Drug liking and wanting, not impulsive action or reflection is increased by 4-fluoroamphetamine

Drug liking and wanting, not impulsive action or reflection is increased by 4-fluoroamphetamine Background New psychoactive substances (NPS) are chemical analogues designed to mimic the effects of various classic recreational drugs of abuse including MDMA, LSD, and cannabis. NPS use is associated with concern about the acute and longer-term effects particular substances might have, with abuse and addiction as potential consequences. Impulsivity and sensitivity to the rewarding effects of drugs have been considered as risk factors for drug abuse. In light of the popularity of 4-fluoroamphetamine (4-FA), it is important to assess whether 4-FA can lead to subjective drug liking and wanting, and impulsive behavior, all factors contributing to the abuse likelihood of a substance. Methods A placebo-controlled 2-way crossover study in 12 healthy poly-drug using participants was conducted to test subjective and behavioral effects of 4-FA (100 mg). 4-FA concentrations were determined in serum up to 12 h after administration and two impulsivity tasks and two drug experience questionnaires assessing drug liking and wanting, and good and bad drug effect, were administered between 1 and 11 h post-administration. Results Findings showed that 4-FA did not affect impulsive behavior. Self-ratings of drug liking and wanting and good drug effect were increased 1 h after administration; this effect was absent 11 h after drug intake. Discussion and conclusion To conclude, 4-FA (single dose) increased self-rated liking and wanting, which is known to contribute to the abuse likelihood of a substance; however, it left another factor impulsive behavior unaffected. It has to be noted that the current picture is limited and might change with increased sample size, and/or different 4-FA doses. Clinical trial registration Trial acronym: 4-FA. URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6164. Registration number: NTR6164 (Dutch clinical trial registry number). . . . . . Keywords 4-FA Impulsive reflection Impulsive action Drug liking Drug wanting Good drug effect Introduction substantiated yet in human experimental studies (Hondebrink et al. 2017;Liechti 2015). Scientific knowledge New psychoactive substances (NPS) are chemical analogues about NPS’s acute effects is needed, seen their exponential designed to mimic the effects of various classic recreational increase in availability and number over the last 10 years. drugs of abuse including MDMA, LSD, and cannabis Moreover, this surge has gone hand in hand with an increase (EMCDDA 2015). Anecdotal evidence by users suggests that in use, and emergency department visits due to over- NPS have subjective effects comparable to the classical psy- intoxication (EMCDDA 2015;Woodet al. 2013). choactive substances though these effects have not been 4-Fluoroamphetamine (4-FA) is a prototypical example of an NPS, belonging to the chemical class of phenethylamines (Hondebrink et al. 2017). It appeared on the Dutch Bdrug market^ between 2007 and 2009 where after reports of acute * K. P. C. Kuypers toxic effects steadily increased to even 16% of all reported k.kuypers@maastrichtuniversity.nl cases on large scale events (Wijers et al. 2017). Although it was first used as an adulterant in drugs such as amphetamine Department of Neuropsychology and Psychopharmacology, Faculty and MDMA, it became a drug of choice, liked by users for its of Psychology and Neuroscience, Maastricht University, P. O. Box 616, 6200 MD Maastricht, the Netherlands effects (Linsen et al. 2015). While it has become a popular drug with a recent survey amongst Dutch partygoers revealing Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University of Frankfurt, Frankfurt, Germany that a quarter of the respondents between 15 and 35 years of 2350 Psychopharmacology (2018) 235:2349–2356 age had used 4-FA in the past year, the majority (80%) also though when it does, an enhancing effect was found only in states that their 4-FA use remained limited to just a few times people who either performed badly at baseline (de Wit et al. (Monshouwer et al. 2016). 2000; de Wit et al. 2002) or when presented with complex The effects of 4-FA reportedly range between those of am- stimuli (Fillmore et al. 2003). Likewise, studies with phetamine, a stimulant, and MDMA, an empathogen (Linsen MDMA have shown that in doses ranging from 25 to et al. 2015) which is in line with the biological profile that is 125 mg, MDMA either leads to improvement of behavioral also suggested to be in between that of MDMA and amphet- inhibition or induces no change (Bosker et al. 2010;Kuypers amine. Studies determining the monoamine transporter and et al. 2007; Schmidt et al. 2017). In one single study, MDMA receptor binding profile in animals and human tissue showed led to an increase in impulsive action and impulsive reflection that 4-FA has relatively more serotonergic transporter action (van Wel et al. 2012). The effects of amphetamine and compared to amphetamine. Next to the promotion of norepi- MDMA on subjective measures of drug liking also seem to nephrine (NE) and dopamine (DA) release, it was shown to be similar, with an increase in self-rating up to 3 h after ad- release serotonin (5-HT) similarly to MDMA (Nagai et al. ministration of a single dose (Cami et al. 2000;Harris et al. 2007;Rickli etal. 2015). 2002;Rush etal. 2001). Linked to NPS use is the concern about the acute and po- In light of the popularity of 4-FA (Monshouwer et al. tential long(er) term effects the particular substance might 2016), it is important to assess whether 4-FA can lead to sub- have on behavior and cognitive processes (Schifano et al. jective drug liking and impulsive behavior, two risk factors 2015) with abuse and addiction as potential consequences. It linked to abuse liability of a substance. Given the similarity to is known that substances with more pronounced action at the amphetamine and MDMA, it was hypothesized that 4-FA DA-transporter (DAT) can have a higher abuse potential com- would not lead to effects on impulsive action or reflection pared to substances that increase activity of the 5-HT system and would lead to a subjective state of drug liking and want- (Wee et al. 2005). Furthermore, a high DAT-to-serotonin ing, and good drug effect around peak drug concentrations transporter (SERT) ratio is a pharmacological characteristic and not after 4-FA plasma concentrations have decreased predicting more stimulant effects and a higher potential for substantially. addiction. The DAT/SERT ratio of 4-FA is approximately five The data presented in this paper are part of a larger project times higher than MDMA and seven times lower than d- PREDICT ( www.predictnps.eu ) focusing at the safety profile amphetamine (Hondebrink et al. 2017; Rickli et al. 2015). of NPS in humans, in vitro and in silico. Additional data of the Drug abuse and addiction are related to impulse control, with present study including the safety profile and neurocognitive substances disturbing impulse control eventually evolving in- effects of 4-FA are published in a separate paper (de Sousa to drug abuse when the behavior becomes driven by drug-cues Fernandes Perna et al. 2018). (de Wit 2009; Winstanley et al. 2010). Similarly, sensitivity to the rewarding effects of drugs have also been considered as risk factors for drug abuse (Waefer and de Wit 2013). Methods The most sensitive and reliable measures of abuse likeli- hood of a substance are self-ratings of drug liking, or the Study design and treatment report of how much the user likes the drug (Carter and Griffiths 2009). In addition, the measures wanting, good drug The study was conducted according to a two-way crossover, effect, and bad drug effect seem to co-vary with liking (Carter randomized, counter-balanced, and placebo-controlled de- and Griffiths 2009). On the other hand, typical paradigms to sign. Treatment was 100 mg of 4-FA or placebo mixed with assess different components of impulsivity are the matching 100 mL of bitter lemon. The drink was ingested at once. The familiar figures task (MFFT) and the stop-signal task (SST). 100 mg dose was based on a user survey amongst Dutch 4-FA In the latter SST-paradigm, which tests motor impulsivity or users. The majority (75%) of the users who knew which dose impulsive action, the participant has to respond continuously they ingest typically indicated it to be between 50 and 150 mg, to stimuli and withhold their pre-potent response to Bstop^ the remainder used larger doses. In general, the subjective stimuli (Logan et al. 1984). In the former MFFT-paradigm, effectslast between4 and6h(Linsen et al. 2015). 4-FA has which tests cognitive impulsivity or reflection impulsivity, an estimated half-life of 3.7 h in the rat brain (Fuller et al. the participant has to match a target figure to one of the six 1975). shown Blook-a-likes^ of which five differ from the original A permit for obtaining, storing, and administering 4-FA one by only a small detail. The skill is to withhold the reaction was obtained from the Dutch drug enforcement administra- until the match is found (D’Amour-Horvat and Leyton 2014; tion. The study was performed in accordance with the Perales et al. 2009). Helsinki Declaration of 1975, and its subsequent amend- In general, it has been shown that amphetamine (10– ments, and was approved by the Medical Ethics Committee 40 mg) does not affect impulsive action (Dolder et al. 2018), of the Academic Hospital of Maastricht and the University of Psychopharmacology (2018) 235:2349–2356 2351 Maastricht. It was registered in the Dutch Clinical Trial medical questionnaire and medical examination); liver dys- Register (Registration Number: NTR6164). function; (serious) side effects to previous psychostimulant use; history of cardiac dysfunctions (arrhythmia, ischemic Participants heart disease,…); simultaneous participation in another clini- cal trial; being a blood donor; and for women: not using reli- Participants were 12 healthy recreational polydrug users aged able contraceptive. 