Common intuition suggests that expressing moderate views would allow people to appeal to the broadest audience possible. But is that really the case? Do moderates please all sides or please no side? Across five preregistered studies (N = 3,272), we show that people holding a partisan view on a sociopolitical issue perceive moderates (i.e., people disclosing a genuinely non-extreme position) as belonging to the out-group ideology. We find that the ‘moderate as out-group’ effect occurs when sociopolitical issues are moralized and at the same time the opposing side is perceived to be a threat to oneself, close ones, or society at large. We also present evidence that the effect is due to partisans’ perception that moderates lack out-group hate, rather than lack in-group love. In other words, partisans perceive that moderates agree with—or simply don’t condemn—the opposing (immoral and threatening) ideology, rather than disagree with their own. Consistent with this, the ‘moderate as out-group’ effect occurs when the moderate view is framed as pro-both sides, but it is attenuated when it is framed as pro-neither side. ©American Psychological Association, 2026. This paper is not the copy of record and may not exactly replicate the authoritative document published in the APA journal. The final article is available, upon publication, at: 10.1037/xge0001957

Traditional models of rational choice assume that preferences are complete, but the completeness axiom is neither normatively compelling nor psychologically plausible. Building on recent work in economics, we develop a rational analysis of decision making with incomplete preferences. The analysis sheds surprising light on a range of well-known behavioral "anomalies," including the endowment effect, status quo maintenance, the sunk cost effect, and coherent arbitrariness. We propose a two-part division of rational choice theory-into preference theory and "implementation theory"-and show how conservative and coherently arbitrary policies can effectively implement incomplete preferences. The two-part normative framework motivates a psychological distinction between evaluation and implementation phases in decision making. We argue that the endowment effect and related phenomena, which have usually been attributed to loss aversion in the evaluation phase, are better explained by conservatism in the implementation phase. The rational analysis challenges the normative adequacy of expected utility theory and raises questions about the explanatory scope of prospect theory. It illustrates the rich interplay between psychological models of value structure and normative models of rational choice. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

The rapid structural evolution and extensive metabolism of synthetic cannabinoid receptor agonists (SCRAs) following consumption makes their detection in biological samples challenging, especially in urine. In vitro metabolite identification studies are an essential tool for identifying analytical targets to confirm SCRA consumption in clinical and forensic toxicology casework. Systematic studies on structurally related SCRAs allow structure–metabolism relationships (SMRs) to be determined, helping to predict the metabolites of emerging and future compounds. In this study, a series of amino acid-derived 4-pentenyl SCRAs and the OXIZID 4-pentenyl SCRA BZO-4en-POXIZID were incubated at 5 µM with pooled human hepatocytes for up to 3 h. Metabolites were identified using liquid chromatography–quadrupole time-of-flight mass spectrometry (LC–QTOF-MS) and SMRs investigated using the proportion that each type of biotransformation contributed to the total abundance of metabolites for each parent compound. Metabolites were mainly produced via terminal amide/ester hydrolysis, dihydrodiol formation on the tail, hydroxylation and N-dealkylation, but also by ketone formation, dehydrogenation, glucuronidation and combinations thereof. Methyl valinate (MMB) and ethyl valinate (EMB) SCRAs underwent extensive ester hydrolysis (90.9–96.0

