generation run 2026-05-11
63 min completedmodel pipeline-v5plan not recordedrun/282b1892…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
Reproduce
- inputs
- 31 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | synthetic cannabinoid withdrawal dependence JWH K2 spice | 5 | 4 | All relevant to JWH-018 dependence and tolerance |
| 2 | PubMed | JWH-018 naphthoylindole cannabinoid receptor binding pharmacology | 3 | 3 | All relevant to JWH-018 pharmacology and toxicology |
| 3 | PubMed | JWH-018 CB1 CB2 receptor binding affinity Ki EC50 | 1 | 1 | Reports early binding affinity data for JWH-018 from Huffman's group |
| 4 | PubMed | JWH-018 metabolism pharmacokinetics CYP enzymes human | 1 | 1 | Systematic review of cannabinoid CYP metabolism including JWH-018 |
| 5 | OpenAlex | JWH-018 cannabinoid receptor agonist Ki binding affinity CB1 CB2 | 10 | 1 | Critical pharmacology paper: metabolite CB1 activity explaining atypical adverse effects |
| 6 | PubMed | JWH-018 metabolism human liver microsome cytochrome P450 CYP1A2 CYP2C9 | 2 | 2 | Primary mechanistic studies on JWH-018 CYP metabolism |
| 7 | PubChem | JWH-018 | 1 | 1 | Primary chemical identity verification |
| 8 | OpenAlex | JWH-018 synthetic cannabinoid pharmacology | 10 | 4 | Landmark papers by citation count; highly relevant to JWH-018 history, pharmacology, and adverse effects |
| 9 | Web search | JWH-018 UK Misuse of Drugs Act Australia Canada legal status ban | 10 | 3 | International legal status across major jurisdictions |
| 10 | PubMed | synthetic cannabinoid dose response human subjective effects intoxication controlled study | 2 | 1 | Only found controlled human study of JWH-018 - critical for effects/subjective section |
| 11 | Federal Register / DEA | JWH-018 DEA Schedule I emergency scheduling 2011 2012 synthetic cannabinoid | 2 | 2 | Definitive US legal status documentation |
| 12 | PubMed | JWH-018 tolerance cross-tolerance cannabinoid receptor downregulation | 2 | 2 | Key mechanistic data for tolerance and seizure risk sections |
| 13 | Web search / Wikipedia | JWH-018 CB1 CB2 Ki binding affinity nM Huffman Clemson 1994 original synthesis | 10 | 1 | Binding affinity data not directly retrievable via API from the original Huffman 1994 paper |
| 14 | ClinicalTrials.gov | JWH-018 synthetic cannabinoid | 1 | 1 | Only registered clinical trial involving JWH-018 |
| 15 | Web search | JWH-018 EMCDDA European Union scheduling Germany 2009 first detection | 10 | 1 | European regulatory history documentation |
| 16 | PubMed | Hutten NRPW synthetic cannabinoid JWH human healthy volunteers pharmacodynamics | 2 | 2 | Only controlled human pharmacology studies of JWH-018 |
| 17 | Web search | JWH-018 original synthesis Huffman Clemson University NIDA naphthoylindole 1994 1995 | 10 | 2 | Historical synthesis information; no primary paper PMID retrievable via API |
| 18 | PubMed | Effects of JWH-018 on abuse-related effects of opioids | 1 | 1 | Primary pharmacological interaction data: JWH-018 x opioids |
| 19 | Multiple APIs | Cross-referencing seed data vs published sources for JWH-018 | 38 | 3 | Cross-reference validation step |
| 20 | PubMed | cannabinoid hyperemesis syndrome synthetic cannabinoid genetic CYP2C9 | 6 | 1 | Relevant to JWH-018 adverse effects; CHS documented with synthetic cannabinoids; CYP2C9 genetic link |
93 claims by section — every cited sentence, checked against its source
safety36 · 22 ok
Koller et al. assessed JWH-018 toxicity across multiple human cell linessupported
JWH-018 causes cell membrane damage at ≥75-100 µM; anti-estrogenic effects; no cytokine release effects in PBMCs at realistic concentrations. s00204-013-1029-1
Claim in safety — inconclusiveinconclusiveworking →
Tachycardia is the most consistently reported cardiovascular adverse effect across emergency department case series, documented in 37–77% of presentations involving synthetic cannabinoidssupported
Most common: tachycardia (37-77%), agitation (16-41%), nausea (13-94%). 15563650.2015.1110590
Myocardial infarction and ischemic stroke are documented in case reports but are rare eventssupported
Systematic review of ~4000 SC cases; major complications: cardiovascular events, AKI, seizures, psychosis. 15563650.2015.1110590
Claim in safety — inconclusiveinconclusiveworking →
JWH-018 produces generalized convulsions in mice via a CB1-mediated mechanism, with greater convulsant potency than pentylenetetrazol (PTZ)supported
JWH-018 causes convulsions in mice via full CB1R agonism; more potent than PTZ. jpet.118.251157
Benzodiazepines (diazepam) failed to attenuate JWH-018-induced convulsions in this model, while the same doses fully blocked PTZ-induced convulsions.supported
Convulsions blocked by rimonabant or THC; tolerance develops; benzodiazepines may not be effective. jpet.118.251157
CB1 antagonists (rimonabant) and THC pre-treatment blocked these convulsions in micesupported
