A First-in-Man Study with 4-Fluoroamphetamine Demonstrates it Produces a Mild Psychedelic State

ABSTRACT

The phenethylamine 4-fluoroamphetamine (4-FA) is a so-called novel psychoactive substance with a chemical structure resembling that of amphetamine and MDMA. Since 4-FA users report their subjective experience ranges between the effects induced by amphetamine and MDMA, and it is known that both substances can produce an altered state of consciousness, this study tests whether 4-FA induces a psychedelic state. A placebo-controlled two-way crossover study in 12 healthy poly-drug users was conducted to test subjective and behavioral effects of 4-FA. 4-FA concentrations were determined in serum up to 12 hours after administration and a series of questionnaires and the picture concept test were administered between one hour and 11 hours post-administration. Findings showed that 4-FA induced a psychedelic state which was highest one hour after 4-FA administration, at peak 4-FA serum concentrations. The 4-FA-induced psychedelic state decreased over time and was in general associated with the decreasing 4-FA serum concentrations. There was no 4-FA-induced change in creative (flexible) thinking. It is concluded that while the 4-FA-induced psychedelic state is mild in intensity and in between that produced by amphetamine and MDMA as hypothesized, more research is needed to indicate whether 4-FA can change creative thinking.

KEYWORDS:

• 4-FA
• creative thinking
• dissociative state
• psychedelic state serum concentrations

Introduction

Over the last 10 years, the number of novel psychoactive substances (NPS), substances with chemical profiles related to but not identical to classical drugs, has grown exponentially (EMCDDA 2015). One of these substances, the phenethylamine 4-fluoroamphetamine (4-FA), has—according to users—a behavioral profile intermediate between the stimulant amphetamine and the pro-social, entactogenic MDMA (Hondebrink, Zwartsen, and Westerink 2017; Linsen et al. 2015; Monshouwer et al. 2016; Rickli, Hoener, and Liechti 2015). Together, amphetamine, 4-FA and MDMA are described as non- or mild hallucinogenic phenethylamines (Hondebrink, Zwartsen, and Westerink 2017).

While hallucinations only seldom occur, amphetamine (10–20 mg) and MDMA (75–125 mg) have been shown to induce alterations in mood, perception, thinking, body awareness, and self-control as demonstrated on the hallucinogenic rating scale (HRS) (Johanson et al. 2006), and the clinician-administered dissociative rating scale in the case of MDMA (Puxty et al. 2017; van Heugten-Van der Kloet et al. 2015). The change in consciousness produced by both substances seemed to be comparable, affecting the rating scales in the same direction, as shown by a discrimination study, with the most pronounced effects for MDMA (1.5 mg/kg) and smaller effects for d-amphetamine (20 mg) (Johanson et al. 2006). Since 4-FA users report that the subjective experience ranges between the effects induced by amphetamine and MDMA, it is reasonable to test whether 4-FA induces a so-called “altered state of consciousness” or psychedelic state like its classic analogues amphetamine and MDMA.

Enhanced mood and dissociative states have been linked with increased creativity or creative thinking (DeDreu, Baas, and Nijstad 2008; Pérez-Fabello and Campos 2011; van Heugten–van der Kloet et al. 2015). Previously, studies have shown that psychedelics like LSD and ayahuasca are associated with enhanced creativity (Harman et al. 1966; Iszáj, Griffiths, and Demetrovics 2017). Many studies looking into the acute effects of psychedelics on creativity were conducted decades ago using flawed methodology (Harman et al. 1966; Iszáj, Griffiths, and Demetrovics 2017). However, a quasi-experimental study recently tested the acute effects of the psychedelic tea ayahuasca on creative thinking using the picture concept test and showed selective enhancement of flexible divergent thinking together with an impairment of convergent rigid thinking (Kuypers et al. 2016).