BACKGROUND AND AIM:Citations in academia have long been regarded as a fundamental means of acknowledging the contribution of past work and promoting scientific advancement. The aim of this paper was to investigate the impact that misconduct allegations made against scholars have on the citations of their work, comparing allegations of sexual misconduct (unrelated to the research merit) and allegations of scientific misconduct (directly related to the research merit). METHODS:We collected citation data from the Web of Science (WoS) in 2021, encompassing 31,941 publications from 172 accused and control scholars across 18 disciplines. We also conducted two studies: one on non-academics (N = 231) and one on academics (N = 240). RESULTS:The WoS data shows that scholars accused of sexual misconduct incur a significant citation decrease in the three years after the accusations become public, while we do not detect a significant citation decrease for scholars accused of scientific misconduct. The study involving non-academics suggests that individuals are more averse to sexual than to scientific misconduct. Finally, contrary to the WoS data findings, a sample of academics indicates they are more likely to cite scholars accused of sexual misconduct than those accused of scientific misconduct. CONCLUSIONS:In the first three years after accusations became public, scholars accused of sexual misconduct incur a larger citation penalty than scholars accused of scientific misconduct. However, when asked to predict their citing behavior, scholars indicated the reverse pattern, suggesting they might mis-predict their behavior or be reluctant to disclose their preferences.

: In this paper, we consider two ways in which traditional approaches to testing lay moral theories have oversimplified our picture of moral psychology. Based on thought experiments (e.g., Foot 1967 and Thomson 1976) concerning the moral permissibility of certainly killing one to certainly saving five, psychological experiments (e.g., Cushman et al. 2006) have been constructed that purport to sort instances of reasoning into an implicit consequentialist moral theory (according to which only consequences are morally relevant) or a non-consequentialist moral theory (according to which other considerations, such as rights, always override the maximization of good consequences). In earlier work (Ryazanov et al. 2020, unpublished manuscript, and in preparation), we have shown that asking participants questions in which we vary the ratio of lives saved to lives lost and probability of outcomes reveals that people may be appealing to a more subtle non-consequentialist theory known as threshold deontology. According to that theory, rights matter and can override the maximization of consequences in moral decision-making, but they do not always do so. Rights are not absolute in that if the cost to well-being becomes high enough , rights do not play an overriding role. We explain why varying the questions in these ways leads to a more nuanced and truer picture, and we briefly explore the implications of these results here. We then turn to a second way in which asking a different kind of question can bring out a fuller picture of implicit moral theorizing. We discuss several studies that ask participants comparative questions that involve not just comparing acting in such a way that there

A great deal of current research on moral judgments centers on moral dilemmas concerning tradeoffs between one and five lives. Whether one considers killing one innocent person to save five others to be morally required or impermissible has been taken to determine whether one is appealing to consequentialist or non-consequentialist reasoning. But this focus on tradeoffs between one and five may obscure more nuanced commitments involved in moral decision-making that are revealed when the numbers and ratio of lives to be traded off are varied, and when the probabilities of each outcome occurring are less than certain. Four studies examine participants' reactions to scenarios that diverge in these ways from the standard ones. Study 1 examines the extent to which people are sensitive to the ratio of lives saved to lives ended by a particular action. Study 2 verifies that the ratio rather than the difference between the two values is operative. Study 3 examines whether participants treat probabilistic harm to some as equivalent to certainly harming fewer, holding expected ratio constant. Study 4 explores an analogous issue regarding the sensitivity of probabilistic saving. Participants are remarkably sensitive to expected ratio for probabilistic harms while deviating from expected value for probabilistic saving. Collectively, the studies provide evidence that people's moral judgments are consistent with the principle of threshold deontology.

This chapter considers two ways in which traditional approaches to testing lay moral theories have oversimplified our picture of moral psychology. One oversimplification is to sort instances of reasoning into an implicit consequentialism or an absolutist non-consequentialism. Prior research by the authors reveals another option that people appeal to threshold deontology, a non-absolutist version of non-consequentialism according to which rights sometimes override the maximization of consequences, but not always. This chapter explains why varying questions on surveys in certain ways leads to a more nuanced and truer picture, and briefly explores the implications of that research. The chapter then turns to a second way in which asking a different kind of question can bring out a fuller picture of implicit moral theorizing, by considering several studies that ask participants comparative questions that involve not just comparing acting in such a way that there is a risk of killing vs. allowing to die, but how the risk is distributed. Asking the comparative question offers intriguing results that contrast with those that emerge from asking non-comparative questions. The chapter then considers the challenging methodological question of whether results should be privileged based on one way of asking the questions over the other.

