by a Temporary Class Drug Order since 11 June. Permanent control would go further, including criminalising ordinary possession.
**Why does this deserve particular scrutiny?**
I fully recognise the serious harms associated with emerging synthetic opioids. Several orphines have been implicated in fatal overdoses, and these risks cannot be dismissed.

But SR-17018 is scientifically unusual, and there are important distinctions worth examining.

**1. The government’s own evidence distinguishes between the compounds.**

The April 2026 Advisory Council on the Misuse of Drugs (ACMD) report describes more than 15 UK deaths involving orphines, specifically identifying cychlorphine and spirochlorphine. A separate mortality dataset identified cychlorphine and chlorphine.
I could not find an SR-17018-attributed fatality in the UK deaths described in that report.
This doesn’t establish that SR-17018 is safe. It raises a legitimate question: **has the evidence for its individual risks and pharmacology been adequately distinguished from those of other compounds in the same chemical family?**

**2. SR-17018 has published evidence of potentially valuable pharmacological properties.**

In 2019, researchers at Scripps, including Laura Bohn’s team, reported that SR-17018 suppressed morphine withdrawal and restored morphine responsiveness in dependent mice.
Subsequent studies showed a more complicated picture, including tolerance in certain experimental assays. So it is not a magic receptor reset or a dependence-free opioid.
Nevertheless, researchers at the **University of Dundee** presented findings in 2024 indicating that SR-17018 interacts with μ-opioid receptors through a mechanism distinct from other agonists they tested.
This isn’t an ordinary research chemical whose only interesting property is producing opioid effects.

**3. The first published human observational evidence has now appeared.**

A September 2026 paper in *Frontiers in Pharmacology* examined 55 self-selected people who reported using SR-17018, predominantly in the context of opioid reduction or withdrawal.
Many reported reducing or stopping their previous opioid while using SR-17018.
These were unverified, self-reported outcomes in a highly selected sample—not clinical proof of efficacy, successful complete detoxification, or safety.
But they provide testable hypotheses for properly supervised human trials.

**4. Research access matters.**

The UK already requires Home Office licensing for legitimate research involving SR-17018 under its temporary controls. Permanent scheduling would not automatically prohibit scientific investigation, but regulatory requirements can introduce practical barriers.
The question is whether the government has properly considered SR-17018’s distinctive research value and whether meaningful access will be preserved.
There is an important difference between saying a compound has **no currently authorised medical use** and saying it has **no potential future medical value**.

**What can we actually do?**

I’m based in the UK and have already contacted organisations including Transform and Students for Sensible Drug Policy, as well as academic researchers, to draw attention to this proposal.
I’m hoping this thread reaches people with the expertise or connections to help establish a serious dialogue before the legislation is approved.

In particular:

Are any UK pharmacologists, addiction researchers, toxicologists or clinicians aware of this proposed classification?

Has anybody asked the ACMD or Home Office to publish a more detailed SR-17018-specific risk assessment?
Can organisations such as Transform, Release, Drug Science or SSDP help raise the issue with MPs, peers or parliamentary committees?

Could researchers familiar with the Scripps or Dundee findings provide an independent scientific perspective?
Is there a practical way to request further scrutiny and research-access protections before the parliamentary process is complete?

**I’m not arguing that SR-17018 should be sold freely, or recommending unsupervised human experimentation. I’m asking whether the decision is sufficiently evidence-specific, proportionate and compatible with future medical research.**

The consequences of controlling a dangerous recreational opioid and those of restricting a potentially useful research compound may overlap, but they are not necessarily identical.
If we want better treatments for opioid dependence, withdrawal and chronic pain, shouldn’t we take the time to understand compounds that might offer genuinely different mechanisms?
**If you work in this field, know somebody who does, or are already involved in a UK response, please speak up. Even identifying the appropriate parliamentary or scientific contacts would be valuable.**
I’d like this to become a constructive, evidence-based discussion rather than another argument over drug prohibition.

**Sources:**
UK draft legislation (September 2026):
https://www.legislation.gov.uk/ukdsi/2026/9780348287127/article/2
ACMD research and recommendations (see seventh addendum, 30 April 2026):
https://www.gov.uk/government/publications/acmd-advice-on-2-benzyl-benzimidazole-and-piperidine-benzimidazolone-opioids
Original Scripps animal research:
https://pmc.ncbi.nlm.nih.gov/articles/PMC6901606/
University of Dundee research, British Pain Society 2024 (abstract P-45):
https://pmc.ncbi.nlm.nih.gov/articles/PMC11418731/
2026 human observational study:
https://doi.org/10.3389/fphar.2026.1899247
Parliamentary progress tracker:
https://statutoryinstruments.parliament.uk/instrument/BYXGeOCM
*No sourcing, vendors, sales or dosing advice, please. This thread is about UK legislation, pharmacology and research access.*

Several low-molecular-weight chemical compounds have been described to induce neuronal cell proliferation.

Compounds such as LiCl, 4-aminothiazoles, Pregnenolone, ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFκB, Wnt, BDNF, and NPAS3. Moreover, combinations of these compounds can potentially transform somatic cells into neurons.