Psychedelics exert their main effects via agonistic action at the 5-HT_2A/C receptor. 4-FA, on the other hand, exerts effects on the monoamine transporters, with the most pronounced effects on the 5-HT transporter and, to a lesser extent, on the dopamine (DA) and norepinephrine (NE) transporter (Hondebrink et al. 2017; Nagai, Nonaka, and Satoh Hisashi Kamimura 2007; Nugteren-van Lonkhuyzen et al. 2015; Rickli, Hoener, and Liechti 2015). The stimulation of DA and 5-HT release by 4-FA is similar in magnitude to that caused by amphetamine and MDMA, respectively (Rickli, Hoener, and Liechti 2015). Next to this, 4-FA has also been shown to exhibit affinity for the 5-HT_2A receptor, similar to MDMA, though substantially lower than the true hallucinogenic NPS like 2C-B and the NBOMes (Hondebrink, Zwartsen, and Westerink 2017; Rickli, Hoener, and Liechti 2015). In light of the renewed interest in psychedelics as therapeutic tools in the treatment of psychopathologies like depression and anxiety disorders, where rigid thinking is one of the hallmarks, it is important to test whether this new compound “4-FA” can induce flexible thinking.

The present study aimed to assess whether 4-FA induces an altered state of consciousness and a change in creative thinking and, secondly, whether these self-rated consciousness state and creative performance effects are associated. Based on previous amphetamine and MDMA studies, it was hypothesized that 4-FA would induce an “altered state of consciousness,” which would, based on its mechanism of action, resemble MDMA more than amphetamine. In addition, also based on the mechanism of action, it was hypothesized that 4-FA would enhance creative thinking, though to a lesser extent than typical psychedelics. For explorative reasons, we tested whether subjective effects are related to 4-FA serum concentrations.

The data presented in the current paper are part of a larger project called Predicting Risk of Emerging Drugs with In Silico and Clinical Toxicology (www.predictnps.eu), focusing on the safety profile of NPS in humans, in vitro, and in silico (de Sousa Fernandes Perna et al. 2018; Dolder et al. 2018).

Methods

Study design and treatment

The study used a double-blind, two-way, cross-over, randomized placebo-controlled design. Treatment was 100 mg of 4-FA or placebo mixed with 100 mL of bitter lemon. The drink was ingested at once. The 100 mg dose was based on a user survey among Dutch 4-FA users. The majority (75%) of the users who knew the dose they ingest typically indicated it to be between 50–150 mg; the remainder used larger doses. In general, the subjective effects last between 4–6 hours (Linsen et al. 2015). 4-FA has an estimated half-life of 3.7 hours in the rat brain (Fuller et al. 1975).

A permit for obtaining, storing, and administering 4-FA was obtained from the Dutch Drug Enforcement Administration. The study was performed in accordance with the Helsinki Declaration of 1975 and its subsequent amendments, and was approved by the Medical Ethics Committee of the Academic Hospital of Maastricht and the University of Maastricht (METC163030). It was registered in the Dutch Clinical Trial Register (Registration Number: NTR6164).

Participants

Since this was a first-in-man study, primarily assessing the safety aspects of 4-FA administration in humans, the power calculation was based on the primary safety measure heart rate. The resulting sample size (N = 12) was therefore lower than the typical placebo-controlled experimental study assessing the effects of a substance on behavioral measures.

Participants were 12 healthy male (n = 7) and female (n = 5) volunteers who had experience with stimulant use, since we wanted to minimize the risk of having adverse reactions after intake of a stimulant which could occur in drug-naïve users. They were aged 22.3 (±3.4 SD) years on average. Males had a mean BMI of 22.9 (±1.3 SD); females had an average BMI of 21.5 (±2.8 SD). All of them had experience with alcohol use, with the units consumed per week ranging from 2 to 20. One participant smoked regular cigarettes with an average of 15 per day, and seven smoked cannabis with an average of one “unit” per week. The use of other drugs was expressed in “lifetime use,” the minimum and maximum (min-max) times used, together with the number of participants with experience (n) listed per drug category (and drug n; min-max): stimulants: amphetamines (8; 1–32) and cocaine (6; 1–26); entactogens: ecstasy (11; 1–35); novel psychoactive substances: 4-FA (5; 1–25); classical psychedelics: LSD (3; 7–17). Next to these fixed categories, participants were asked to indicate whether they used “other drugs” that were not listed; these drugs included classical psychedelics: (psilocybin (truffles and dried mushrooms; n = 7), DMT (n = 1), and mescaline (n = 1); stimulant (medicinal) drugs: dextroamphetamine (n = 1), modafinil (n = 1), and methylphenidate (n = 1); and novel psychoactive substances (2C-B (n = 1), 5ABP/6ABP (n = 1), 25I-NBOMe (n = 1).