22.3 (± 3.4) years on average (± SD) of whom 7 were male After study inclusion and prior to the test days, participants with a mean BMI of 22.9 (± 1.3 SD) and 5 were female with were familiarized with the study procedures, tests, and ques- an average BMI of 21.5 (± 2.8 SD). All of them had experi- tionnaires. On a test day, participants arrived early in the ence with alcohol use with the units consumed per week rang- morning and they were tested for the absence of drugs in urine ing from 2 to 20. One participant smoked cigarettes with an and alcohol in breath. In case of females, an additional test for average of 15 per day and seven smoked cannabis with an pregnancy was conducted in urine. When all tests were nega- average of 1 Bunit^ per week. The use of other drugs was tive, participants were given baseline questionnaires, a blood expressed in Blifetime use^; the minimum and maximum sample was taken and they received a light-standardized (min-max) times used, together with the number of partici- breakfast. Table 1 provides an overview of timing of the ques- pants with experience (N) is listed per drug (N; min-max): tionnaire, the impulsivity tests and blood samples during the amphetamines (8; 1–32), cocaine (6; 1–26), ecstasy (11; 1– test day, which took 12.5 h in total. The test schedule was 35), 4-FA (5; 1–25), LSD (3; 7–17), and other drugs like identical for each test day and each participant. Participants mushrooms and ketamine (8; 1–33). were paid upon completion of the testing periods for their participation. Procedures Drug experience questionnaires Participants were recruited by means of flyers in the university building, an advert on a research-Facebook page, and by word Sensitivity to drug reinforcement questionnaire of mouth. When interested, they were sent the information brochure explaining the background, aims and study proce- The sensitivity to drug reinforcement questionnaire (SDRQ) dure, and two questionnaires (medical and drug use history). asks participants to rate their liking and wanting of 4-FA use When they were fully informed, potential questions were an- during their present condition on a 5-point rating scale (1 = swered, and if they fulfilled at first sight of the inclusion somewhat; 2 = slightly; 3 = moderately; 4 = very; 5 = ex- criteria, they were invited for a medical screening. When no tremely). The questionnaire is comprised of two questions, objections were raised during the physical examination in- BHow pleasant is using 4-FA right now?^ and BHow much cluding a standard blood and urine screens and an electrocar- do you want to use 4-FA right now?^ referring respectively to diogram (EKG) and participants signed the informed consent, drug liking and drug wanting. they were included in the study. Inclusion criteria were previous experience with Profile of mood states psychostimulants (≤ 1 time/week) and at least one time during the previous year; age between 18 and 40 years; free from The Profile of Mood States (POMS) (de Wit et al. 2002)is a psychotropic medication; healthy based on the assessment of self-assessment mood questionnaire with 72 five-point-Likert medical history, physical examination, vital signs, EKG (with scale items on which participants have to indicate to what heart rate 51–100 bpm; lower limit for fit people, 45 bpm), a extent these items were representing their mood. Items are resting systolic blood pressure 91–140 mmHg, a resting dia- clustered to represent eight basic mood states: anxiety, depres- stolic blood pressure 51–90 mmHg, and the results of the sion, anger, vigor, fatigue, confusion, friendliness, and elation. hematology, clinical chemistry, urinalysis, and serology with- From those scales, two composite scales were derived, good in the reference ranges; normal binocular visual acuity, drug effect (vigor + friendliness + elation/22) and bad drug corrected or uncorrected; absence of any major medical, en- effect (anxiety + depression + anger + fatigue + confusion/50). docrine and neurological conditions, and normal weight as defined by a body mass index between 19.5 and 28 kg/m ; Impulsivity tests written informed consent. Exclusion criteria were history of drug abuse or addiction (determined by the medical question- Stop signal test naire, drug questionnaire, and medical examination); exces- sive drinking (> 20 alcoholic consumptions a week); pregnan- The current stop-signal test (SST) is adapted from an earlier cy or lactation; hypertension (diastolic > 90; systolic > 140); version of Fillmore and colleagues (Fillmore et al. 2002), it current or history of psychiatric disorder (determined by the assesses impulsive action and it has previously been used in 2352 Psychopharmacology (2018) 235:2349–2356 Table 1 Time schedule of the T0 T1 T2 T3 T4 T5 −1T5 T5+1 impulsivity paradigms and drug experience questionnaires relative Post-treatment 0 h 1 h 2 h30 min 4 h 8 h 10 h 11 h 12 h to treatment administration; blood samples were collected more Motor impulsivity (SST) X X X frequently than depicted here, Reflective impulsivity (MFFT) X only samples collected around Drug liking and wanting (SDRQ) X X times of tests reported here are shown Good and Bad drug effect (POMS) X X X X 4-FA serum concentrations X X X X X similar research (Kuypers et al. 2007;van Welet al. 2012). It time at the nth percentile of the RT distribution. The resulting requires participants to make quick key responses to visually values for each stop signal delay were then averaged to yield a presented go signals and to inhibit any response when a visual single measure of stop reaction time for the test. stop signal (an asterisk) is suddenly presented in one of the corners of the screen. This can occur after one of four fixed Matching familiar figures test delays (50, 150, 250, and 350 ms) after the onset of the go signal. The go signals were four letters presented one at a time The matching familiar figures test (MFFT) assesses impulsive for 500 ms in the center of a computer screen. Participants are reflection, which is the tendency to reflect on the validity of required to respond to each letter as quickly as possible by problem solving under the special condition of several possi- pressing on of two response buttons. The computer screen is ble alternatives. The test involves simultaneous presentation blank for 1.5 s before the next letter is displayed. This pro- of a target figure positioned on the left of the screen and an vides a period of 2 s in which the participant can respond to the array of six alternatives on the right half of the screen, all go signal. A single test consists of 176 trials in which each of except one differing in one or more details from the target the 4-letter stimuli will be presented equally often. A stop figure. The participant is asked to select from the alternatives signal occurs in 48 trials during a test. Participants are required the figure that exactly matches the target as quickly as possi- to withhold any response in case a stop signal is presented. ble. If the initial selection is incorrect, this is signaled with a The task lasts about 10 min. Dependent variables are propor- beep and subjects are required to give another answer. Each tion of correct go responses and failed inhibitions on stop trials participant is given 2 examples followed by 20 test items. The and corresponding reaction times (Logan et al. 1984). The response latency and number of errors before the correct Stop reaction time (stop RT) to stop signal represents the es- match are collected per item. The main dependent variables timated mean time required to inhibit a response. resulting from these measures are the mean latency for first The method for calculating stop reaction time was taken response, the accumulated number of errors made before the from the race model of inhibitory control (Logan 1994). This correct match, an impulsivity score (I-score), and an efficiency model proposes that the response to stop signals is defined by score (E-score). The I-score is a composite index of impulsiv- two parallel processes: execution of a motor action in response ity, whereas the E-score reflects the balance between Bfast and to a signal and inhibition of a motor action in response to a accurate^ and Bslow and inaccurate.