Background: Ion mobility spectrometry is used for the rapid detection of drugs at points of security but are unable to differentiate some drugs leading to the instrument alarming for a drug not present in the sample. This can be particularly problematic for samples that alarm for fentanyl. In this study, fentanyl immunoassay strips were evaluated for use as a secondary test for fentanyl, including for the testing of alternative matrices, such as powders, e-liquids, and infused papers and textiles.Methods: The limit of detection of fentanyl immunoassay strips was examined along with their selectivity to 18 fentanyl analogsand 72 other drugs and cutting agents. The effectiveness of the test strips at the detection of fentanyl in the presence of other drugs was examined by testing a series of concentrations of fentanyl in solution in combination with other drugs. The testing of alternative matrices was explored with laboratory prepared samples through sampling with cotton buds and extraction in water.Results: The fentanyl immunoassay strips detected fentanyl at concentrations of 45 ng/mL and reacted with 16 of 18 tested fentanyl analogs with carfentanil and norfentanyl being the only analogs to not react. There was no reactivity with other drugs or cutting agents. The effectiveness of the fentanyl test strips was not reduced when fentanyl was mixed with other drugs. Fentanyl was successfully detected with high sensitivity in all alternative matrices.Conclusion: The fentanyl immunoassay strips were found to be an effective secondary test for fentanyl and at least 16 fentanyl analogs in seized drug samples, including when mixed with other drugs. The effectiveness of the sampling methods for alternative matrices should be further evaluated using fentanyl and fentanyl analog casework samples. The use of this method by law enforcement and other agencies should be examined to assess its effectiveness and ease of use in operational settings.

The synthetic cannabinoid receptor agonist (SCRA) market is undergoing important changes since the enactment of the 2021 class-wide generic SCRA ban in China, one of the most important source countries for new psychoactive substances (NPS). Recently, various compounds with new structural features, synthesized to bypass this legislation, have entered the recreational drug market. Certain monocyclic pyrazole-carrying "FUPPYCA" SCRAs have been sporadically detected since 2015 without gaining further popularity. However, as evidenced by their recent detection in Scottish prisons, 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA have re-emerged, potentially triggered by the new legislative ban. The aim of this study was to characterize the in vitro intrinsic CB1 and CB2 receptor activation potential of 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA, as well as 4 analogs (5F-3,5-ADB-PFUPPYCA, 3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA) using live cell β-arrestin 2 recruitment assays. Most analogs were essentially inactive at either CB1 or CB2, with only 3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA showing a limited activation potential at CB1. Furthermore, the importance of the position of the tail structure was demonstrated, with 5,3 regioisomers being more active than their 3,5 analogs. Moreover, all compounds exhibited antagonistic behavior at both receptors, which may be associated with their structural resemblance to cannabinoid antagonists and inverse agonists. Although the 3,5 regioisomers of these "FUPPYCA" SCRAs circumvent the Chinese ban, it is unlikely that these SCRAs will pose a major threat to public health, given the lack of pronounced CB receptor activity.

Drug use within prisons is increasingly complex and unpredictable. Benzodiazepines are currently one of the most common drugs detected in individuals leaving Scottish prisons; however, understanding illicit benzodiazepine use within prisons and assessing the potential harm to individuals is challenging due to the lack of available analytical data on the substances circulating. Increasingly, materials, such as paper and clothing, infused with novel benzodiazepines have been identified as a smuggling route into Scottish prisons. Methods were developed for the qualitative and quantitative analysis of benzodiazepines using gas chromatography-mass spectrometry (GC-MS) and applied to 495 seized samples from 11 Scottish prisons, including papers, cards, blotters, powders, tablets, and clothing. Evolution in the benzodiazepines being detected was demonstrated, with etizolam being the most prevalent throughout 2020/2021 following which flubromazepam and bromazolam detections increased. Additionally, significant changes in the smuggling methods and drug formats detected occurred over time following policy changes within prisons. These data represent the first reported widescale etizolam quantitation data and demonstrate high levels of variability across all sample types, most notably within tablets (0.34-2.33 mg per tablet). Additionally, concentration mapping of a whole seized card sample revealed the total concentration of drug present (312.5 mg) and demonstrated variability across the surface of the card (1.16-1.87 mg/cm2). These data highlight the challenges of consistent dosing for individuals and the high risks of unintentional overdose. Increased understanding of the challenge of such drug smuggling and benzodiazepine use will aid in the development of strategies to reduce supply and mitigate harm.