Procedures

Participants were recruited by means of flyers in the university building, an advertisement on a research-Facebook page, and by word of mouth. When interested, they were sent the information brochure and two questionnaires (medical and drug use history). When they were fully informed, potential questions were answered, and they fulfilled at first sight the inclusion criteria, they were invited for a medical screening. When no objections were raised during the physical examination (including a standard blood and urine screen and an electrocardiogram (EKG)) and participants signed the informed consent, they were included in the study.

Inclusion criteria were previous experience with psychostimulants (≤ 1 time/week) and at least one time during the previous year, age between 18 and 40, and free from psychotropic medication. An additional inclusion criterion was that participants were healthy based on their medical history: physical examination, vital signs, EKG (with heart rate 51–100 bpm; lower limit for fit people: 45 bpm), a resting blood pressure under under 140/90 mmHg, and the results of the hematology, clinical chemistry, urinalysis, serology all within the reference ranges. Last, we included participants with normal binocular visual acuity, corrected or uncorrected, absence of any major medical, endocrine, and neurological conditions, and normal weight as defined by a body mass index between 19.5 and 28 kg/m². Exclusion criteria were: history of drug abuse or addiction (determined by the medical questionnaire, drug questionnaire, and medical examination); excessive drinking (> 20 alcoholic consumptions a week); pregnancy or lactation; hypertension (diastolic > 90; systolic > 140); current or history of psychiatric disorder; liver dysfunction; (serious) side effects to previous psychostimulant use; history of cardiac dysfunctions (e.g., arrhythmia, ischemic heart disease); simultaneous participation in another clinical trial; being a blood donor; and for women, not using a reliable contraceptive.

Prior to the test days, participants were familiarized with the study procedures, tests, and questionnaires. On a test day, participants arrived early in the morning and were tested for the absence of drugs in urine and alcohol in breath. In the case of females, an additional test for pregnancy was conducted in the urine. When all tests were negative, participants were given baseline questionnaires, a blood sample was taken, and they received a light standardized breakfast. Table 1 provides an overview of timing of questionnaires, the creativity test, and blood samples during the test day. Test days were separated by minimally seven days. Participants were paid upon completion of the testing periods for their participation.

Table 1. Time schedule of psychedelic questionnaire assessment and blood samples.

Data collection	T0	T1	T2	T3	T4–1	T4	T4 + 1	T5	T5 + 1
Time post-treatment	0	60 min	4 h	6 h	8 h	9 h	10 h	11 h	12 h
B-VAS	X	X	X					X
CADSS		X	X			X
5D-ASC						X
HRS								X
PCT				X
4-FA serum concentrations	X	X	X	X	X		X		X

Questionnaires

Questionnaires asking about the subjective experience in real-time

Two questionnaires, the Bowdle visual analogue scale and the Clinician Administered Dissociative States Scale, were administered during the peak effects and afterwards. Participants were asked to rate what they experienced at the moment they were asked.

The Bowdle Visual Analogue Scale (B-VAS) assesses the psychedelic state. It consists of 13 100-mm visual analogue scales from which two composite scales, internal perception (six items) and external perception (five items) are calculated; there are two filler items. The former scale reflects inner feelings not corresponding to reality and the latter scale reflects a misperception of an external stimulus or a change in the awareness of the person’s surroundings (Bowdle et al. 1998).

The Clinician Administered Dissociative States Scale (CADSS) is a standardized measure of present-state dissociative symptomatology and comprises 19 subjective items, with response options ranging from 0 (not at all) to 4 (extremely). There are also seven observer-rated items in the scale, which were not used in this study. The CADSS is divided into three components—depersonalization, derealization, and amnesia—with maximum scores of 10, 24, and 2, respectively. Summed together, these subscales form the total dissociative score (Bremner et al. 1998).