Abstract

Endocannabinoids (eCBs) are lipid-derived neuromodulators that regulate numerous neurophysiological processes by modulating synaptic transmission. Synthesised on demand in response to increased postsynaptic intracellular calcium or activation of postsynaptic G-protein coupled receptors, eCBs are rapidly degraded, resulting in transient, tightly regulated signalling. Dysregulation in the endocannabinoid system (ECS), including altered peripheral and central eCB concentrations and/or cannabinoid-1 receptor (CB1R) expression, has been observed across psychiatric syndromes, including major depressive disorder, psychotic disorders, and post-traumatic stress disorder (PTSD). These associations have prompted growing interest in pharmacological strategies targeting the ECS. Though medical cannabis is increasingly prescribed for psychiatric symptoms, its clinical use remains controversial due to limited high-quality evidence, psychotropic side effects, and regulatory constraints. An alternative is to enhance the signalling of a principal eCB, anandamide (AEA), potentially offering more physiologically constrained CB1R engagement, by inhibiting fatty acid amide hydrolase (FAAH), the main enzyme degrading AEA and its congener, N-acylethanolamines (NAE), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This review consolidates recent clinical evidence for FAAH inhibitors, examining their influence on AEA, safety and efficacy in ameliorating symptoms across a range of psychiatric conditions, including depression, anxiety, PTSD, and cannabis use disorder (CUD). Presently, only two compounds, PF-04457845 (JZP150) and JNJ-42165279, have progressed to Phase II trials, demonstrating modest clinical benefit in CUD, with no efficacy in PTSD or osteoarthritis pain. Herein, we discuss emerging insights, safety considerations, broader mechanistic implications, and future directions for FAAH-targeted therapeutics, advocating for a precision medicine approach to realise their potential in the treatment of psychiatric disorders.

Selective 5-HT2AR agonism without 5-HT2BR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HT2AR and 5-HT2BR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we design derivatives across tryptamine and phenethylamine scaffolds that integrate SEP and EBP engagement with scaffold modification to reinforce 5-HT2AR activation while limiting 5-HT2BR activity. Cryo-EM structures of 5-HT2AR and 5-HT2BR bound to IHCH-2330, a selective 5-HT2AR agonist and 5-HT2BR antagonist, confirm the design principle. These findings show differential activation mechanisms between 5-HT2AR and 5-HT2BR and provide a rational framework for engineering safer, functionally selective serotonergic compounds, mitigating 5-HT2BR–mediated side effects while preserving therapeutic efficacy.

Abstract:

Definition of terms is necessary to address the motion. First, “psychostimulants” are defined as methylphenidate and amphetamine, which inherently are short-acting drugs characterized by pharmacokinetic and pharmacodynamic properties of immediate-release formulations that act for a few hours. Sustained effects across the day can be achieved by controlled-release formulations, but positive carry-over to the next day is not significant, so on subsequent days these medications must be administered again to reinstate pharmacological effects. Second, “effective” refers to treatment-as-usual, whereas “efficacious” refers to enhanced or optimized treatment (that may set a maximum for effectiveness). Magnitude of effectiveness (eg, small, medium, or large effect size) depends on who is treated, how treatment is delivered, what outcome is evaluated, and other factors (including treatment adherence and study design). Third, “long term” refers to a given time frame (eg, 1 year), which can be applied to specify duration of treatment, length of follow-up, or both. Some studies evaluate long-term effectiveness of treatment while it is continued, whereas others evaluate long-term effectiveness of treatment during the follow-up after it is discontinued. Given these definitions, the following questions address long-term effectiveness of stimulant medication.

The full paper can be had on Sci Hub and is an interesting read. I'm not brave enough to share the link here.

Psychedelics exert therapeutic effects largely through 5-HT2A receptor activation, yet growing evidence shows that serotonin transporter (SERT)–mediated efflux also shapes signaling and behavior. Our recent work demonstrates that α-ethyltryptamine (AET) and its isomers engage both pathways, revealing a dual mechanism that enables separation of receptor-intrinsic efficacy from transporter-driven actions. Also, prior studies show that indole substitutions, particularly methoxy or bromo groups at positions 4–7, systematically alter 5-HT2AR affinity and behavioral potency, paralleling trends in DMT analogs where electron-donating and halogen substituents modify electron density, steric fit, and hydrogen-bonding within the orthosteric site. Building on this structure-guided framework, we evaluate two rationally designed AET analogs, 5-Br-AET and 7-MeO-AET, to test how receptor- versus transporter-dependent mechanisms shape serotonergic signaling.

Abstract Of the classic psychedelics, lysergic acid diethylamide (LSD) is perhaps the best-known, but its complex chemical architecture has limited synthetic investigations aimed at generating analogues with improved safety and efficacy profiles. Here, we systematically deconstruct the tetracyclic ergoline core of LSD to create 9 simplified ergoline analogues (i.e., ergologs) and evaluate them in pharmacological assays relevant to 5-HT2A, 5-HT2B, and 5-HT2C receptor function. Our work revealed the key molecular features and minimal pharmacophore of LSD necessary to produce maximal agonism of 5-HT2A receptors and hallucinogenic behavioral effects.

They should've used PRO-LAD...or even 2-MeO-PHENETH-LAD.

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.