Background: Pharmacological profiles of new psychoactive substances can be established rapidly in vitro and provide information on potential psychoactive effects in humans. The present study investigated whether specific in vitro monoamine transporter and receptor interactions can predict effective psychoactive doses in humans. Methods: We correlated previously assessed in vitro data of stimulants and psychedelics with human doses that are reported on the Internet and in books. Results: For stimulants, dopamine and norepinephrine transporter inhibition potency was positively correlated with human doses, whereas serotonin transporter inhibition potency was inversely correlated with human doses. Serotonin 5-hydroxytryptamine-2A (5-HT ) and 5-HT receptor affinity was significantly correlated with psychedelic doses, but 5-HT 2A 2C 1A receptor affinity and 5-HT and 5-HT receptor activation potency were not. 2A 2B Conclusions: The rapid assessment of in vitro pharmacological profiles of new psychoactive substances can help to predict psychoactive doses and effects in humans and facilitate the appropriate scheduling of new psychoactive substances. Keywords: new psychoactive substance, stimulants, psychedelics, receptor, transporter Introduction The unprecedented proliferation of new psychoactive sub- The compounds that we investigated can predominantly be stances (NPSs) over the last decade has introduced a variety classified as stimulants or psychedelics based on their pharma- of substance classes to recreational drug users worldwide. The cological and reported psychoactive effect profiles. Stimulants Internet plays a major role in the distribution of such com- exert their pharmacological effects mainly by interacting with pounds and in acquiring information about their effects and transmembrane monoamine transporters (i.e., norepineph- reported subjective effective doses in substance users. From 2011 rine [NE], dopamine [DA], and serotonin [5-hydroxytryptamine to 2017, we assessed the monoamine transporter and receptor (5-HT)] transporters [NET, DAT, and SERT, respectively]), either interaction profiles of more than 100 NPSs and related classic as inhibitors or as transporter substrates that mediate the amphetamine-type and psychedelic drugs of abuse using the non-exocytotic release of neurotransmitters (Rothman and same in vitro assays and procedures in our laboratory (Simmler Baumann, 2003). Psychedelics mediate their mind-altering et al., 2013; Simmler et al., 2014a, 2014b; Rickli et al., 2015a, effects by interacting with 5-HT receptors, mainly 5-HT recep - 2A 2015b, 2015c, 2016; Luethi et al., 2018a, 2018b, 2018c, 2018d). tor agonism (Nichols, 2016; Liechti, 2017). The present study Received: January 24, 2018; Revised: April 17, 2018; Accepted: May 24, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 1 provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy047/5021350 by guest on 13 July 2018 2 | International Journal of Neuropsychopharmacology, 2018 investigated whether (1) in vitro monoamine transporter inhib- 5-HT Receptor Binding Affinities ition potencies and (2) in vitro serotonin receptor binding and Radioligand binding affinities for 5-HT receptors were assessed activation can be used to predict human doses of stimulants as previously described in detail (Luethi et al., 2018d). Briefly, and psychedelics, respectively, that are reported on online drug membrane preparations overexpressing the respective human information websites and in books. receptors were incubated for 30 minutes (5-HT and 5-HT 1A 2A receptors) or 2 hours (5-HT receptor) with radiolabeled select- 2C Methods ive ligands at concentrations equal to K, and ligand displace- ment by the compounds was measured. Specific binding of Drugs the radioligand to the target receptor was defined as the dif- ference between total binding and nonspecific binding that The present study included drugs for which we previously inves- was determined in the presence of competitors. The following tigated and published in vitro pharmacological profiles using radioligands and competitors, respectively, were used: 1.39 nM identical assays and procedures in our laboratory (Simmler [ H]8-hydroxy-2-(di-n-propylamine)tetralin and 10 μM pindolol et al., 2013; Simmler et al., 2014a, 2014b; Rickli et al., 2015a, 2015b, (5-HT receptor), 0.45 nM [ H]ketanserin and 10 μM spiperone 1A 2015c, 2016; Luethi et al., 2018a, 2018b, 2018c, 2018d). These drugs (5-HT receptor), and 1.6 nM [ H]mesulgerine and 10 μM mian- 2A could be categorized as either psychostimulants or psychedelics serin (5-HT receptor). 