Questionnaires asking about the subjective experience in retrospect

Two questionnaires, the altered states of consciousness rating scale and the hallucinogenic rating scale, were administered after the peak effects had subsided. Participants were asked to rate the experience in retrospect.

The Altered States of Consciousness Rating Scale (5D-ASC) consists of 94 items that are 100-mm visual analogue scales, which are grouped into five main dimensions and 11 lower-order scales (Studerus, Gamma, and Vollenweider 2010). The first dimension—oceanic boundlessness (OB, 27 items)—measures derealization and depersonalization, accompanied by changes in affect, ranging from heightened mood to euphoria and/or exaltation, as well as alterations in the sense of time. The second dimension—anxious ego dissolution (AED, 21 items)—measures ego disintegration associated with loss of self-control, thought disorder, arousal, and anxiety. The third dimension—visionary restructuralization (VR, 18 items)—refers to elementary hallucinations, visual (pseudo-) hallucinations, synesthesia, changed meaning of percepts, facilitated recollection, and facilitated imagination. The fourth dimension—auditory alterations (AA, 16 items)—refers to acoustic hallucinations and distortions in auditory experiences, and the fifth dimension—reduction of vigilance (RV, 12 items)—relates to states of drowsiness, reduced alertness, and related mpairment of cognitive function (Dittrich 1998).

Of the 11 lower-order scales, four are associated with OB: experience of unity, spiritual experience, blissful state, and insightfulness; three are associated with AED: disembodiement, impaired control and cognition, and anxiety; and four are associated with VR: complex imagery, elemental imagery, audio-visual synesthesia, and changed meaning of percepts (Studerus, Gamma, and Vollenweider 2010).

The Hallucinogenic Rating Scale includes 71 items with response options ranging from 0 (not at all) to 4 (extremely); items are sorted into six subscales: somaesthesia (13 items), reflecting somatic effects including interoceptive, visceral, and tactile effects; affect (17 items), sensitive to emotional and affective responses; volition (8 items), indicating the subject’s capacity to willfully interact with his/her “self” and/or the environment; cognition (12 items), describing alterations in thought processes or content; perception (17 items), measuring visual, auditory, gustatory, and olfactory experiences; and finally, intensity (4 items), which reflects the strength of the overall experience. The scores for the different scales are obtained by calculating the average over the scale’s individual items. The range of scores for all HRS scales is 0 to 4. The grouping of these items in six scales was derived from empirical studies with DMT and ketamine (Riba et al. 2001; Strassman et al. 1994).

Picture Concept Test

The Picture Concept Test is a creativity test that assesses both convergent and divergent thinking (Kuypers et al. 2016). It consists of 17 stimuli; each stimulus contains a matrix with 4 to 12 color pictures shown in two or three rows. Participants have to find an association between one of the pictures in each row. They are instructed to provide the correct solution, as there is only one correct answer. In total, 28 stimuli were shown and participants had to respond within a timeframe of one minute per stimulus. The percentage of correct answers was calculated and taken as the dependent measure of convergent thinking.

Next to asking participants to provide the correct solution, they were also asked to provide as many alternative answers as possible within a set time limit of one minute. For the generated answers, a number of parameters were calculated; i.e., fluency, originality, and the ratio of both. Fluency is defined as the number of alternative associations and reflects the quantity of generated output. Originality is calculated by evaluating the originality of the alternative association relative to those provided by all other participants in a session; this reflects the quality of the generated output. Alternative answers that were uniquely reported by a single participant received an originality score of 2. Answers that were shared with a single participant were valued as 1, and answers that were shared by three or more participants were rated zero. Mean originality scores were weighed for fluency (originality/fluency) and used as measures of divergent thinking. Parallel versions were used for separate test days.

Pharmacokinetics

A blood sample (5 mL) was collected at baseline and at regular times after treatment (30 min, 60 min, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 12 h). Samples were centrifuged immediately and the resulting serum was pipetted into a clean tube and stored at −20°C until 4-FA concentration determination, which took place after study completion. Blood serum (0.5 mL) was diluted with buffer and internal standard solution was added. After liquid-liquid extraction, the extract was analyzed using LC-MSMS with 0.04 ng/mL as the lower limit of quantification.