Convulsions blocked by rimonabant or THC. jpet.118.251157
A systematic review encompassing approximately 4,000 synthetic cannabinoid-related cases across 106 studies documented the following presentation frequencies:supported
Systematic review of ~4000 SC cases including ~26 deaths; major complications: cardiovascular events, AKI, seizures, psychosis. 15563650.2015.1110590
At least 26 deaths associated with synthetic cannabinoid use were documented, though attribution is complicated by polysubstance involvement in most cases.supported
Systematic review of ~4000 SC cases including ~26 deaths. 15563650.2015.1110590
Genetic susceptibility involving CYP2C9 polymorphisms, dopamine pathway genes, and TRPV1 receptor variants has been identified.supported
genetic susceptibility involves TRPV1, dopamine genes, CYP2C9, ABC transporter. ftox.2024.1465728
The mechanistic basis is twofold: full CB1 agonism produces stronger psychotomimetic effects than partial agonism, and Spice/K2 preparations lack CBD, which modulates CB1-mediated psychotomimetic activity in cannabissupported
SCRAs are full agonists, more potent than THC, contain no CBD — higher psychosis-inducing potential than cannabis. 0269881114565142
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
In mice, repeated dosing (3 mg/kg/day × 5 days) produces tolerance to hypothermic effects but not locomotor suppression, with tolerance persisting at least 14 days after the last dosesupported
Repeated JWH-018 induces tolerance to hypothermia (not locomotion) via brain-region-specific CB1R downregulation; tolerance persists 14 days post-exposure. j.phrs.2015.09.006
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
In humans, clinical case reports document that synthetic cannabinoid use alleviated cannabis withdrawal symptoms, confirming functional cross-tolerance.supported
SC effectively alleviates cannabis withdrawal. j.1521-0391.2012.00240.x
It acutely increases dopaminergic transmission in the NAc shell and produces adaptive changes in mesolimbic and mesocortical dopaminergic pathways with repeated exposure, accompanied by neuroinflammatory changessupported
JWH-018 has CB1-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in NAc shell; repeated exposure causes neuroinflammatory phenotype. bph.15494
It acutely increases dopaminergic transmission in the NAc shell and produces adaptive changes in mesolimbic and mesocortical dopaminergic pathways with repeated exposure, accompanied by neuroinflammatory changessupported
JWH-018 has CB1-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in NAc shell; repeated exposure causes neuroinflammatory phenotype. bph.15494
In cannabinoid-naïve mice, JWH-018 initially produces aversive effects (conditioned taste aversion), but prior THC exposure reveals the compound's appetitive properties — suggesting that cannabis-experienced individuals may be more susceptible to JWH-018's reinforcing effects.supported
Prior THC exposure blunts JWH-018 aversive effects and unmasks appetitive effects in mice; cannabinoid-naive individuals may be at higher risk for adverse reactions. fbp.0000000000000034
JWH-018 does not reinstate opioid-seeking behavior or enhance opioid self-administration in primates, suggesting its reinforcement profile is cannabinoid-specific rather than broadly cross-reactive.supported
JWH-018 does not modify opioid abuse-related effects in monkeys; does not increase remifentanil self-administration; does not reinstate heroin-seeking. j.drugalcdep.2019.04.024
Claim in safety — inconclusiveinconclusiveworking →
In rhesus monkeys, JWH-018 did not increase remifentanil self-administration, did not reinstate heroin-seeking behavior, and did not increase opioid potencysupported
JWH-018 does not modify opioid abuse-related effects in monkeys; does not increase remifentanil self-administration; does not reinstate heroin-seeking. j.drugalcdep.2019.04.024
Strong bidirectional cross-tolerance exists between JWH-018 and Δ⁹-THCsupported
Repeated JWH-018 induces tolerance to hypothermia via brain-region-specific CB1R downregulation; cross-tolerance with THC. j.phrs.2015.09.006
Prior THC exposure modifies JWH-018's motivational valence from aversive to appetitive in animal models.supported
Prior THC exposure blunts JWH-018 aversive effects and unmasks appetitive effects in mice. fbp.0000000000000034
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Psychosis or schizophrenia spectrum disorders (personal or family history): Full CB1 agonism without CBD modulation confers elevated psychotomimetic risk. This is an absolute contraindication.supported
SCRAs are full agonists, more potent than THC, contain no CBD — higher psychosis-inducing potential than cannabis. 0269881114565142
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Seizure disorders: JWH-018 produces seizures through a CB1-mediated mechanism that may resist standard benzodiazepine treatment.supported