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D7.4 ranging from 2.48 (AB-FUBINACA) to 4.95 (4F-ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB-BUTINACA) to 99.9% (BZO-HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser-bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market.

Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5'Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5'Br-INACA (ADMB-5Br-INACA), MDMB-5'Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5'Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5'F-BUTINACA (ADMB-B-5F-INACA), using CB1 and CB2 β-arrestin 2 recruitment assays and a CB1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5'Br-INACA and (S)-MDMB-5'Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5'Br-BUTINACA and (S)-MDMB-5'Br-BUTINACA, respectively, which were potent and efficacious CB1 agonists. Also, at CB2, tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB1; however, this effect was less prominent at CB2. Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5'F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5'Br-INACA and MDMB-5'Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5'Br-INACA and MDMB-5'Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected.

Synthetic cannabinoid receptor agonists (SCRAs) remain a major public health concern, with their use implicated in intoxications and drug-related deaths worldwide. Increasing our systematic understanding of SCRA metabolism supports clinical and forensic toxicology casework, facilitating the timely identification of analytical targets for toxicological screening procedures and confirmatory analysis. This is particularly important as new SCRAs continue to emerge on the illicit drug market. In this work, the metabolism of ADB-HEXINACA (ADB-HINACA, N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-hexyl-1H-indazole-3-carboxamide), which has increased in prevalence in the United Kingdom and other jurisdictions, was investigated using in vitro techniques. The (S)-enantiomer of ADB-HEXINACA was incubated with pooled human hepatocytes over 3 hours to identify unique and abundant metabolites using liquid chromatography-quadrupole time-of-flight mass spectrometry. In total, 16 metabolites were identified, resulting from mono-hydroxylation, di-hydroxylation, ketone formation (mono-hydroxylation then dehydrogenation), carboxylic acid formation, terminal amide hydrolysis, dihydrodiol formation, glucuronidation and combinations thereof. The majority of metabolism took place on the hexyl tail, forming ketone and mono-hydroxylated products. The major metabolite was the 5-oxo-hexyl product (M9), while the most significant mono-hydroxylation product was the 4-hydroxy-hexyl product (M8), both of which were confirmed by comparison to in-house synthesized reference standards. The 5-hydroxy-hexyl (M6) and 6-hydroxy-hexyl (M7) metabolites were not chromatographically resolved, and the 5-hydroxy-hexyl product was the second largest mono-hydroxylated metabolite. The structures of the terminal amide hydrolysis products without (M16, third largest metabolite) and with the 5-positioned ketone (M13) were also confirmed by comparison to synthesized reference standards, along with the 4-oxo-hexyl metabolite (M11). The 5-oxo-hexyl and 4-hydroxy-hexyl metabolites are suggested as biomarkers for ADB-HEXINACA consumption.

Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS) and new structural scaffolds have emerged on the recreational drug market since the enactment of Chinese SCRA analog controls in 2021. This study reports the first SCRAs to be detected with a bromide at the 5 position (5'Br) on the phenyl ring of the indazole core and without a tail moiety. ADB-5'Br-INACA (ADMB-5'Br-INACA) and MDMB-5'Br-INACA were detected in seized samples from Scottish prisons, Belgian customs, and US forensic casework. The brominated analog with a tail moiety, ADB-5'Br-BUTINACA (ADMB-5'Br-BUTINACA), was also detected in Scottish prisons and US forensic casework. The metabolites of these compounds and the predicted compound MDMB-5'Br-BUTINACA were identified through incubation with primary human hepatocytes to aid in their toxicological identification. The bromide on the indazole remains intact on metabolites, allowing these compounds to be easily distinguished in toxicological samples from their non-brominated analogs. Glucuronidation was more common for tail-less analogs than their butyl tail-containing counterparts. Forensic toxicologists are advised to update their analytical methods with the characteristic ions for these compounds, as well as their anticipated urinary markers: amide hydrolysis and monoOH at tert-butyl metabolites (after β-glucuronidase treatment) for ADB-5'Br-INACA; monoOH at tert-butyl and amide hydrolysis metabolites for ADB-5'Br-BUTINACA; and ester hydrolysis metabolites with additional metabolites for MDMB-5'Br-INACA and MDMB-5'Br-BUTINACA. Toxicologists should remain vigilant to the emergence of new SCRAs with halogenation of the indazole core and tail-less analogs, which have already started to emerge.

A new class of synthetic cannabinoids termed OXIZIDs has recently emerged on the recreational drug market. In order to continue the detection of new drugs in biological specimens, the identification of metabolites is essential. The aim of this study was to elucidate the metabolites of BZO-4en-POXIZID produced in human liver microsomes (HLMs) and human hepatocyte incubations and to compare the results with closely related analogs using the same experimental setup. Each drug was incubated for 1 h in HLM and BZO-4en-POXIZID was also incubated in human hepatocytes for up to 3 h. Subsequently, the incubates were analyzed by liquid chromatography-high-resolution mass spectrometry. BZO-4en-POXIZID metabolites were obtained in the incubation with HLMs and human hepatocytes, via the metabolic pathways of dihydrodiol formation, hydroxylation, reduction of the alkene bond and glucuronidation. The major metabolic pathway was found to be dihydrodiol formation at the pentenyl tail moiety. BZO-POXIZID, 5 F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID underwent similar metabolism to those reported in the literature, via the metabolic pathways of N-dealkylation, hydroxylation, ketone formation and oxidative defluorination (to alcohol or carboxylic acid). The results suggest that OXIZIDs are mainly metabolized at the N-alkyl moiety and the major metabolic pathways are hydroxylation when the N-alkyl moiety is a simple hydrocarbon, whereas functional-group-specific pathways (dihydrodiol formation and oxidative defluorination) are preferred when the moiety contains specific functional groups (alkene or fluoro), as has been observed for other synthetic cannabinoids. The major metabolites generated via these major metabolic pathways should serve as useful analytical targets for urine analysis. Furthermore, the higher abundance of glucuronidated metabolite suggests that enzymatic hydrolysis of glucuronides may be necessary for urine analysis to increase phase I metabolite concentration and improve detection.

Although all birth orders in the "birth sequence problem" are equiprobable, most participants judge the less representative order as less likely than the more representative order. But this well-known problem confounds representativeness with the direction in which birth orders are compared. We hypothesized and corroborated in three experiments (total N = 1,136) that participants pragmatically infer the birth orders' relative prevalence from the direction of comparison. Experiment 1 found that participants judged the less representative sequence as more common when we reversed the comparison. Experiment 2 reproduced these results despite removing representativeness as a cue. In Experiment 3, participants preferred to place the relatively common sequence as the referent in an inverted "speaker" problem. Our results turn the iconic problem's interpretation on its head: Rather than indicating flawed human cognition, the birth sequence problem illustrates people's ability to adaptively extract subtle linguistic meaning beyond the literal content.

The normative principle of description invariance presupposes that rational preferences must be complete. The completeness axiom is normatively dubious, however, and its rejection opens the door to rational framing effects. In this commentary, we suggest that Bermúdez's insightful challenge to the standard normative view of framing can be clarified and extended by situating it within a broader critique of completeness.