Statistical analyses

Data of the B-VAS and CADSS entered a general linear model (GLM) repeated measures ANOVA (SPSS, version 24.0) with Treatment (two levels: 4-FA, placebo) and Measurement (three levels) as the main within-subject factors. In the case of the main effect for Measurement or interaction effects, Bonferroni corrected multiple comparisons were conducted. Before ANOVA was conducted on the B-VAS, paired t-tests were conducted to test for the absence of baseline differences. Since the HRS, the 5D-ASC, and the PCT were administered only once, the treatment effect on the subscales was analyzed by means of paired sample t-tests.

In order to test whether subjective experience under influence of 4-FA correlated with 4-FA serum concentrations, Pearson’s correlations were calculated between difference scores of subjective responses on the B-VAS and CADSS subscales (subjective response during 4-FA minus subjective response during placebo) and 4-FA serum levels. For the last measurement of the B-VAS (at 11 h post-treatment) and the CADSS (at 9 h post-treatment), an average 4-FA serum concentration was calculated using the data points that were adjacent to the subjective measures. In the case of the B-VAS, the 4-FA concentrations of the blood samples taken 10 and 12 hours post-treatment were averaged; in the case of the CADSS, 4-FA concentrations of blood samples taken 8 and 10 hours post-treatment were averaged.

The alpha criterion level of statistical significance for all analyses was set at p = 0.05. Partial eta squared (ƞ_p²) is reported in the case of significant effects in the ANOVA GLM to demonstrate the effect’s magnitude, where 0.01 is defined as small, 0.06 as moderate, and 0.14 as large. Partial eta squared is based on Cohen’s f, which defines small, medium, and large as 0.10, 0.25, and 0.50, respectively, which corresponds to η² of 0.0099, 0.0588, and 0.1379 (Richardson 2011).

Results

Pharmacokinetics

Mean (±SE) 4-FA serum concentrations were the highest (167.28 ng/mL ±15.41) at T1, 60 min post-treatment, and descended over time to 97.22 ng/mL (±10.03) at T5 + 1, 12 hours after 4-FA administration.

Questionnaires

Questionnaires asking about the subjective experience in real time

Bowdle visual analogue scales

A paired sample t-test to test for baseline differences between placebo and 4-FA test days on ratings of internal and external perception did not show statistically significant differences. Repeated measures ANOVA showed a main effect of Treatment on internal perception (F_1,11 = −6.68; p = −0.02; ƞ_p² = −0.38) and external perception (F_1,11 = −6.68; p = 0.02; ƞ_p² = 0.38). Ratings of internal and external perception were on average, respectively, 0.11 and 0.26 units higher after 4-FA administration compared to the placebo. There was also a main effect of Measurement (F_2,22 = 9.57; p = 0.001; ƞ_p² = 0.46) and an interaction effect of Treatment by Measurement (F_2,22 = 8.55; p = 0.002; ƞ_p² = −0.44) on external perception. It was shown that ratings at T1 were higher than ratings at T2 (p = −0.03) and ratings at T2 were higher than ratings at T5 (p = −0.04); this was particularly the case in the 4-FA condition, while placebo ratings remained constant (Figure 1, Panel A). There was no main effect of Measurement or an interaction effect between Treatment and Measurement on internal perception (Figure 1, Panel B).

Figure 1. Mean (±SE) of ratings on the two scales of the B-VAS (units on the left Y-axis)—i.e., (A) external perception and (B) internal perception—and the ratings on the three subscales of the CADSS (on the left Y-axis)—amnesia (C), depersonalization (D), derealization (E)—and the total dissociative score (F) in the placebo (•) and 4-FA condition (□) at 1 h post-treatment (T1), 4 h post-treatment (T2), and 9 h post-treatment (T4) for the B-VAS and 11 min post-treatment (T5) for the CADSS, and corresponding 4-FA serum concentrations (on the right Y-axis) in the 4-FA condition (•).

Pearson correlation analyses demonstrated a statistically significant correlation between external perception and 4-FA serum concentrations (r₃₆ = −0.44; p = −0.008), and an absence of association between internal perception and 4-FA serum concentrations (r₃₆ = −0.31; p = −0.07).