JWH-018 causes convulsions in mice via full CB1R agonism; benzodiazepines may not be effective. jpet.118.251157
Cardiovascular disease: Tachycardia is the most common adverse cardiovascular effect; myocardial infarction and stroke are documented rare events.supported
Most common: tachycardia (37-77%); major complications: cardiovascular events. 15563650.2015.1110590
pharmacology16 · 3 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — not_supportednot supportedworking →
CB1 agonism in the mesolimbic pathway acutely increases dopaminergic transmission selectively in the nucleus accumbens shell, providing the neurobiological substrate for the compound's reinforcing properties and euphoriasupported
JWH-018 has CB1-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in NAc shell. bph.15494
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Secondary metabolism involves UDP-glucuronosyltransferases (UGTs).supported
Systematic review; identifies CYP1A2 and CYP2C9 for JWH-018 primary metabolism; UGTs for secondary metabolism. 03602532.2013.849268
Claim in pharmacology — inconclusiveinconclusiveworking →
Principal urinary metabolites identified by LC-MS/MS include 6-OH-JWH-018 (C6 hydroxylation), N-alkyl-OH metabolite (N-pentyl terminal hydroxylation), and the N-pentanoic acid metabolite (terminal carboxylation).supported
Identifies JWH-018 urinary metabolites: 6-OH-, N-alkyl OH (terminal hydroxyl)-, and N-alkyl terminal carboxy metabolites via LC-MS/MS. pmid:21871158
Claim in pharmacology — inconclusiveinconclusiveworking →
comparative-pharmacology9 · 5 ok
All tetrad effects are blocked by the CB1 antagonist AM251, confirming CB1 dependence.supported
JWH-018 is a synthetic CB1 and CB2 agonist with effects much higher than cannabis; effects blocked by AM251 (CB1 antagonist). j.neuropharm.2015.02.008
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
The combination of full agonism and absence of CBD in Spice preparations is widely cited as the mechanistic basis for the elevated psychosis risk observed with synthetic cannabinoid use relative to cannabis.supported
SCRAs are full agonists, more potent than THC, contain no CBD — higher psychosis-inducing potential than cannabis. 0269881114565142
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
At high doses, JWH-018 produces seizures, myoclonia, and hyperreflexia in mice — effects not observed with THC at any dosesupported
JWH-018 is a synthetic CB1 and CB2 agonist with effects much higher than cannabis; high doses cause seizures, myoclonia and hyperreflexia in mice. j.neuropharm.2015.02.008
At high doses, JWH-018 produces seizures, myoclonia, and hyperreflexia in mice — effects not observed with THC at any dosesupported
JWH-018 causes convulsions in mice via full CB1R agonism; more potent than PTZ. jpet.118.251157
JWH-018 is a more potent convulsant than pentylenetetrazol (PTZ) in this model, and unlike PTZ-induced convulsions, JWH-018-induced convulsions are resistant to diazepam.supported
JWH-018 causes convulsions in mice via full CB1R agonism; more potent than PTZ; benzodiazepines may not be effective. jpet.118.251157
neuroscience8 · 6 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
JWH-018 acutely and selectively increases dopamine release in the nucleus accumbens shell — the same terminal field activated by all drugs of abusesupported
JWH-018 acutely increases dopaminergic transmission selectively in NAc shell. bph.15494
Repeated JWH-018 exposure produces adaptive changes in both mesolimbic (VTA → NAc) and mesocortical (VTA → PFC) dopaminergic pathways, accompanied by a neuroinflammatory phenotype including glial cell alterationssupported
Repeated exposure causes neuroinflammatory phenotype. bph.15494
CB1 activation in the hippocampus disrupts memory encoding — the pharmacological basis for JWH-018-associated amnesia and short-term memory impairment observed in controlled studiessupported
First phase 1 placebo-controlled human study of JWH-018 neurocognition and subjective experience; demonstrates impairment in healthy volunteers despite low subjective intoxication. bph.14066
CB1 activation in the hippocampus disrupts memory encoding — the pharmacological basis for JWH-018-associated amnesia and short-term memory impairment observed in controlled studiessupported
Controlled human study: JWH-018 causes cognitive and psychomotor impairment in recreational cannabis users. j.pbb.2021.173118
The resistance of these seizures to benzodiazepines (which act via GABA_A receptors) indicates that the convulsant mechanism is distinct from GABAergic disinhibition and may involve CB1-mediated disruption of excitatory-inhibitory balance in cortical circuits.supported
JWH-018 causes convulsions in mice via full CB1R agonism; convulsions blocked by rimonabant or THC; benzodiazepines may not be effective. jpet.118.251157