Synthetic cannabinoids (SCs) are amongst the most prevalent of the new psychoactive substances. They encompass various structural classes with a wide range of CB1 activity. Most SCs are extensively bio-transformed in vivo and in vitro. The available data on the CB1 activity of SC metabolites are limited but such knowledge is needed to evaluate SC toxicology, duration of effects and to develop bioassays for screening purposes. To evaluate any structure-activity relationships, we determined the human CB1 receptor efficacy and potency of three SC classes and their metabolites. An activity assay incorporating AequoScreen recombinant CHO-K1 cells expressing the human CB1 receptor was used to study SCs and their metabolites. Dose-response curves were prepared in triplicate in three independent experiments and GraphPad Prism was used to calculate substance efficacy and potency. Eight concentrations, 29 nM–60 μM, were used for each drug and JWH-018 was used as a reference. The three SC classes investigated were (i) JWH-018, AM2201, THJ-018 and THJ-2201 and their corresponding 4-OH-pentyl and 5OH-pentyl metabolites; (ii) MMB-4en-PICA (MMB022) and MDMB-4en-PINACA and their corresponding ester-hydrolysis and dihydrodiol metabolites; and (iii) 5F-MDMB-PINACA, 5F-MDMB-PICA, 4F-MDMB-BINACA, and 4F-MDMB-BICA and their oxidative-defluorination and ester-hydrolysis metabolites. Parent SC potency values ranged from 7-200 nM. The 4-OH-pentyl metabolites of JWH-018, AM2201, THJ-018 and THJ-2201 had similar potency to their respective parent SC. The 5-OH-pentyl-JWH-018 and 5-OH-pentyl-THJ-018 metabolites were 5–10 times less potent than their parent SCs. No CB1 activity was observed for MMB-4en-PICA ester-hydrolysis and dihydrodiol metabolites, possibly due to the lower activity of the parent and a subsequent large loss of activity, whilst the dihydrodiol and ester-hydrolysis MDMB-4en-PINACA metabolites were 53 times and 130 times less potent respectively than MDMB-4en-PINACA. 5F-MDMB-PINACA and 5F-MDMB-PICA oxidative-defluorinated metabolites were 7 and 27 times less potent than the parent SCs. The 4OH-butyl metabolites of 4F-MDMB-BINACA, and 4F-MDMB-BICA were 6 and 11 times less potent than the parent drug, respectively, and their ester-hydrolysis metabolites were 21-47 times less potent. Where hydroxylations occur at the non-terminal (4) position of the pentyl tail of JWH-018 and THJ -2201 there is no loss of CB1 activity. The CB1 potency of the JWH-018 and THJ -2201 5OH-pentyl metabolites is reduced but in the same potency range as those reported for other parent SCs. Dihydrodiol metabolites of 4en-compounds show a large reduction in CB1 activity (> 53 times) compared to the parent, as do their ester hydrolysis metabolites (> 130-times). The oxidative defluorinated metabolites of the 4F-MDMB and 5F-MDMB compounds retain some CB1 activity (7–27 times reduction) but a more significant loss of activity is observed when ester hydrolysis occurs in the head group (21–417 times reduction). The head and core moieties of SCs are most influential in determining CB1 potency. The tail, when fulfilling certain steric requirements, acts as an anchor point in the CB1 receptor, influencing the overall position and rigidity of the SC in the CB1 receptor. From a urinary bioassay perspective, where metabolites can be 10 times more abundant than parent SCs, the activity of the metabolites might be important for SC detection. We have established a structure-activity relationship for three SC classes and their metabolites. The relative change in CB1 activity caused by a biotransformation on the tail of the SC depends on the head structure present and biotransformation of the head group leads to a greater reduction in potency than single hydroxylations on the tail. So, "the tail of the SC metabolite needs to know what the head is doing" when activating the CB1 receptor. The study is part of Eurostars-2 Joint Programme NPS-REFORM.