Clinician administered dissociative states scale

Analysis revealed main effects of Treatment and Measurement, and interaction effects of Treatment by Measurement, on depersonalization, derealization, and the total dissociative score. Depersonalization, derealization, and total dissociative scores were respectively 0.91, 4.15, and 5.70 units higher in the 4-FA condition compared to the placebo. Ratings decreased linearly for depersonalization (p = −0.04), derealization (p = −0.006), and total dissociation score (p = −0.01) over time; this was particularly the case in the 4-FA condition, while placebo ratings remained constant. The main effect of Treatment was driven by the statistically significant difference between 4-FA and the placebo one hour after administration: depersonalization (t_1,10 = −3.09; p = −0.01), derealization (t_1,10 = −3.50; p = −0.006), and total dissociation score (t_1,10 = −3.27; p = −0.008), while this difference was not significant four and nine hours after intake. There was no effect of Treatment, Measurement, or their interaction on amnesia (Figure 1, Panel C−F, Table 2).

Table 2. Main and interaction effects of treatment and measurement on the subscales and total scale of the CADSS and mean (±SE) ratings on the six scales of the HRS, 11 hours post-treatment, and paired samples t-test values and corresponding p-values.

	Treatment (T)			Measurement (M)			T*M
CADSS Scales	F1,11	p	ƞp^2	F2,22	p	ƞp^2	F	p	ƞp^2
Amnesia	2.62	0.14	0.21	1.39	0.27	0.12	1.45	0.26	0.13
Depersonalization	9.96	0.01	0.50	5.16	0.02	0.34	6.18	0.008	0.38
Derealization	9.93	0.01	0.50	9.46	0.001	0.49	8.62	0.002	0.46
Total CADSS	8.86	0.01	0.47	7.76	0.003	0.44	7.91	0.003	0.44
	Treatment (Mean ±SE)		Paired Samples t-tests
HRS Scales	Placebo	4-FA	t11	p
Affect	0.30 (0.05)	1.12 (0.16)	−4.61	0.001
Perception	0.00 (0.00)	0.22 (0.05)	−4.50	0.001
Cognition	0.05 (0.04)	0.78 (0.17)	−4.34	0.001
Volition	2.03 (0.88)	1.33 (0.35)	2.75	0.02
Intensity	1.39 (0.05)	2.89 (0.22)	−6.62	<0.001
Somaesthesia	0.02 (0.02)	1.23 (0.22)	−5.61	<0.001

Pearson correlation analyses demonstrated statistically significant correlations between 4-FA serum concentrations and amnesia (r₃₅ = −0.45; p = −0.006), derealization (r₃₅ = −0.42; p = −0.01), and the total dissociative score (r₃₅ = 0.42; p = 0.01). Analysis showed that depersonalisation and 4-FA serum concentrations were not statistically associated (r₃₅ = −0.23; p = −0.18)

Questionnaires asking about the subjective experience in retrospect

Altered states of consciousness rating scale (5D-ASC)

Paired sample t-tests revealed significant differences between ratings under influence of 4-FA and the placebo on four out of five main dimensions (Figure 2, Panel A): oceanic boundlessness (t₁₁ = −2.81; p = −0.02), anxious ego dissolution (t₁₁ = −2.43; p = 0.03), visual restructuralization (t₁₁ = −2.96; p = 0.01), and reduction of vigilance (t₁₁ = −2.94; p = −0.01); 3 out of 11 lower-order scales (Figure 2, Panel B): blissful state (t₁₁ = −2.81; p = −0.02), impaired control and cognition (t₁₁ = −2.35; p = −0.04), and complex imagery (t₁₁ = −2.14; p = −0.05), and the total 5D-ASC score (t₁₁ = −3.91; p = −0.002; Figure 2, Panel A). Ratings on all of the mentioned 5D-ASC scales were higher in the 4-FA condition, nine hours after administration, compared to the placebo.

Figure 2. Main (±SE) ratings on the five dimensions of the 5D-ASC (panel A) and 11 lower-order 5D-ASC scales, OB (Panel B), AED (Panel C), and VR (Panel D) in the placebo (•) and 4-FA condition (□), * indicate statistically significant differences between treatment condition at alpha = –0.05.