^ The I-score is calculated stop signal. Crucial to the outcome of the race is the speed of by subtracting the standardized mean latency from the stan- both processes. Response inhibition will fail if the time re- dardized number of errors. The E-score is calculated by quired to inhibit exceeds the time to complete a motor re- adding the standardized mean latency to the standardized sponse at the time of the stop signal. number of errors and multiplying the result by −1(Perales The speed of the inhibition response cannot be observed et al. 2009). directly but can be derived mathematically on the basis of three factors: stop-signal delay, reaction time distribution on Pharmacokinetics go trials, and the probability of successful response inhibitions in stop signal trials. First, reaction times to 128 go trials were A blood sample (5 mL) was collected at baseline and at reg- rank ordered from shortest to longest. The finishing time of ular times after treatment (see Table 1). Samples were centri- the inhibition response was then determined from the proba- fuged immediately and resulting serum was pipetted into a bility of successful response inhibition and the distribution of clean tube and stored at − 20 °C until 4-FA concentration reaction times. If n percent of the responses on stop-signal determination which took place after study completion. trials would be unsuccessfully inhibited (failed inhibitions), Blood serum (0.5 mL) was diluted with buffer and internal then the finishing time would be associated with the nth per- standard solution was added. After liquid-liquid extraction the centile of the RT distribution. Stop RTwas then determined by extract was analyzed using LC-MSMS, with 0.04 ng/mL as subtracting the appropriate stop-signal delay from reaction the lower limit of quantification. Psychopharmacology (2018) 235:2349–2356 2353 Statistical analyses baseline-corrected scores entered the analyses. RM GLM ANOVA showed main effects of treatment (F =7.55; p = 1,10 2 2 Questionnaire data and data of the SST was analyzed with 0.02; ƞ = 0.43) and time (F = 17.81; p < 0.001; ƞ = p 2,20 p repeated measures general linear models (RM GLM) 0.64) and a treatment by time interaction effect (F =8.12; 2,20 ANOVAwith treatment (two levels) and time of measurement p = 0.003; ƞ = 0.45) on good drug effect. The good drug (two levels SDRQ, three levels POMS and SST) as within effect was higher after 4-FA compared to placebo; the overall subject factors (SPSS, version 24.0). In case of main effects effect was the highest on T1 compared to T3 and T5. The of time of measurement, Bonferroni-corrected post-hoc tests quadratic interaction (F =12.57; p =0.005; ƞ = 0.56) be- 1,10 p were conducted. Data of the MFFT was analyzed by means of tween treatment and time demonstrated that while the ratings paired samples t tests since there was only one assessment. in the placebo condition were low and decreased slightly over The alpha criterion level of statistical significance for all anal- time, the ratings in the 4-FA condition were very pronounced yses was set at p = 0.05. Partial eta squared (ƞ )isreported in at T1 and steeply decreased from T1 to T3 while remaining at case of significant effects in the ANOVA GLM to demonstrate the same low level at T5 compared to T3 (Fig. 1c). the effect’s magnitude, where 0.01 is defined as small, 0.06 as Analyses showed a significant treatment by time interac- moderate and 0.14 as large. Partial eta squared is based on tion effect (F = 6.59; p = 0.006; ƞ = 0.43) on bad drug 1,10 p Cohen’s f which defines small, medium and large as respec- effect. Post-hoc analyses showed that this was a quadratic 2 2 tively 0.10, 0.25, and 0.50 which corresponds to η of 0.0099, effect (F =2.19; p =0.02; ƞ = 0.43) with the highest rat- 1,10 p 0.0588, and 0.1379 (Richardson 2011). ing showing at T3 for 4-FA compared to the other time-points and placebo; this effect was probably driven by the statistical- ly significant increased levels of fatigue and confusion, two of Results the sub-scales included in this composite scale bad drug effect which were the highest at this time-point. There was no main Pharmacokinetics effect of treatment (F =2.19; p =0.02; ƞ = 0.43) or time 1,10 p on bad drug effect (Fig. 1d). Mean (± SE) 4-FA serum concentrations were 167.3 ng/mL (±15) at T1, 60′ post-treatment, peaked 2 h after intake Impulsivity tasks (205.4 ng/mL ± 45) and descended over time to 97.2 ng/mL (± 10), 12 h after 4-FA administration (T5 +1). Stop signal task Drug experience questionnaires One participant was excluded from the analysis because of an absence of responses on go trials on four occasions (three Sensitivity to drug reinforcement questionnaire times placebo condition, once 4-FA). Repeated measures GLM ANOVA demonstrated a main effect of time of mea- RM GLM ANOVA showed statistically significant effects of surement (F =3.57; p =0.05; ƞ = 0.26) and a treatment 2,20 p Treatment, Time and Treatment by Time on both scales of the by time of measurement interaction effect (F =3.52; p = 2,20 SDRQ. Ratings of liking were higher after 4-FA compared to 0.05; ƞ = 0.26) on the proportion of failed inhibitions. Post- placebo (F = 26.16; p < 0.001; ƞ = 0.70), they were hoc tests did not reveal statistically significant differences be- 1,11 p highest at T1 compared to T5 (F = 22.99; p =0.001; tween separate time of measurements or treatment by time of 1,11 ƞ = 0.68), and while the liking ratings remained stable in measurement performances. Inspecting the data visually led to the placebo condition, they decreased substantially in the 4- the suggestion that these effects were mainly driven by the FA condition over time (F =13.13; p =0.004; ƞ =0.54) high number of failed inhibitions 1 h after 4-FA administration 1,11 p (Fig. 1a). For wanting the same pattern was observed with while the number of inhibition failures in the placebo condi- higher ratings of wanting after 4-FA compared to placebo tion was lower and stable over time. The number of failed (F = 19.06; p = 0.001; ƞ = 0.63), highest ratings at T1 inhibitions4and8hafter 4-FA administration wascompara- 1,11 p compared to T5 (F =14.73; p = 0.003; ƞ = 0.57), and ble to placebo-levels. Analyses did not reveal statistically sig- 1,11 p while ratings of wanting remained stable in the placebo con- nificant main effects of treatment or time of measurement, or dition, they substantially decreased in the 4-FA condition over their interaction on proportion of correct go responses, go-RT time (F =22.18; p =0.001; ƞ = 0.67) (Fig. 1b). or stop-RT (Table 2). 1,11 p Profile of mood states Matching familiar figures test Since one of the POMS sub-scales included in the composite Paired samples t tests did not reveal statistically significant scales displayed a baseline difference between test days, differences between 4-FA and placebo on the dependent 2354 Psychopharmacology (2018) 235:2349–2356 Fig. 1 Mean (± SE) ratings of 4-FA liking (a) and 4-FAwanting (b) 1 and 11 h after treatments, and ratings of good drug effect (c) and bad drug effect (d) 1, 4, and 11 h after treatments and corresponding 4-FA serum concentrations variables mean latency of first response (t = − 0.64; p = Discussion 1,11 0.53) and errors (t =0.12; p = 0.9), or the two composite 1,11 score, impulsivity (t =0.72; p = 0.48) and efficiency The present study aimed to assess whether 4-FA elicits risk 1,11 (t =0.27; p = 0.79). Mean (± SE) scores after placebo and factors for drug abuse, namely impulsive reflection and action, 1,11 4-FA were respectively 13 (1) and 15 (2) for latency in sec- a subjective state of drug liking and wanting, and good versus onds, 4.00 (1.1) and 3.75 (1.5) for total number of errors, 0.2 bad drug effect. It was hypothesized that 4-FA would not lead (0.3) and − 0.2 (0.5) for I-score, and 0.1 (0.4) and − 0.1 (0.5) to effects on impulsive behavior but would produce a state of for E-score. drug liking at peak drug concentrations. As expected, findings Table 2 Mean (± SE) of dependent variables of the SST F-, p-, and partial eta - values of RM GLM ANOVA Mean (± SE) RM GLM ANOVA, main and interaction effects Treatment Treatment Time Treatment by time 2 2 2 Stop signal task T PLA 4-FA F p ƞ F p ƞ F p ƞ 1,10 p 2,20 p 2,20 p Failed inhibitions (%) T1 0.35 (0.06) 0.47 (0.10) 0.31 0.59 0.03 3.57 0.05 0.26 3.52 0.05 0.26 T3 0.35 (0.06) 0.32 (0.06) T4 0.34 (0.06) 0.33 (0.06) Stop-RT T1 286 (15) 327 (26) 1.63 0.23 0.14 2.25 0.13 0.18 1.36 0.28 0.12 T3 291 (21) 287 (12) T3 266 (10) 291 (12) Correct go’s (%) T1 0.70 (0.01) 0.69 (0.01) 0.44 0.52 0.04 2.72 0.09 0.21 1.15 0.33 0.10 T3 0.67 (0.01) 0.69 (0.02) T4 0.69 (0.01) 0.70 (0.01) Go-RT (ms) T1 569 (42) 554 (42) 0.13 0.72 0.01 1.47 0.25 0.13 2.78 0.09 0.22 T3 571 (44) 583 (39) T4 558 (38) 584 (44) Psychopharmacology (2018) 235:2349–2356 2355 showed an absence of 4-FA effects on impulsive reflection peak effects have subsided, it has to be noted that the current and action and an increase in self-ratings of drug liking, drug picture is limited and might change with increased sample wanting and good drug effect, 1 h after administration and a size, including participants with poor baseline impulse control peak in bad drug effect 4 h after intake. The liking, wanting, and attention capacity, and/or different 4-FA doses. and good drug effects were absent 11 h after drug intake. Furthermore, additional repetitions of self-rated liking and The absence of drug effects on the impulsivity measures wanting are needed to know whether these feelings are present was in line with expectations and previous studies with am- when for example bad drug effects are high and good drug phetamine, MDMA and cocaine (Bosker et al. 2010; de Wit et effects are low, a few hours after drug intake, as this could al. 2000; de Wit et al. 2002; Dolder et al. 2018; Kuypers et al. push the individual to repeated drug use. 2007; Schmidt et al. 2017). The average scores during drug Acknowledgements The authors would like to thank Cees van Leeuwen and placebo conditions were also comparable to those found and Lizzy Vuurman for medical supervision; Johannes Reckweg, Lukas in previous drug studies by our group using the same para- Basedow, Drew Puxty, and Ignas Oppewal for helping with data acqui- digms (e.g., (Kuypers et al. 2007;van Welet al. 2012). sition; and the DSMB members (Wim Riedel, Therese van Amelsvoort, Although present findings suggest that a single dose of 4-FA Jan Schepers, and Robbert-Jan Verkes) for evaluating the data and pro- viding advice. (100 mg) does not induce impulsive behavior, previous stud- ies have shown that personal characteristics, like baseline per- Funding This research was funded by the European Commission (Grant formance and task-related characteristics like stimulus/ Number: HOME/2014/JDRF/AG/DRUG/7082, Predicting Risk of response complexity, can play a role in drug-induced changes. Emerging Drugs with In silico and Clinical Toxicology (PREDICT)). People performing badly at baseline or who were presented with complex stimuli showed an enhancing effect after am- Compliance with