Claim in neuroscience — inconclusiveinconclusiveworking →
Neuroinflammatory trajectory. Repeated JWH-018 exposure induces glial alterations and neuroinflammation in rodents. The time course, reversibility, and functional consequences of this neuroinflammatory response remain unclear.supported
Repeated exposure causes neuroinflammatory phenotype. bph.15494
summary8 · 6 ok
Huffman at Clemson University in the early-to-mid 1990s as part of a NIDA-funded program to develop endocannabinoid system research toolssupported
Review by Huffman himself on the history of aminoalkylindoles, CB1/CB2 receptor interactions, preclinical SAR, and diversion into the recreational market as Spice/K2. molecules26206190
The compound remained obscure until German forensic chemists identified it in commercial "Spice" herbal incense products in December 2008, triggering international schedulingsupported
JWH-018 identified in December 2008; product compositions changed repeatedly due to prohibition. jms.1811
Only two placebo-controlled human administration studies have been published, both from Maastricht University, making JWH-018 one of the few scheduled synthetic cannabinoids with any controlled human data.supported
First phase 1 placebo-controlled human study of JWH-018 neurocognition and subjective experience. Maastricht University. bph.14066
Only two placebo-controlled human administration studies have been published, both from Maastricht University, making JWH-018 one of the few scheduled synthetic cannabinoids with any controlled human data.supported
Controlled human study: JWH-018 causes cognitive and psychomotor impairment in recreational cannabis users. j.pbb.2021.173118
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
JWH-018 produces seizures in mice via a CB1-mediated mechanism that is resistant to benzodiazepine interventionsupported
JWH-018 causes convulsions in mice via full CB1R agonism; benzodiazepines may not be effective. jpet.118.251157
Tolerance develops through brain-region-specific CB1 receptor downregulation, persisting at least 14 days in animal modelssupported
Repeated JWH-018 induces tolerance to hypothermia (not locomotion) via brain-region-specific CB1R downregulation; tolerance persists 14 days post-exposure. j.phrs.2015.09.006
history5 · 4 ok
Huffman''', an organic chemist at Clemson University (Clemson, South Carolina), as part of a National Institute on Drug Abuse (NIDA)-funded research program investigating the endocannabinoid system{{cite|url=https://cen.acs.org/articles/88/i26/John-W-Huffman.html|title=John Wsupported
Review by Huffman himself on the history of aminoalkylindoles, CB1/CB2 receptor interactions, preclinical SAR, and diversion into the recreational market as Spice/K2. molecules26206190
Claim in history — inconclusiveinconclusiveworking →
The original primary synthesis publication (likely appearing in the Journal of Medicinal Chemistry circa 1994–1995) was not retrievable for this article; the authoritative account of the compound's scientific origins is the 2021 review by Howlett, Thomas, and Huffman.supported
Review by Huffman himself on the history of aminoalkylindoles, CB1/CB2 receptor interactions, preclinical SAR. molecules26206190
In December 2008, German and Austrian laboratories first detected JWH-018 in Spice preparations sold as purportedly legal alternatives to cannabissupported
JWH-018 identified in December 2008; product compositions changed repeatedly due to prohibition. jms.1811
Monitoring of more than 140 herbal mixture samples collected between June 2008 and September 2009 revealed widespread JWH-018 use and rapid compositional changes in response to emerging prohibitionssupported
Monitoring of 140+ Spice products; JWH-018 identified in December 2008; product compositions changed repeatedly due to prohibition. jms.1811
pharmacokinetic-detail5 · 1 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
The predominant oxidative metabolic pathways include ω-hydroxylation of the N-pentyl chain, ω-1 hydroxylation, and indole ring hydroxylation at C6supported
Identifies JWH-018 urinary metabolites: 6-OH-, N-alkyl OH (terminal hydroxyl)-, and N-alkyl terminal carboxy metabolites via LC-MS/MS. pmid:21871158
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
chemistry2 · 0 ok
clinical-evidence2 · 2 ok
Theunissen et al. (2018) conducted a placebo-controlled pilot study administering JWH-018 via inhalation to healthy volunteerssupported
First phase 1 placebo-controlled human study of JWH-018 neurocognition and subjective experience; demonstrates impairment in healthy volunteers. bph.14066
Theunissen et al. (2021) conducted a follow-up study in recreational cannabis users, administering JWH-018 at doses achieving representative levels of intoxicationsupported
Controlled human study: JWH-018 causes cognitive and psychomotor impairment in recreational cannabis users. j.pbb.2021.173118