Hallucinogen rating scale (HRS)

The first item of the questionnaire—“Amount of time between when the drug was administered and feeling an effect,” with response options “Not applicable, no effect,” “0–5 seconds,” “5–15 seconds,” “15–30 seconds,” “30–60 seconds,” and “More than one minute”—reflects the fast-acting drugs (DMT and ketamine) for which the questionnaire was initially developed. This item was scored “0” by all of the participants in all conditions and it was therefore not included in the intensity scale, which resulted in three instead of four items conforming (Tancer and Johanson 2003).

Paired sample t-tests revealed statistically significant differences between 4-FA and the placebo on the six scales: affect (t₁₁ = −4.61; p = −0.001), perception (t₁₁ = −4.50; p = −0.001), cognition (t₁₁ = −4.34; p = 0.001), volition (t₁₁ = 2.75; p = 0.02), intensity (t₁₁ = −6.62; p < 0.001), and somaesthesia (t11 = −5.61; p < –0.001), with higher ratings of affect, perception, cognition, intensity, and somaesthesia, and lower ratings of volition, 11 hours after 4-FA intake compared to the placebo (Table 2).

Picture concept test

Paired sample t-tests did not reveal statistically significant differences between 4-FA and the placebo on convergent or divergent thinking. Participants had on average (±SE) 56.86% (3.85) correct during placebo, while this was 61.76 (3.02) in the 4-FA condition. On the divergent thinking measures, they scored 8.58 (1.19) on fluency, 17.92 (2.79) on originality, and 0.51 (0.04) on the ratio of fluency and originality during the placebo, while these scores in the 4-FA condition were: 10.17 (1.69), 21.08 (3.47), and 0.51 (0.05) for fluency, originality, and ratio, respectively.

Discussion

This study investigated whether 4-FA induces an altered state of consciousness, and whether it enhances flexible creative thinking. In addition, it tested whether subjective experiences were associated with 4-FA serum concentrations. The findings showed that 4-FA induced a psychedelic state that was highest one hour after 4-FA administration, at the peak 4-FA serum concentration. The 4-FA-induced psychedelic state decreased over time and was generally associated with the decreasing concentrations of 4-FA in the serum. There was no 4-FA-induced change in creative (flexible) thinking.

Previous studies using the retrospective questionnaires have shown that typical stimulants, such as d-amphetamine and meta-chlorophenylpiperazine (mCPP), psychedelics such as salvia divinorium, ayahuasca, LSD, and DMT, dissociative agents such as ketamine, and empathogens such as MDMA increase ratings on the Hallucinogenic Rating Scale (HRS) and/or the five-dimensional Altered States of Consciousness Scale (5D-ASC) (González et al. 2006; Johanson et al. 2006; MacLean et al. 2013; Riba et al. 2006; Tancer and Johanson 2003). However, when visually comparing the scores after administration of some the aforementioned substances and 4-FA on the three main scales of the 5D-ASC—oceanic boundlessness, anxious ego dissolution, and visionary restructuralization—it is notable that 4-FA produces a psychedelic state that is substantially milder than said psychedelics (Liechti, Dolder, and Schmid 2017) and a high dose (0.9–1.0 mg/kg) of amphetamine (Vollenweider et al. 1998). However, when comparing to a more common dose of amphetamine (40 mg; unpublished data), ratings after 4-FA are similar to slightly higher, though still low. These findings show that the psychedelic state induced by amphetamine, a substance closely related to 4-FA, is dose-dependent, with higher doses leading to a more pronounced subjective effect compared to lower doses of the substance, suggesting that higher doses of 4-FA potentially induce a stronger psychedelic state. While for the 5D-ASC there are a reasonable number of studies to compare with, for the HRS there is not a lot of reference material. A closer look at the phenomenology is not possible since the scores on the lower-order scales of the 5D-ASC, which could reveal more about the detail of the experience, are not always presented in papers.