ethical standards phetamine (de Wit et al. 2000; de Wit et al. 2002;Fillmore et al. 2003). Additionally, stimulants like amphetamine and co- The study was performed in accordance with the Helsinki Declaration of 1975, and its subsequent amendments, and was approved by the Medical caine have shown to exert enhancing effects on response con- Ethics Committee of the Academic Hospital of Maastricht and the trol in individuals with impulse control problems, like ADHD University of Maastricht. and drug addiction (Arnsten 2006;Fillmore etal. 2002, 2005). Self-ratings of liking, wanting, and good drug effect, all Conflict of interest The authors declare that they have no conflict of reliable and sensitive indicators of drug abuse likelihood, were interest. increased compared to placebo 1 h after intake. Ten hours Open Access This article is distributed under the terms of the Creative later, the self-ratings in the 4-FA condition were indistinguish- Commons Attribution 4.0 International License (http:// able from ratings in the placebo condition. Findings demon- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, strate that a single dose of 4-FA (100 mg) does not lead to distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the craving (wanting) when the good drug effects are subsiding Creative Commons license, and indicate if changes were made. and bad drug effects increasing, suggesting an absence of repeated or compulsive use of this drug at this dose. However, similar to behavioral performance, studies have shown that personal or biological factors like baseline perfor- References mance or DA receptor availability can play a role in subjective drug experience (Brewer and Potenza 2008; McCloskey et al. Arnsten AFT (2006) Stimulants: therapeutic actions in ADHD. 2010). It was demonstrated previously that participants who Neuropsychopharmacology 31:2376–2383 Bosker WM, Kuypers KPC, Conen S, Ramaekers JG (2010) Dose-related performed worse on an attention paradigm-liked amphet- effects of MDMA on psychomotor function and mood before, dur- amine (20 mg) less and reported smaller increases in wanting ing, and after a night of sleep loss. Psychopharmacology 209:69–76 compared to participants who exhibited better attentional ca- Brewer JA, Potenza MN (2008) The neurobiology and genetics of im- pacities. It was concluded that participants’ attention capaci- pulse control disorders: relationships to drug addictions. Biochem ties determined the sensitivity to stimulant-induced effects Pharmacol 75:63–75 Cami J, Farre M, Mas M, Roset PN, Poudevida S, Mas A, San L, de la with worse capacity signaling reduced sensitivity to Torre R (2000) Human pharmacology of 3,4-methylenedioxymeth- stimulant-induced euphoria (McCloskey et al. 2010). In addi- amphetamine (Becstasy^): psychomotor performance and subjective tion, low baseline measures of D2 receptor availability in non- effects. J Clin Psychopharmacol 20:455–466 addicted people was shown to predict methylphenidate liking Carter LP, Griffiths RR (2009) Principles of laboratory assessment of drug abuse liability and implications for clinical development. and high levels of impulsivity in rats (Brewer and Potenza Drug Alcohol Depend 105(Suppl 1):S14–S25 2008). D’Amour-Horvat V, Leyton M (2014) Impulsive actions and choices in While the findings of the present study suggest that a single laboratory animals and humans: effects of high vs. low dopamine dose of 4-FA (100 mg) does not lead to either impulsive action states produced by systemic treatments given to neurologically in- or reflection, or to liking and wanting of the drug when the tact subjects. Front Behav Neurosci 8:432 2356 Psychopharmacology (2018) 235:2349–2356 Dolder PC, Strajhar P, Vizeli P, Odermatt A, Liechti ME (2018) Acute Perales JC, Verdejo-García A, Moya M, Lozano Ó, Pérez-García M (2009) Bright and dark sides of impulsivity: performance of women effects of lisdexamfetamine and D-amphetamine on social cognition and cognitive performance in a placebo-controlled study in healthy with high and low trait impulsivity on neuropsychological tasks. J subjects. Psychopharmacology 235:1389–1402 Clin Exp Neuropsychol 31:927–944 EMCDDA (2015) New psychoactive substances in Europe: an update Richardson JTE (2011) Eta squared and partial eta squared as measures of from the EU early warning system. European Monitoring Centre effect size in educational research. Educational Res Rev 6:135–147 for Drugs and Drug Addiction, Lisbon Rickli A, Hoener MC, Liechti ME (2015) Monoamine transporter and Fillmore MT, Rush CR, Hays L (2002) Acute effects of oral cocaine on receptor interaction profiles of novel psychoactive substances: Para- inhibitory control of behavior in humans. Drug Alcohol Depend 67: halogenated amphetamines and pyrovalerone cathinones. Eur 157–167 Neuropsychopharmacol 25:365–376 Fillmore MT, Rush CR, Marczinski CA (2003) Effects of d-amphetamine Rush CR, Essman WD, Simpson CA, Baker RW (2001) Reinforcing and on behavioral control in stimulant abusers: the role of prepotent subject-rated effects of methylphenidate and d-amphetamine in response tendencies. Drug Alcohol Depend 71:143–152 non–drug-abusing humans. J Clin Psychopharmacol 21:273–286 Fillmore MT, Rush CR, Hays L (2005) Cocaine improves inhibitory Schifano F, Orsolini L, Duccio Papanti G, Corkery JM (2015) Novel control in a human model of response conflict. Exp Clin psychoactive substances of interest for psychiatry. World Psychopharmacol 13:327–335 Psychiatry 14:15–26 Fuller RW, Baker JC, Perry KW, Molloy BB (1975) Comparison of 4- Schmidt A, Muller F, Dolder PC, Schmid Y, Zanchi D, Liechti ME, chloro-, 4-bromo- and 4-fluoroamphetamine in rats: drug levels in Borgwardt S (2017) Comparative effects of methylphenidate, brain and effects on brain serotonin metabolism. Neuropharmacol- modafinil, and MDMA on response inhibition neural networks in ogy 14:739–746 healthy subjects. Int J Neuropsychopharmacol 20:712–720 Harris DS, Baggott M, Mendelson JH, Mendelson JE, Jones RT (2002) de Sousa Fernandes Perna EB, Theunissen EL, Dolder PC, Mason NL, Subjective and hormonal effects of 3,4-methylenedioxymetham- Hutten NRPW, Toennes SW, Kuypers KPC, Ramaekers JG (2018) phetamine (MDMA) in humans. Psychopharmacology 162:396– Safety profile and neurocognitive function following acute 4- fluoroamphetamine (4-FA) administration in humans. Under review Hondebrink L, Zwartsen A, Westerink RHS (2017) Effect fingerprinting Waefer J, de Wit H (2013) Inattention, impulsive action, and subjective of new psychoactive substances (NPS): what can we learn from in response to d-amphetamine. Drug Alcohol Depend 133:127–133 vitro data? Pharmacol Ther Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Kuypers KPC, Wingen M, Limbert N, Samyn N, Ramaekers JG (2007) Woolverton WL (2005) Relationship between the serotonergic ac- Acute effects of nocturnal doses of MDMA on measures of impul- tivity and reinforcing effects of a series of amphetamine analogs. J sivity and psychomotor performance throughout the night. Pharmacol Exp Ther 313:848–854 Psychopharmacology 192:111–119 van Wel JHP, Kuypers KPC, Theunissen EL, Bosker WM, Bakker K, Liechti M (2015) Novel psychoactive substances (designer drugs): over- Ramaekers JG (2012) Effects of acute MDMA intoxication on view and pharmacology of modulators of monoamine signaling. mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors. Swiss Med Wkly 145:w14043 PLoS ONE 7:e40187 Linsen F, Koning RPJ, van Laar M, Niesink RJM, Koeter MW, Brunt TM Wijers CHW, van Litsenburg RTH, Hondebrink L, Niesink RJM, Croes (2015) 4-Fluoroamphetamine in the Netherlands: more than a one- EA (2017) Acute toxic effects related to 4-fluoroamphetamine. night stand. Addiction 110:1138–1143 Lancet 389:600 Logan GD (1994) On the ability to inhibit thought and action. A user’s Winstanley CA, Olausson P, Taylor JR, Jentsch JD (2010) Insight into the guide to the stop signal paradigm. In: Carr DDTH (ed) Inhibitory relationship between impulsivity and substance abuse from studies processes in attention, memory, and language. Academic Press, San using animal models. Alcohol Clin Exp Res 34:1306–1318 Diego, California, pp 189–239 de Wit H (2009) Impulsivity as a determinant and consequence of drug Logan GD, Cowan WB, Davis KA (1984) On the ability to inhibit simple use: a review of underlying processes. Addict Biol 14:22–31 and choice reaction time responses: a model and a method. J de Wit H, Crean J, Richards JB (2000) Effects of d-amphetamine and Experimental Psychology Human Perception Performance 10: ethanol on a measure of behavioral inhibition in humans. Behav 276–291 Neurosci 114:830–837 McCloskey M, Palmer AA, de Wit H (2010) Are attention lapses related de Wit H, Enggasser JL, Richards JB (2002) Acute administration of d- to d-amphetamine liking? Psychopharmacology 208:201–209 amphetamine decreases impulsivity in healthy volunteers. Monshouwer K, van der Pol P, Drost YC, van Laar MW (2016) Het grote Neuropsychopharmacology Official Publication Am College uitgaansonderzoek 2016: Uigaanspatronen, middelengebruik en Neuropsychopharmacology 27:813–825 preventieve maatregelen onder uitgaande jongeren en jongvolwassenen. Trimbos Institute, Utrecht Wood DM, Greene SL, Dargan PI (2013) Five-year trends in self-reported Nagai F, Nonaka R, Satoh Hisashi Kamimura K (2007) The effects of recreational drugs associated with presentation to a UK emergency non-medically used psychoactive drugs on monoamine neurotrans- department with suspected drug-related toxicity. Eur J Emerg Med mission in rat brain. Eur J Pharmacol 559:132–137 20:263–267 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Psychopharmacology Springer Journals

Drug liking and wanting, not impulsive action or reflection is increased by 4-fluoroamphetamine

Free
8 pages

Loading next page...