2C based on their chemical structure and reported pharmacological effects. Substances that predominantly inhibited monoamine Activity at the 5-HT Receptor transporters were classified as stimulants. Substances that 2A most potently bound to 5-HT receptors were pharmacologically Activity at the 5-HT receptor was assessed as previously 2A classified as psychedelics. Five aminoindanes, 8 benzofurans, 28 described in detail (Luethi et al., 2018a). Briefly, NIH-3T3 cells cathinones, 3 piperazines, 10 piperidines, and 6 other NPSs were expressing the human 5-HT receptor were incubated in buffer 2A categorized as psychostimulants. One benzodifuran, 1 ergo- for 1 hour at 37°C before 100 μL of dye solution (fluorescence line, and 7 tryptamines were categorized as psychedelics. The imaging plate reader [FLIPR] calcium 5 assay kit; Molecular class of phenethylamines was further divided into 15 stimulant Devices) was added to each well, and the plates were again incu- phenethylamines (amphetamine-type substances) and 36 psy- bated for 1 hour at 37°C. The plates were then placed in a FLIPR, chedelic phenethylamines (ring-substituted phenethylamines, and 25 μL of the test drugs that were diluted in buffer was added including 2C drugs and their methoxybenzyl [NBOMe] analogs). online. The increase in fluorescence was measured for 51 s. EC The stimulants are listed in supplementary Table 1. The psych- values were derived from the concentration-response curves edelics are listed in supplementary Table 2. using nonlinear regression. Dose Estimates Activity at the 5-HT Receptor 2B Dose estimates for human psychoactive doses were based on Activity at the 5-HT receptor was assessed as previously 2B information that is found on the websites erowid.org, psycho- described in detail (Luethi et al., 2018a). Briefly, human embry- nautwiki.org, and tripsit.me (accessed December 17, 2017) and onic kidney 293 cells that expressed the human 5-HT recep - 2B in published books and other publications (Shulgin and Shulgin, tor were incubated in growth medium overnight. The growth 1995, 1997; Simmler et al., 2013; Trachsel et al., 2013). The aver - medium was then removed by snap inversion, and 100 μL of age midrange of the common dose range that is reported on the the calcium indicator Fluo-4 solution (Molecular Probes) was websites or in the books was taken as the dose estimate. Unless added to each well. The plates were incubated for 45 minutes stated otherwise, oral doses of the racemic mixtures were used at 31°C. The Fluo-4 solution was then removed by snap inver - for this study. sion, and 100 μL of Fluo-4 solution was added a second time for 45 minutes at 31°C. The cells were washed using an EMBLA cell washer, and 100 μL of assay buffer was added. The plates Monoamine Transporter Inhibition were then placed in a FLIPR, and 25 μL of the test substances Norepinephrine, DA, and 5-HT uptake inhibition was assessed that were diluted in buffer was added online. The increase in in human embryonic kidney 293 cells that were transfected fluorescence was measured for 51 seconds. EC values were with the human NET, DAT, or SERT as previously described in derived from the concentration-response curves using nonlin- detail (Luethi et al., 2018c). Briefly, the cells were suspended in ear regression. buffer and incubated with the drugs for 10 minutes before [ H]- 3 3 NE, [ H]-DA, or [ H]-5-HT at a final concentration of 5 nM was Statistical Correlation added for an additional 10 minutes to initiate uptake transport. Mean estimated dose values were correlated with previously The cells were then separated from the uptake buffer by cen- trifugation through silicone oil. The centrifugation tubes were published mean IC values for the monoamine transporter inhibition of stimulants and the mean serotonin receptor frozen in liquid nitrogen, and the cell pellet was cut into scin- tillation vials that contained lysis buffer. Scintillation fluid was affinity (K ) and receptor activation (EC) values of psych- i 50 edelics. The Spearman rank-order correlation coefficient (r ) added, and uptake was quantified by liquid scintillation count- ing. Transporter inhibitors (10 μM nisoxetine for the NET, 10 μM was computed using Prism 7.0a software (GraphPad). Values of P < .05 (2-tailed) were considered statistically significant. mazindol for the DAT, and 10 μM fluoxetine for the SERT) were added to assess nonspecific monoamine uptake. Monoamine Multiple regression analysis was conducted to assess the rela- tive contribution of different predictors to the dose estimate uptake data were fit by nonlinear regression to variable-slope sigmoidal dose-response curves, and IC values were deter- using Statistica 12 software (StatSoft) after logarithmic trans- formation of the data. mined using Prism 7.0a software (GraphPad). Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy047/5021350 by guest on 13 July 2018 Luethi and Liechti | 3 Results Based on the reported information, dose estimates could be made for 54 of 75 stimulants and 35 of 45 psychedelics. The doses apply to the oral route of administration if not indicated otherwise (supplementary Tables 1 and 2). References for the information sources of the pharmacological data and for the dose estimates for each substance are listed in supplementary Tables 1 (stimulants) and 2 (psychedelics). Stimulants Correlations between transporter inhibition potencies (mean IC values) of stimulants and their mean dose estimates are shown in Figure 1. Inhibition potency values of the NET and DAT were significantly correlated with the human dose estimates (r = 0.48, P < .001, n = 54, and r = 0.60, P < .001, n = 54, respectively). s s Furthermore, the NET and DAT inhibition potencies were sig- nificantly intercorrelated (r = 0.61, P < .001, n = 74). In contrast, the inhibition potency values of the SERT were inversely correlated with the dose estimates (r = -0.41, P < .01, n = 54) and inversely intercorrelated with DAT inhibition ( = r 0.26, P < .05, n = 73) but not NET inhibition. When DAT and NET inhibition was used as the predictor within a multiple regression analysis to predict the dose, DAT inhibition and NET inhibition alone were significant predictors (R = 0.55, P < .001, and R = 0.51, P < .001, respectively) when entered alone, but adding NET to DAT inhibition only minimally and nonsignificantly increased the overall predic- tion (multiple R = 0.59, P < .001). However, SERT inhibition was inversely correlated with dose when analyzed alone (R = 0.36, P < .01) and relevantly and significantly increased the overall pre- diction when it was added to NET and DAT inhibition (multiple R = 0.63, P < .001, n = 54). Psychedelics Correlations between 5-HT receptor affinities (mean K values) and their dose estimates are shown in Figure 2. Reported human doses for psychedelics were significantly correlated with 5-HT 2A and 5-HT receptor binding (r = 0.62, P < .001, n = 35, and r = 0.69, 2C s s P < .001, n = 35, respectively) but not with 5-HT receptor binding 1A (r = -0.18, P = .3, n = 35). The 5-HT and 5-HT affinity values were s 2A 2C significantly intercorrelated (r = 0.90, P < .001, n = 45), and the 5-HT and 5-HT affinity values were inversely intercorrelated 1A 2A (-0.32, P < .05, n = 45). No correlation was found between 5-HT 1A receptor binding and 5-HT receptor binding. 2c 5-HT receptor activation potencies (mean EC values) did 2A 50 not correlate with reported human doses ( = r -0.08, P = .6, n = 35). Four substances did not activate the 5-HT receptor in the inves- 2B tigated concentration range, and these substances thus could not be included in the statistical analysis. The 5-HT receptor 2B activation of the remaining psychedelics did not correlate with the dose estimates (r = 0.25, P = .2, n = 31). Discussion Stimulants Figure 1. Correlations between dose estimates of stimulants and their trans- porter inhibition potencies (mean IC values). In the present study, we found that both NET and DAT inhib- 50 ition potencies were correlated highly significantly with human doses that are reportedly used across a larger set of psycho- activity is inversely linked to the drug abuse liability of amphet- active, mostly amphetamine-type stimulants. In contrast, SERT amine-type substances (Ritz et al., 1987; Kuhar et al., 1991; Wee inhibition potency was inversely correlated with human doses, et al., 2005; Wee and Woolverton, 2006). We also found a signifi- a finding that is consistent with the notion that serotonergic cant intercorrelation between NET and DAT inhibition potencies Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy047/5021350 by guest on 13 July 2018 4 | International Journal of Neuropsychopharmacology, 2018 oral doses of 5 classic amphetamine-type stimulants used in clinical studies correlated with their NE-releasing potencies, although no significant correlation was shown for DA release (Rothman et al., 2001). In another study, Iversen and colleagues found no correlation between uptake inhibition