The Bowdle VAS and the CADSS were rated multiple times during the experience and give a more detailed view of the time-course of the psychedelic effects compared to the HRS and 5D-ASC. While the subjective experience after 4-FA was rated substantially higher than placebo one hour after intake, these ratings decreased in a linear fashion over time. The ratings of depersonalization and derealization during the peak experience were comparable to those previously assessed after administration of MDMA (75–100 mg) and cocaine (300 mg) (Puxty et al. 2017; van Heugten-Van der Kloet et al. 2015; van Wel et al. 2015), though lower than those of after ketamine (0.5 mg/kg, IV) (Krystal, Karper, and Seibyl et al. 1994). While the 5D-ASC assesses the subjective experience of depersonalization and derealization in combination, these two concepts are assessed separately by the B-VAS and CADSS. It was shown that both depersonalization and derealization were increased by 4-FA, though only derealization/external perception was significantly and positively correlated with 4-FA serum concentrations. This is in line with previous MDMA studies showing an absence of dissociative state after low doses of MDMA (25–50 mg) and a selective effect of MDMA 100 mg on derealization, which seems to indicate that the feeling of being detached from reality depends on the amount of substance present in the blood, with a higher amount leading to more pronounced self-rated feelings. This is in line with the dose-dependent psychedelic state effects of amphetamine mentioned earlier. However, it has to be noted that feelings during descending 4-FA serum concentrations might not be comparable to the self-rated experience during low serum concentrations of a substance at the peak effect.

A closer look at the subscales of the 5D-ASC revealed that the 4-FA effects on the main scales of oceanic boundlessness (OB), anxious ego dissolution (AED), and visionary restructuralization (VR) were due to drug effects on blissful state (OB), impaired control and cognition (AED), and complex imagery (VR), respectively. The latter two effects are interesting in light of the hypothesized effects on creative thinking. The increase in impaired control of cognition and complex imagery suggests impairment of rigid cognitive processes like convergent thinking and enhancement of flexible cognitive processes like divergent thinking, an effect pattern previously observed after administration of the psychedelic tea ayahuasca (Kuypers et al. 2016). However, findings failed to show effects of 4-FA on creative thinking in the PCT, with a non-significant increase in convergent thinking of 10% and no change in divergent thinking compared to the placebo. This absence of statistically significant effects may be due to the timing of the creativity task, which was scheduled six hours after drug administration, when the subjective effects had declined substantially.

While the present study confirmed the hypothesis that 4-FA would induce a psychedelic state that can be categorized in between that produced by amphetamine and MDMA, the hypothesized effect on divergent creative thinking was not confirmed. Although not statistically significant, convergent thinking increased six hours after intake, while divergent thinking performance was placebo-like. This pattern is the opposite of that demonstrated for ayahuasca. Two hours after intake of ayahuasca, convergent thinking decreased by 15% compared to baseline and divergent thinking increased by approximately 20% (Kuypers et al. 2016). To confirm the absence or presence of 4-FA effects on creative thinking, future research needs to include creative performance tests at different time points in the serum curve in a larger sample. In addition, creative thinking should then also be assessed in proximity to the peak of dissociative effects to test whether both are associated, as suggested by previous studies linking dissociative states and creativity (van Heugten–van der Kloet et al. 2015). Furthermore, while previous research with dopaminergic substances such as the amphetamine Adderall and methylphenidate has demonstrated that baseline performance and personality play a role in the effects of these substances on creativity (Farah et al. 2009; Gvirts et al. 2017), future research will have to take this into account when studying the effects of 4-FA on cognitive performance .

It is concluded that while the 4-FA-induced psychedelic state is mild in intensity and in between that of amphetamine and MDMA as hypothesized, more research is needed to indicate whether 4-FA can change creative thinking.

Acknowledgments

The authors would like to thank Cees van Leeuwen and Lizzy Vuurman for medical supervision; Johannes Reckweg, Lukas Basedow, Drew Puxty, and Ignas Oppewal for helping with data acquisition; and the DSMB members (Wim Riedel, Therese van Amelsvoort, Jan Schepers, and Robbert-Jan Verkes) for evaluating the data and providing advice.

Additional information

Funding

This work was supported by the European Commission (Grant number: HOME/2014/JDRF/AG/DRUG/7082, Predicting Risk of Emerging Drugs with In Silico and Clinical Toxicology (PREDICT)).