 
/lp/springer_journal/drug-liking-and-wanting-not-impulsive-action-or-reflection-is-fNRUB0XwnC
Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Neurosciences; Pharmacology/Toxicology; Psychiatry
ISSN
0033-3158
eISSN
1432-2072
D.O.I.
10.1007/s00213-018-4931-7
Publisher site
See Article on Publisher Site

Abstract

Background New psychoactive substances (NPS) are chemical analogues designed to mimic the effects of various classic recreational drugs of abuse including MDMA, LSD, and cannabis. NPS use is associated with concern about the acute and longer-term effects particular substances might have, with abuse and addiction as potential consequences. Impulsivity and sensitivity to the rewarding effects of drugs have been considered as risk factors for drug abuse. In light of the popularity of 4-fluoroamphetamine (4-FA), it is important to assess whether 4-FA can lead to subjective drug liking and wanting, and impulsive behavior, all factors contributing to the abuse likelihood of a substance. Methods A placebo-controlled 2-way crossover study in 12 healthy poly-drug using participants was conducted to test subjective and behavioral effects of 4-FA (100 mg). 4-FA concentrations were determined in serum up to 12 h after administration and two impulsivity tasks and two drug experience questionnaires assessing drug liking and wanting, and good and bad drug effect, were administered between 1 and 11 h post-administration. Results Findings showed that 4-FA did not affect impulsive behavior. Self-ratings of drug liking and wanting and good drug effect were increased 1 h after administration; this effect was absent 11 h after drug intake. Discussion and conclusion To conclude, 4-FA (single dose) increased self-rated liking and wanting, which is known to contribute to the abuse likelihood of a substance; however, it left another factor impulsive behavior unaffected. It has to be noted that the current picture is limited and might change with increased sample size, and/or different 4-FA doses. Clinical trial registration Trial acronym: 4-FA. URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6164. Registration number: NTR6164 (Dutch clinical trial registry number). . . . . . Keywords 4-FA Impulsive reflection Impulsive action Drug liking Drug wanting Good drug effect Introduction substantiated yet in human experimental studies (Hondebrink et al. 2017;Liechti 2015). Scientific knowledge New psychoactive substances (NPS) are chemical analogues about NPS’s acute effects is needed, seen their exponential designed to mimic the effects of various classic recreational increase in availability and number over the last 10 years. drugs of abuse including MDMA, LSD, and cannabis Moreover, this surge has gone hand in hand with an increase (EMCDDA 2015). Anecdotal evidence by users suggests that in use, and emergency department visits due to over- NPS have subjective effects comparable to the classical psy- intoxication (EMCDDA 2015;Woodet al. 2013). choactive substances though these effects have not been 4-Fluoroamphetamine (4-FA) is a prototypical example of an NPS, belonging to the chemical class of phenethylamines (Hondebrink et al. 2017). It appeared on the Dutch Bdrug market^ between 2007 and 2009 where after reports of acute * K. P. C. Kuypers toxic effects steadily increased to even 16% of all reported k.kuypers@maastrichtuniversity.nl cases on large scale events (Wijers et al. 2017). Although it was first used as an adulterant in drugs such as amphetamine Department of Neuropsychology and Psychopharmacology, Faculty and MDMA, it became a drug of choice, liked by users for its of Psychology and Neuroscience, Maastricht University, P. O. Box 616, 6200 MD Maastricht, the Netherlands effects (Linsen et al. 2015). While it has become a popular drug with a recent survey amongst Dutch partygoers revealing Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University of Frankfurt, Frankfurt, Germany that a quarter of the respondents between 15 and 35 years of 2350 Psychopharmacology (2018) 235:2349–2356 age had used 4-FA in the past year, the majority (80%) also though when it does, an enhancing effect was found only in states that their 4-FA use remained limited to just a few times people who either performed badly at baseline (de Wit et al. (Monshouwer et al. 2016). 2000; de Wit et al. 2002) or when presented with complex The effects of 4-FA reportedly range between those of am- stimuli (Fillmore et al. 2003). Likewise, studies with phetamine, a stimulant, and MDMA, an empathogen (Linsen MDMA have shown that in doses ranging from 25 to et al. 2015) which is in line with the biological profile that is 125 mg, MDMA either leads to improvement of behavioral also suggested to be in between that of MDMA and amphet- inhibition or induces no change (Bosker et al. 2010;Kuypers amine. Studies determining the monoamine transporter and et al. 2007; Schmidt et al. 2017). In one single study, MDMA receptor binding profile in animals and human tissue showed led to an increase in impulsive action and impulsive reflection that 4-FA has relatively more serotonergic transporter action (van Wel et al. 2012). The effects of amphetamine and compared to amphetamine. Next to the promotion of norepi- MDMA on subjective measures of drug liking also seem to nephrine (NE) and dopamine (DA) release, it was shown to be similar, with an increase in self-rating up to 3 h after ad- release serotonin (5-HT) similarly to MDMA (Nagai et al. ministration of a single dose (Cami et al. 2000;Harris et al. 2007;Rickli etal. 2015). 2002;Rush etal. 2001). Linked to NPS use is the concern about the acute and po- In light of the popularity of 4-FA (Monshouwer et al. tential long(er) term effects the particular substance might 2016), it is important to assess whether 4-FA can lead to sub- have on behavior and cognitive processes (Schifano et al. jective drug liking and impulsive behavior, two risk factors 2015) with abuse and addiction as potential consequences. It linked to abuse liability of a substance. Given the similarity to is known that substances with more pronounced action at the amphetamine and MDMA, it was hypothesized that 4-FA DA-transporter (DAT) can have a higher abuse potential com- would not lead to effects on impulsive action or reflection pared to substances that increase activity of the 5-HT system and would lead to a subjective state of drug liking and want- (Wee et al. 2005). Furthermore, a high DAT-to-serotonin ing, and good drug effect around peak drug concentrations transporter (SERT) ratio is a pharmacological characteristic and not after 4-FA plasma concentrations have decreased predicting more stimulant effects and a higher potential for substantially. addiction. The DAT/SERT ratio of 4-FA is approximately five The data presented in this paper are part of a larger project times higher than MDMA and seven times lower than d- PREDICT ( www.predictnps.eu ) focusing at the safety profile amphetamine (Hondebrink et al. 2017; Rickli et al. 2015). of NPS in humans, in vitro and in silico. Additional data of the Drug abuse and addiction are related to impulse control, with present study including the safety profile and neurocognitive substances disturbing impulse control eventually evolving in- effects of 4-FA are published in a separate paper (de Sousa to drug abuse when the behavior becomes driven by drug-cues Fernandes Perna et al. 2018). (de Wit 2009; Winstanley et al. 2010). Similarly, sensitivity to the rewarding effects of drugs have also been considered as risk factors for drug abuse (Waefer and de Wit 2013). Methods The most sensitive and reliable measures of abuse likeli- hood of a substance are self-ratings of drug liking, or the Study design and treatment report of how much the user likes the drug (Carter and Griffiths 2009). In addition, the measures wanting, good drug The study was conducted according to a two-way crossover, effect, and bad drug effect seem to co-vary with liking (Carter randomized, counter-balanced, and placebo-controlled de- and Griffiths 2009). On the other hand, typical paradigms to sign. Treatment was 100 mg of 4-FA or placebo mixed with assess different components of impulsivity are the matching 100 mL of bitter lemon. The drink was ingested at once. The familiar figures task (MFFT) and the stop-signal task (SST). 100 mg dose was based on a user survey amongst Dutch 4-FA In the latter SST-paradigm, which tests motor impulsivity or users. The majority (75%) of the users who knew which dose impulsive action, the participant has to respond continuously they ingest typically indicated it to be between 50 and 150 mg, to stimuli and withhold their pre-potent response to Bstop^ the remainder used larger doses. In general, the subjective stimuli (Logan et al. 1984). In the former MFFT-paradigm, effectslast between4 and6h(Linsen et al. 2015). 4-FA has which tests cognitive impulsivity or reflection impulsivity, an estimated half-life of 3.7 h in the rat brain (Fuller et al. the participant has to match a target figure to one of the six 1975). shown Blook-a-likes^ of which five differ from the original A permit for obtaining, storing, and administering 4-FA one by only a small detail. The skill is to withhold the reaction was obtained from the Dutch drug enforcement administra- until the match is found (D’Amour-Horvat and Leyton 2014; tion. The study was performed in accordance with the Perales et al. 2009). Helsinki Declaration of 1975, and its subsequent amend- In general, it has been shown that amphetamine (10– ments, and was approved by the Medical Ethics Committee 40 mg) does not affect impulsive action (Dolder et al. 2018), of the Academic Hospital of Maastricht and the University of Psychopharmacology (2018) 235:2349–2356 2351 Maastricht. It was registered in the Dutch Clinical Trial medical questionnaire and medical examination); liver dys- Register (Registration Number: NTR6164). function; (serious) side effects to previous psychostimulant use; history of cardiac dysfunctions (arrhythmia, ischemic Participants heart disease,…); simultaneous participation in another clini- cal trial; being a blood donor; and for women: not using reli- Participants were 12 healthy recreational polydrug users aged able contraceptive. 