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 polydrug 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.

The use patterns of novel psychedelics: experiential fingerprints of substituted phenethylamines, tryptamines and lysergamides

“…The nature of these subscales is described in the supplementary materials. The 5D-ASC has been validated using a range of hallucinogens, entactogens, stimulants and non-pharmacological altered states of consciousness (Liechti et al 2017 ; Mueller et al 2018 ; Kuypers et al 2019 ; Luke et al 2019 ; Holze et al 2020 ; Mason et al 2020 ; Uthaug et al 2021 ).…”

Designer drugs: a medicinal chemistry perspective (II)

“…Moreover, substitution at the 4‐position prevents P450 oxidase metabolism to afford the corresponding 4‐hydroxyamphetamine, which has been hypothesized to be aversive to the intake of stimulants, 49 thereby affecting the user's experience. Evaluation of 4‐fluoroamphetamine ( B26 ) in rodents has shown it to fully substitute for the discriminative effects of MDMA and amphetamine 50 consistent with a clinical study that has concluded that B26 induces a mild psychedelic state that lies between these caused by MDMA and amphetamine 51 . Suppressed ambulation was reported to result from administration of B26 50 but, in a separate study, B26 was found to enhance forward motion, but not as significantly as the isomeric 3‐fluoroamphetamine ( B25 ) 52 …”

Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy

“…Furthermore, 4-FA was also a partial agonist at postsynaptic 5-HT receptors, which could help explain its entactogenic effects ( Rickli et al, 2015 ). The entactogenic effects of 4-FA lie somewhere between the effects of MDMA and dextroamphetamine ( Kuypers et al, 2019 ), which indicates that 4-FA is less entactogenic than MDMA, although users still report a significant increase in empathy and desire to engage in conversation while under the influence of 4-FA. Indeed, some users even prefer 4-FA as an entactogen over MDMA, due to its being far more ‘clear-headed’ than the latter.…”

“…To date, 4-FA has not been compared with MDMA in any drug discrimination paradigms in animals, although one study found that 4-FA substituted for dextroamphetamine in rats, but failed to substitute for MBDB and the highly selective 5-HT releasing agent MMAI ( Marona-Lewicka et al, 1995 ). Fortunately, a recent clinical study has been conducted with human volunteers who were given 4-FA, providing the direct opportunity to learn if 4-FA produces MDMA’s qualitative effects in humans ( De Sousa Fernandes Perna et al, 2018 ; Dolder et al, 2018b ; Kuypers et al, 2018b , 2019 ). Additionally, in 2012, the Drug Information and Monitoring System conducted a survey of drug-users who had consumed street tablets that they believed to contain only MDMA, but which in reality contained a variety of psychoactive substances ( Brunt et al, 2012 ).…”

“…In a double-blind placebo controlled study, 4-FA was found to greatly enhance feelings of ‘friendliness’ ( De Sousa Fernandes Perna et al, 2018 ) which one would expect from an entactogen or psychostimulant ( Bershad et al, 2016 ). The same volunteers completed questionnaires that were interpreted by the administrators as showing that 4-FA produces a mild psychedelic state ( Kuypers et al, 2019 ), albeit substantially milder than psychedelics such as LSD or dimethyltryptamine. The conclusion reached by these authors was that the effects of 4-FA lie between those of dextroamphetamine and MDMA, which would indicate that the term psychedelic may be somewhat inaccurate in describing the qualitative effects of 4-FA.…”