potency and doses of stimulant drugs producing subjective effects (Iversen et al., 2013). The lack of correlation may relate to the small num- ber of compounds tested. We previously showed that DAT and NET inhibition potency but not SERT inhibition potency (IC values) were correlated with psychotropic effective doses within a subset of substances that were also included in the present analysis (Simmler et al., 2013). Altogether, the present study showed that DAT and NET inhibition potency values that are defined in vitro can be used to estimate whether a novel substance is psychoactive in humans, and the dose can be predicted when other known substances are co-analyzed as references. This finding has important implica- tions because it indicates that relatively fast and simple in vitro measures are useful for legally scheduling novel substances as psychoactive and thus as illegal NPSs. Both the DAT and NET may serve as predictors of the human dose, whereas SERT inhi- bition potency can be used as an additional indicator, predicting lower clinical potency of the substance. Furthermore, the DAT/ SERT inhibition ratio, which is defined as 1/DAT IC : 1/SERT IC 50 50 (Baumann et al., 2012), is a marker of the reinforcing effects and abuse liability of a substance (Baumann et al., 2000). Compounds with higher SERT vs DAT inhibition potency are typically associ- ated with 3,4-methylenedioxymethamphetamine-like entacto- genic effects, whereas drugs with high DAT vs SERT inhibition potency exert amphetamine-type psychostimulant effects and pose a higher risk for addiction (Simmler et al., 2013, 2014a; Liechti, 2014; Suyama et al., 2016). Psychedelics We showed that the doses of psychedelics were correlated with 5-HT receptor affinity (K values) but not with receptor activa- 2A i tion potency in the calcium release assay used to determine EC values. 5-HT receptor activation is assumed to mediate 50 2A the mind-altering effects of psychedelics (Glennon et al., 1984; Titeler et al., 1988) and such effects can be blocked by 5-HT 2A receptor antagonists, such as ketanserin (Preller et al., 2017). All of the psychedelics that were included in our study were receptor agonists, and the correlation with receptor binding but not activation might be explained by higher sensitivity of the ligand-binding assays compared with the receptor activation assay. There are different 5-HT receptor activation assays, and 2A the potencies for inducing calcium release in the assay that was used in the present study may not reflect the same pathway or mechanism that mediates the subjective effects of hallucinogens in humans. In fact, others have also reported that high-affinity agonist binding did not correlate well with the receptor activa- tion of 5-HT receptors (Roth et al., 1997; Acuña-Castillo et al., 2002). Despite the lack of utility for predicting doses, the deter - mination of 5-HT receptor activity remains crucial for deter - 2A mining whether a NPS has receptor agonist properties and may Figure 2. Correlations between dose estimates of psychedelics and their seroto- thus be classified as a psychedelic or whether it is an antagonist nin 5-HT receptor affinities (mean K values). that only binds to the receptor. The present study showed that 5-HT receptor binding allows an estimate of the dose at which 2A across substances, which is unsurprising given their similar - the substance is psychoactive in humans. Besides the correla- ity (i.e., high amino acid sequence similarity [Andersen et al., tion of the dose estimates for psychedelics with 5-HT receptor 2A 2015]) and the ability of both transporters to transport NE and affinities, we also found a correlation with 5-HT receptor affini- 2C DA across the cell membrane (Gu et al., 1994). The present data ties. Today, it is widely accepted that 5-HT receptor activation 2A are consistent with a small previous study that reported that is crucial for the action of psychedelics (Preller et al., 2017); the Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy047/5021350 by guest on 13 July 2018 Luethi and Liechti | 5 role of 5-HT receptor activation, however, remains enigmatic. 2C Statement of Interest As all known psychedelics are both 5-HT and 5-HT agonists, 2A 2C None. a contribution of 5-HT activation to psychedelic effects cannot 2C be excluded (reviewed in Nichols, 2004, 2016). 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International Journal of Neuropsychopharmacology – Oxford University Press
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