22.3 (± 3.4) years on average (± SD) of whom 7 were male After study inclusion and prior to the test days, participants with a mean BMI of 22.9 (± 1.3 SD) and 5 were female with were familiarized with the study procedures, tests, and ques- an average BMI of 21.5 (± 2.8 SD). All of them had experi- tionnaires. On a test day, participants arrived early in the ence with alcohol use with the units consumed per week rang- morning and they were tested for the absence of drugs in urine ing from 2 to 20. One participant smoked cigarettes with an and alcohol in breath. In case of females, an additional test for average of 15 per day and seven smoked cannabis with an pregnancy was conducted in urine. When all tests were nega- average of 1 Bunit^ per week. The use of other drugs was tive, participants were given baseline questionnaires, a blood expressed in Blifetime use^; the minimum and maximum sample was taken and they received a light-standardized (min-max) times used, together with the number of partici- breakfast. Table 1 provides an overview of timing of the ques- pants with experience (N) is listed per drug (N; min-max): tionnaire, the impulsivity tests and blood samples during the amphetamines (8; 1–32), cocaine (6; 1–26), ecstasy (11; 1– test day, which took 12.5 h in total. The test schedule was 35), 4-FA (5; 1–25), LSD (3; 7–17), and other drugs like identical for each test day and each participant. Participants mushrooms and ketamine (8; 1–33). were paid upon completion of the testing periods for their participation. Procedures Drug experience questionnaires Participants were recruited by means of flyers in the university building, an advert on a research-Facebook page, and by word Sensitivity to drug reinforcement questionnaire of mouth. When interested, they were sent the information brochure explaining the background, aims and study proce- The sensitivity to drug reinforcement questionnaire (SDRQ) dure, and two questionnaires (medical and drug use history). asks participants to rate their liking and wanting of 4-FA use When they were fully informed, potential questions were an- during their present condition on a 5-point rating scale (1 = swered, and if they fulfilled at first sight of the inclusion somewhat; 2 = slightly; 3 = moderately; 4 = very; 5 = ex- criteria, they were invited for a medical screening. When no tremely). The questionnaire is comprised of two questions, objections were raised during the physical examination in- BHow pleasant is using 4-FA right now?^ and BHow much cluding a standard blood and urine screens and an electrocar- do you want to use 4-FA right now?^ referring respectively to diogram (EKG) and participants signed the informed consent, drug liking and drug wanting. they were included in the study. Inclusion criteria were previous experience with Profile of mood states psychostimulants (≤ 1 time/week) and at least one time during the previous year; age between 18 and 40 years; free from The Profile of Mood States (POMS) (de Wit et al. 2002)is a psychotropic medication; healthy based on the assessment of self-assessment mood questionnaire with 72 five-point-Likert medical history, physical examination, vital signs, EKG (with scale items on which participants have to indicate to what heart rate 51–100 bpm; lower limit for fit people, 45 bpm), a extent these items were representing their mood. Items are resting systolic blood pressure 91–140 mmHg, a resting dia- clustered to represent eight basic mood states: anxiety, depres- stolic blood pressure 51–90 mmHg, and the results of the sion, anger, vigor, fatigue, confusion, friendliness, and elation. hematology, clinical chemistry, urinalysis, and serology with- From those scales, two composite scales were derived, good in the reference ranges; normal binocular visual acuity, drug effect (vigor + friendliness + elation/22) and bad drug corrected or uncorrected; absence of any major medical, en- effect (anxiety + depression + anger + fatigue + confusion/50). docrine and neurological conditions, and normal weight as defined by a body mass index between 19.5 and 28 kg/m ; Impulsivity tests written informed consent. Exclusion criteria were history of drug abuse or addiction (determined by the medical question- Stop signal test naire, drug questionnaire, and medical examination); exces- sive drinking (> 20 alcoholic consumptions a week); pregnan- The current stop-signal test (SST) is adapted from an earlier cy or lactation; hypertension (diastolic > 90; systolic > 140); version of Fillmore and colleagues (Fillmore et al. 2002), it current or history of psychiatric disorder (determined by the assesses impulsive action and it has previously been used in 2352 Psychopharmacology (2018) 235:2349–2356 Table 1 Time schedule of the T0 T1 T2 T3 T4 T5 −1T5 T5+1 impulsivity paradigms and drug experience questionnaires relative Post-treatment 0 h 1 h 2 h30 min 4 h 8 h 10 h 11 h 12 h to treatment administration; blood samples were collected more Motor impulsivity (SST) X X X frequently than depicted here, Reflective impulsivity (MFFT) X only samples collected around Drug liking and wanting (SDRQ) X X times of tests reported here are shown Good and Bad drug effect (POMS) X X X X 4-FA serum concentrations X X X X X similar research (Kuypers et al. 2007;van Welet al. 2012). It time at the nth percentile of the RT distribution. The resulting requires participants to make quick key responses to visually values for each stop signal delay were then averaged to yield a presented go signals and to inhibit any response when a visual single measure of stop reaction time for the test. stop signal (an asterisk) is suddenly presented in one of the corners of the screen. This can occur after one of four fixed Matching familiar figures test delays (50, 150, 250, and 350 ms) after the onset of the go signal. The go signals were four letters presented one at a time The matching familiar figures test (MFFT) assesses impulsive for 500 ms in the center of a computer screen. Participants are reflection, which is the tendency to reflect on the validity of required to respond to each letter as quickly as possible by problem solving under the special condition of several possi- pressing on of two response buttons. The computer screen is ble alternatives. The test involves simultaneous presentation blank for 1.5 s before the next letter is displayed. This pro- of a target figure positioned on the left of the screen and an vides a period of 2 s in which the participant can respond to the array of six alternatives on the right half of the screen, all go signal. A single test consists of 176 trials in which each of except one differing in one or more details from the target the 4-letter stimuli will be presented equally often. A stop figure. The participant is asked to select from the alternatives signal occurs in 48 trials during a test. Participants are required the figure that exactly matches the target as quickly as possi- to withhold any response in case a stop signal is presented. ble. If the initial selection is incorrect, this is signaled with a The task lasts about 10 min. Dependent variables are propor- beep and subjects are required to give another answer. Each tion of correct go responses and failed inhibitions on stop trials participant is given 2 examples followed by 20 test items. The and corresponding reaction times (Logan et al. 1984). The response latency and number of errors before the correct Stop reaction time (stop RT) to stop signal represents the es- match are collected per item. The main dependent variables timated mean time required to inhibit a response. resulting from these measures are the mean latency for first The method for calculating stop reaction time was taken response, the accumulated number of errors made before the from the race model of inhibitory control (Logan 1994). This correct match, an impulsivity score (I-score), and an efficiency model proposes that the response to stop signals is defined by score (E-score). The I-score is a composite index of impulsiv- two parallel processes: execution of a motor action in response ity, whereas the E-score reflects the balance between Bfast and to a signal and inhibition of a motor action in response to a accurate^ and Bslow and inaccurate.^ The I-score is calculated stop signal. Crucial to the outcome of the race is the speed of by subtracting the standardized mean latency from the stan- both processes. Response inhibition will fail if the time re- dardized number of errors. The E-score is calculated by quired to inhibit exceeds the time to complete a motor re- adding the standardized mean latency to the standardized sponse at the time of the stop signal. number of errors and multiplying the result by −1(Perales The speed of the inhibition response cannot be observed et al. 2009). directly but can be derived mathematically on the basis of three factors: stop-signal delay, reaction time distribution on Pharmacokinetics go trials, and the probability of successful response inhibitions in stop signal trials. First, reaction times to 128 go trials were A blood sample (5 mL) was collected at baseline and at reg- rank ordered from shortest to longest. The finishing time of ular times after treatment (see Table 1). Samples were centri- the inhibition response was then determined from the proba- fuged immediately and resulting serum was pipetted into a bility of successful response inhibition and the distribution of clean tube and stored at − 20 °C until 4-FA concentration reaction times. If n percent of the responses on stop-signal determination which took place after study completion. trials would be unsuccessfully inhibited (failed inhibitions), Blood serum (0.5 mL) was diluted with buffer and internal then the finishing time would be associated with the nth per- standard solution was added. After liquid-liquid extraction the centile of the RT distribution. Stop RTwas then determined by extract was analyzed using LC-MSMS, with 0.04 ng/mL as subtracting the appropriate stop-signal delay from reaction the lower limit of quantification. Psychopharmacology (2018) 235:2349–2356 2353 Statistical analyses baseline-corrected scores entered the analyses. RM GLM ANOVA showed main effects of treatment (F =7.55; p = 1,10 2 2 Questionnaire data and data of the SST was analyzed with 0.02; ƞ = 0.43) and time (F = 17.81; p < 0.001; ƞ = p 2,20 p repeated measures general linear models (RM GLM) 0.64) and a treatment by time interaction effect (F =8.12; 2,20 ANOVAwith treatment (two levels) and time of measurement p = 0.003; ƞ = 0.45) on good drug effect. The good drug (two levels SDRQ, three levels POMS and SST) as within effect was higher after 4-FA compared to placebo; the overall subject factors (SPSS, version 24.0). In case of main effects effect was the highest on T1 compared to T3 and T5. The of time of measurement, Bonferroni-corrected post-hoc tests quadratic interaction (F =12.57; p =0.005; ƞ = 0.56) be- 1,10 p were conducted. Data of the MFFT was analyzed by means of tween treatment and time demonstrated that while the ratings paired samples t tests since there was only one assessment. in the placebo condition were low and decreased slightly over The alpha criterion level of statistical significance for all anal- time, the ratings in the 4-FA condition were very pronounced yses was set at p = 0.05. Partial eta squared (ƞ )isreported in at T1 and steeply decreased from T1 to T3 while remaining at case of significant effects in the ANOVA GLM to demonstrate the same low level at T5 compared to T3 (Fig. 1c). the effect’s magnitude, where 0.01 is defined as small, 0.06 as Analyses showed a significant treatment by time interac- moderate and 0.14 as large. Partial eta squared is based on tion effect (F = 6.59; p = 0.006; ƞ = 0.43) on bad drug 1,10 p Cohen’s f which defines small, medium and large as respec- effect. Post-hoc analyses showed that this was a quadratic 2 2 tively 0.10, 0.25, and 0.50 which corresponds to η of 0.0099, effect (F =2.19; p =0.02; ƞ = 0.43) with the highest rat- 1,10 p 0.0588, and 0.1379 (Richardson 2011). ing showing at T3 for 4-FA compared to the other time-points and placebo; this effect was probably driven by the statistical- ly significant increased levels of fatigue and confusion, two of Results the sub-scales included in this composite scale bad drug effect which were the highest at this time-point. There was no main Pharmacokinetics effect of treatment (F =2.19; p =0.02; ƞ = 0.43) or time 1,10 p on bad drug effect (Fig. 1d). Mean (± SE) 4-FA serum concentrations were 167.3 ng/mL (±15) at T1, 60′ post-treatment, peaked 2 h after intake Impulsivity tasks (205.4 ng/mL ± 45) and descended over time to 97.2 ng/mL (± 10), 12 h after 4-FA administration (T5 +1). Stop signal task Drug experience questionnaires One participant was excluded from the analysis because of an absence of responses on go trials on four occasions (three Sensitivity to drug reinforcement questionnaire times placebo condition, once 4-FA). Repeated measures GLM ANOVA demonstrated a main effect of time of mea- RM GLM ANOVA showed statistically significant effects of surement (F =3.57; p =0.05; ƞ = 0.26) and a treatment 2,20 p Treatment, Time and Treatment by Time on both scales of the by time of measurement interaction effect (F =3.52; p = 2,20 SDRQ. Ratings of liking were higher after 4-FA compared to 0.05; ƞ = 0.26) on the proportion of failed inhibitions. Post- placebo (F = 26.16; p < 0.001; ƞ = 0.70), they were hoc tests did not reveal statistically significant differences be- 1,11 p highest at T1 compared to T5 (F = 22.99; p =0.001; tween separate time of measurements or treatment by time of 1,11 ƞ = 0.68), and while the liking ratings remained stable in measurement performances. Inspecting the data visually led to the placebo condition, they decreased substantially in the 4- the suggestion that these effects were mainly driven by the FA condition over time (F =13.13; p =0.004; ƞ =0.54) high number of failed inhibitions 1 h after 4-FA administration 1,11 p (Fig. 1a). For wanting the same pattern was observed with while the number of inhibition failures in the placebo condi- higher ratings of wanting after 4-FA compared to placebo tion was lower and stable over time. The number of failed (F = 19.06; p = 0.001; ƞ = 0.63), highest ratings at T1 inhibitions4and8hafter 4-FA administration wascompara- 1,11 p compared to T5 (F =14.73; p = 0.003; ƞ = 0.57), and ble to placebo-levels. Analyses did not reveal statistically sig- 1,11 p while ratings of wanting remained stable in the placebo con- nificant main effects of treatment or time of measurement, or dition, they substantially decreased in the 4-FA condition over their interaction on proportion of correct go responses, go-RT time (F =22.18; p =0.001; ƞ = 0.67) (Fig. 1b). or stop-RT (Table 2). 1,11 p Profile of mood states Matching familiar figures test Since one of the POMS sub-scales included in the composite Paired samples t tests did not reveal statistically significant scales displayed a baseline difference between test days, differences between 4-FA and placebo on the dependent 2354 Psychopharmacology (2018) 235:2349–2356 Fig. 1 Mean (± SE) ratings of 4-FA liking (a) and 4-FAwanting (b) 1 and 11 h after treatments, and ratings of good drug effect (c) and bad drug effect (d) 1, 4, and 11 h after treatments and corresponding 4-FA serum concentrations variables mean latency of first response (t = − 0.64; p = Discussion 1,11 0.53) and errors (t =0.12; p = 0.9), or the two composite 1,11 score, impulsivity (t =0.72; p = 0.48) and efficiency The present study aimed to assess whether 4-FA elicits risk 1,11 (t =0.27; p = 0.79). Mean (± SE) scores after placebo and factors for drug abuse, namely impulsive reflection and action, 1,11 4-FA were respectively 13 (1) and 15 (2) for latency in sec- a subjective state of drug liking and wanting, and good versus onds, 4.00 (1.1) and 3.75 (1.5) for total number of errors, 0.2 bad drug effect. It was hypothesized that 4-FA would not lead (0.3) and − 0.2 (0.5) for I-score, and 0.1 (0.4) and − 0.1 (0.5) to effects on impulsive behavior but would produce a state of for E-score. drug liking at peak drug concentrations. As expected, findings Table 2 Mean (± SE) of dependent variables of the SST F-, p-, and partial eta - values of RM GLM ANOVA Mean (± SE) RM GLM ANOVA, main and interaction effects Treatment Treatment Time Treatment by time 2 2 2 Stop signal task T PLA 4-FA F p ƞ F p ƞ F p ƞ 1,10 p 2,20 p 2,20 p Failed inhibitions (%) T1 0.35 (0.06) 0.47 (0.10) 0.31 0.59 0.03 3.57 0.05 0.26 3.52 0.05 0.26 T3 0.35 (0.06) 0.32 (0.06) T4 0.34 (0.06) 0.33 (0.06) Stop-RT T1 286 (15) 327 (26) 1.63 0.23 0.14 2.25 0.13 0.18 1.36 0.28 0.12 T3 291 (21) 287 (12) T3 266 (10) 291 (12) Correct go’s (%) T1 0.70 (0.01) 0.69 (0.01) 0.44 0.52 0.04 2.72 0.09 0.21 1.15 0.33 0.10 T3 0.67 (0.01) 0.69 (0.02) T4 0.69 (0.01) 0.70 (0.01) Go-RT (ms) T1 569 (42) 554 (42) 0.13 0.72 0.01 1.47 0.25 0.13 2.78 0.09 0.22 T3 571 (44) 583 (39) T4 558 (38) 584 (44) Psychopharmacology (2018) 235:2349–2356 2355 showed an absence of 4-FA effects on impulsive reflection peak effects have subsided, it has to be noted that the current and action and an increase in self-ratings of drug liking, drug picture is limited and might change with increased sample wanting and good drug effect, 1 h after administration and a size, including participants with poor baseline impulse control peak in bad drug effect 4 h after intake. The liking, wanting, and attention capacity, and/or different 4-FA doses. and good drug effects were absent 11 h after drug intake. Furthermore, additional repetitions of self-rated liking and The absence of drug effects on the impulsivity measures wanting are needed to know whether these feelings are present was in line with expectations and previous studies with am- when for example bad drug effects are high and good drug phetamine, MDMA and cocaine (Bosker et al. 2010; de Wit et effects are low, a few hours after drug intake, as this could al. 2000; de Wit et al. 2002; Dolder et al. 2018; Kuypers et al. push the individual to repeated drug use. 2007; Schmidt et al. 2017). The average scores during drug Acknowledgements The authors would like to thank Cees van Leeuwen and placebo conditions were also comparable to those found and Lizzy Vuurman for medical supervision; Johannes Reckweg, Lukas in previous drug studies by our group using the same para- Basedow, Drew Puxty, and Ignas Oppewal for helping with data acqui- digms (e.g., (Kuypers et al. 2007;van Welet al. 2012). sition; and the DSMB members (Wim Riedel, Therese van Amelsvoort, Although present findings suggest that a single dose of 4-FA Jan Schepers, and Robbert-Jan Verkes) for evaluating the data and pro- viding advice. (100 mg) does not induce impulsive behavior, previous stud- ies have shown that personal characteristics, like baseline per- Funding This research was funded by the European Commission (Grant formance and task-related characteristics like stimulus/ Number: HOME/2014/JDRF/AG/DRUG/7082, Predicting Risk of response complexity, can play a role in drug-induced changes. Emerging Drugs with In silico and Clinical Toxicology (PREDICT)). People performing badly at baseline or who were presented with complex stimuli showed an enhancing effect after am- Compliance with ethical standards phetamine (de Wit et al. 2000; de Wit et al. 2002;Fillmore et al. 2003). Additionally, stimulants like amphetamine and co- The study was performed in accordance with the Helsinki Declaration of 1975, and its subsequent amendments, and was approved by the Medical caine have shown to exert enhancing effects on response con- Ethics Committee of the Academic Hospital of Maastricht and the trol in individuals with impulse control problems, like ADHD University of Maastricht. and drug addiction (Arnsten 2006;Fillmore etal. 2002, 2005). Self-ratings of liking, wanting, and good drug effect, all Conflict of interest The authors declare that they have no conflict of reliable and sensitive indicators of drug abuse likelihood, were interest. increased compared to placebo 1 h after intake. Ten hours Open Access This article is distributed under the terms of the Creative later, the self-ratings in the 4-FA condition were indistinguish- Commons Attribution 4.0 International License (http:// able from ratings in the placebo condition. Findings demon- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, strate that a single dose of 4-FA (100 mg) does not lead to distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the craving (wanting) when the good drug effects are subsiding Creative Commons license, and indicate if changes were made. and bad drug effects increasing, suggesting an absence of repeated or compulsive use of this drug at this dose. However, similar to behavioral performance, studies have shown that personal or biological factors like baseline perfor- References mance or DA receptor availability can play a role in subjective drug experience (Brewer and Potenza 2008; McCloskey et al. Arnsten AFT (2006) Stimulants: therapeutic actions in ADHD. 2010). It was demonstrated previously that participants who Neuropsychopharmacology 31:2376–2383 Bosker WM, Kuypers KPC, Conen S, Ramaekers JG (2010) Dose-related performed worse on an attention paradigm-liked amphet- effects of MDMA on psychomotor function and mood before, dur- amine (20 mg) less and reported smaller increases in wanting ing, and after a night of sleep loss. Psychopharmacology 209:69–76 compared to participants who exhibited better attentional ca- Brewer JA, Potenza MN (2008) The neurobiology and genetics of im- pacities. It was concluded that participants’ attention capaci- pulse control disorders: relationships to drug addictions. Biochem ties determined the sensitivity to stimulant-induced effects Pharmacol 75:63–75 Cami J, Farre M, Mas M, Roset PN, Poudevida S, Mas A, San L, de la with worse capacity signaling reduced sensitivity to Torre R (2000) Human pharmacology of 3,4-methylenedioxymeth- stimulant-induced euphoria (McCloskey et al. 2010). In addi- amphetamine (Becstasy^): psychomotor performance and subjective tion, low baseline measures of D2 receptor availability in non- effects. J Clin Psychopharmacol 20:455–466 addicted people was shown to predict methylphenidate liking Carter LP, Griffiths RR (2009) Principles of laboratory assessment of drug abuse liability and implications for clinical development. and high levels of impulsivity in rats (Brewer and Potenza Drug Alcohol Depend 105(Suppl 1):S14–S25 2008). D’Amour-Horvat V, Leyton M (2014) Impulsive actions and choices in While the findings of the present study suggest that a single laboratory animals and humans: effects of high vs. low dopamine dose of 4-FA (100 mg) does not lead to either impulsive action states produced by systemic treatments given to neurologically in- or reflection, or to liking and wanting of the drug when the tact subjects. Front Behav Neurosci 8:432 2356 Psychopharmacology (2018) 235:2349–2356 Dolder PC, Strajhar P, Vizeli P, Odermatt A, Liechti ME (2018) Acute Perales JC, Verdejo-García A, Moya M, Lozano Ó, Pérez-García M (2009) Bright and dark sides of impulsivity: performance of women effects of lisdexamfetamine and D-amphetamine on social cognition and cognitive performance in a placebo-controlled study in healthy with high and low trait impulsivity on neuropsychological tasks. J subjects. Psychopharmacology 235:1389–1402 Clin Exp Neuropsychol 31:927–944 EMCDDA (2015) New psychoactive substances in Europe: an update Richardson JTE (2011) Eta squared and partial eta squared as measures of from the EU early warning system. European Monitoring Centre effect size in educational research. Educational Res Rev 6:135–147 for Drugs and Drug Addiction, Lisbon Rickli A, Hoener MC, Liechti ME (2015) Monoamine transporter and Fillmore MT, Rush CR, Hays L (2002) Acute effects of oral cocaine on receptor interaction profiles of novel psychoactive substances: Para- inhibitory control of behavior in humans. Drug Alcohol Depend 67: halogenated amphetamines and pyrovalerone cathinones. Eur 157–167 Neuropsychopharmacol 25:365–376 Fillmore MT, Rush CR, Marczinski CA (2003) Effects of d-amphetamine Rush CR, Essman WD, Simpson CA, Baker RW (2001) Reinforcing and on behavioral control in stimulant abusers: the role of prepotent subject-rated effects of methylphenidate and d-amphetamine in response tendencies. Drug Alcohol Depend 71:143–152 non–drug-abusing humans. J Clin Psychopharmacol 21:273–286 Fillmore MT, Rush CR, Hays L (2005) Cocaine improves inhibitory Schifano F, Orsolini L, Duccio Papanti G, Corkery JM (2015) Novel control in a human model of response conflict. Exp Clin psychoactive substances of interest for psychiatry. World Psychopharmacol 13:327–335 Psychiatry 14:15–26 Fuller RW, Baker JC, Perry KW, Molloy BB (1975) Comparison of 4- Schmidt A, Muller F, Dolder PC, Schmid Y, Zanchi D, Liechti ME, chloro-, 4-bromo- and 4-fluoroamphetamine in rats: drug levels in Borgwardt S (2017) Comparative effects of methylphenidate, brain and effects on brain serotonin metabolism. Neuropharmacol- modafinil, and MDMA on response inhibition neural networks in ogy 14:739–746 healthy subjects. Int J Neuropsychopharmacol 20:712–720 Harris DS, Baggott M, Mendelson JH, Mendelson JE, Jones RT (2002) de Sousa Fernandes Perna EB, Theunissen EL, Dolder PC, Mason NL, Subjective and hormonal effects of 3,4-methylenedioxymetham- Hutten NRPW, Toennes SW, Kuypers KPC, Ramaekers JG (2018) phetamine (MDMA) in humans. Psychopharmacology 162:396– Safety profile and neurocognitive function following acute 4- fluoroamphetamine (4-FA) administration in humans. Under review Hondebrink L, Zwartsen A, Westerink RHS (2017) Effect fingerprinting Waefer J, de Wit H (2013) Inattention, impulsive action, and subjective of new psychoactive substances (NPS): what can we learn from in response to d-amphetamine. Drug Alcohol Depend 133:127–133 vitro data? Pharmacol Ther Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Kuypers KPC, Wingen M, Limbert N, Samyn N, Ramaekers JG (2007) Woolverton WL (2005) Relationship between the serotonergic ac- Acute effects of nocturnal doses of MDMA on measures of impul- tivity and reinforcing effects of a series of amphetamine analogs. J sivity and psychomotor performance throughout the night. Pharmacol Exp Ther 313:848–854 Psychopharmacology 192:111–119 van Wel JHP, Kuypers KPC, Theunissen EL, Bosker WM, Bakker K, Liechti M (2015) Novel psychoactive substances (designer drugs): over- Ramaekers JG (2012) Effects of acute MDMA intoxication on view and pharmacology of modulators of monoamine signaling. mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors. Swiss Med Wkly 145:w14043 PLoS ONE 7:e40187 Linsen F, Koning RPJ, van Laar M, Niesink RJM, Koeter MW, Brunt TM Wijers CHW, van Litsenburg RTH, Hondebrink L, Niesink RJM, Croes (2015) 4-Fluoroamphetamine in the Netherlands: more than a one- EA (2017) Acute toxic effects related to 4-fluoroamphetamine. night stand. Addiction 110:1138–1143 Lancet 389:600 Logan GD (1994) On the ability to inhibit thought and action. A user’s Winstanley CA, Olausson P, Taylor JR, Jentsch JD (2010) Insight into the guide to the stop signal paradigm. In: Carr DDTH (ed) Inhibitory relationship between impulsivity and substance abuse from studies processes in attention, memory, and language. Academic Press, San using animal models. Alcohol Clin Exp Res 34:1306–1318 Diego, California, pp 189–239 de Wit H (2009) Impulsivity as a determinant and consequence of drug Logan GD, Cowan WB, Davis KA (1984) On the ability to inhibit simple use: a review of underlying processes. Addict Biol 14:22–31 and choice reaction time responses: a model and a method. J de Wit H, Crean J, Richards JB (2000) Effects of d-amphetamine and Experimental Psychology Human Perception Performance 10: ethanol on a measure of behavioral inhibition in humans. Behav 276–291 Neurosci 114:830–837 McCloskey M, Palmer AA, de Wit H (2010) Are attention lapses related de Wit H, Enggasser JL, Richards JB (2002) Acute administration of d- to d-amphetamine liking? Psychopharmacology 208:201–209 amphetamine decreases impulsivity in healthy volunteers. Monshouwer K, van der Pol P, Drost YC, van Laar MW (2016) Het grote Neuropsychopharmacology Official Publication Am College uitgaansonderzoek 2016: Uigaanspatronen, middelengebruik en Neuropsychopharmacology 27:813–825 preventieve maatregelen onder uitgaande jongeren en jongvolwassenen. Trimbos Institute, Utrecht Wood DM, Greene SL, Dargan PI (2013) Five-year trends in self-reported Nagai F, Nonaka R, Satoh Hisashi Kamimura K (2007) The effects of recreational drugs associated with presentation to a UK emergency non-medically used psychoactive drugs on monoamine neurotrans- department with suspected drug-related toxicity. Eur J Emerg Med mission in rat brain. Eur J Pharmacol 559:132–137 20:263–267

Journal

PsychopharmacologySpringer Journals

Published: May 31, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off