Research with psychedelic drugs is at an all-time high. A recent (09 Feb 2024) PubMed query for “psychedelic OR hallucinogen” returned a total of 35,619 hits since 1946, with almost 30% of those manuscripts (10,251) published in just the last 10 years. The therapeutic potential of these agents is actively being explored in numerous clinical trials, and a better understanding of the mechanisms underlying these effects is a major research goal. Structurally and pharmacologically distinct from the classic phenethylamine- and tryptamine-based psychedelics, 3,4-methylenedioxymethamphetamine (MDMA) is a ring-substituted amphetamine analog which elicits some psychedelic-like effects, some psychostimulant-like effects, and some novel effects which are not typically induced by drugs from either of those classes — the most salient of which is MDMA’s capacity to provoke feelings of emotional closeness and empathy (Kaur et al., 2023). However, there are also treatment-limiting effects of MDMA, including significant abuse liability, cardiovascular effects, potential hyperthermia and central serotonergic dysfunction, and a metabolic profile which makes MDMA a likely instigator of problematic drug–drug interactions (Kaur et al., 2023). The development of novel MDMA-like drugs with reduced capacities to produce these adverse effects would be a major advancement.

Toward this end, Johnson and colleagues (Johnson et al., 2024) determined whether a pair of aminoalkyl benzofurans, which are positional isomers of each other, display MDMA-like interactions with monoamine transporters in vitro and elicit MDMA-like interoceptive effects in vivo. This work thus represents an elegant melding of molecular pharmacology and behavioral pharmacology, conducted by some of the best in the business in both disciplines. The specific drugs were 5-(2-methylaminobutyl)benzofuran (5-MABB) and 6-(2-methylaminobutyl)benzofuran (6-MABB), both of which are chiral molecules with some structural similarity to MDMA. In vitro, the R and S enantiomers of 5-MABB and 6-MABB are fully effective at inhibiting monoamine uptake at dopamine transporter (DAT), norepinephrine transporter, and serotonin transporter (SERT). While the S isomers of both benzofurans exhibit the MDMA-like profile of substrate release through all three monoamine transporters, the R enantiomers exhibit a hybrid profile of reduced substrate activity at norepinephrine transporter and DAT, but full capacities to stimulate release through SERT. In vivo, the enantiomers of both benzofurans fully substituted for MDMA in a drug discrimination assay, suggesting that these drugs “feel like” MDMA — at least to rats. These studies thus position the benzofuran scaffold as a promising structure for drug development efforts aimed at preserving therapeutic effects of MDMA while reducing adverse, treatment-limiting effects.

There are several strengths to the paper, the biggest of which is the use of the R and S enantiomers of each benzofuran to determine potential stereoselective effects. Stereochemistry for phenethylamines is well established, with S enantiomers of psychostimulant-like amphetamines typically being much more potent than their R enantiomers, and with R enantiomers of psychedelic-like compounds typically being much more potent than their S enantiomers (Shulgin, 1973; Glennon et al., 1984). However, for MDMA and related drugs, both the R and S enantiomers are active at similar doses, but possess distinct pharmacological effects (Nichols, 1986; Fantegrossi et al., 2005; Fantegrossi, 2008). As such, any evaluation of novel MDMA-like drugs would be incomplete without an assessment of the component stereoisomers.

The concurrent use of in vitro and in vivo methods to evaluate the effects of the benzofurans is a powerful approach, allowing for mechanistic interpretations of behavioral results. There is a strong correlation between discriminative stimulus effects of drugs in nonverbal species and subjective effects reported by humans (Schuster and Johanson, 1988; Brauer et al., 1997), so the fact that the benzofurans fully substitute for MDMA in the present studies implies that these drugs would “feel like” MDMA in humans as well. In the monoamine transporter interaction studies, the benzofuran enantiomers were assessed for their capacities to not only bind these reuptake proteins, but also to stimulate substrate release. This moves the field forward by extending structure–activity relationships for amphetamines and cathinones (Biel and Bopp, 1978; Fuller, 1978; Nichols, 1994; Glennon and Dukat, 2017; Gannon et al., 2018a; Fitzgerald et al., 2024) to the structurally-related benzofurans. Previous reports of MDMA-like neurochemical and behavioral effects of other benzofurans are available (Dolan et al., 2017; Shimshoni et al., 2017; Brandt et al., 2020; Hill et al., 2023; Shaw et al., 2024), and the present data add to a growing body of work characterizing the in vivo pharmacology of this interesting drug class.

Like all scientific publications, there are some areas of this paper where further experiments could shed more light onto the present results. Comparing the component benzofuran enantiomers to racemic MDMA adds a layer of complexity to data interpretation because differences in receptor and monoamine transporter interactions between R-MDMA and S-MDMA have long been known to exist (Battaglia and De Souza, 1989), and because distinct subjective effects of the MDMA isomers have been reported even before their binding profiles were established (Anderson et al., 1978). Numerous studies have found that S-MDMA is better than R-MDMA both at blocking uptake and at stimulating release at the DAT (Johnson et al., 1986; Setola et al., 2003; Fantegrossi, 2008; Huot et al., 2011; Pitts et al., 2018). Consistent with this, administration of S-MDMA significantly increases DA concentrations in striatal dialysate in rhesus monkeys, while R-MDMA does not (Murnane et al., 2010). In mice, the interoceptive effects of S-MDMA are more stimulant-like, while the interoceptive effects of R-MDMA are more psychedelic-like (Murnane et al., 2009), but the discriminative effects of the MDMA enantiomers are qualitatively similar to one another in the rat (Baker et al., 1995). In future studies, comparing the component enantiomers of 5-MABB and 6-MABB to R-MDMA and S-MDMA in vitro and in vivo — as well as studying racemic mixtures of the benzofurans — may allow for a better understanding of the pharmacological similarities and differences among these interesting agents.

There are several references to potency differences between the R and S enantiomers of the presently studied benzofurans, but for the in vivo studies, the estimated ED50 values for the 5-MABB and 6-MABB enantiomers do not appear to be significantly different from one another. In the case of 5-MABB, the confidence intervals for the potency estimates for the R and S enantiomers overlap, suggesting that the 5-MABB enantiomers have comparable potency to substitute for the MDMA training dose. For 6-MABB, the nonlinear regression model used could not capture a lower limit of the ED50 confidence interval for the S enantiomer because the smallest tested dose elicited too much responding on the MDMA lever. It may be the case that the 6-MABB enantiomers do indeed exhibit different potencies to substitute for MDMA, but the present data are insufficient to answer this question. Further drug discrimination studies utilizing a wider range of substitution doses would be informative.

The authors rightly point out that future “assessments of locomotor activity and drug self-administration [of the benzofurans] would be valuable.” In vitro, the R and S enantiomers of 5-MABB and of 6-MABB are more potent than MDMA at inhibiting uptake at DAT. This is significant because DAT inhibition is a critical mediator of locomotor effects (Cline et al., 1992; Izenwasser et al., 1994) and of reinforcing effects (Ritz et al., 1988) among cocaine-like psychostimulants. Moreover, the presently reported DAT/SERT ratios for the enantiomers of 5-MABB and of 6-MABB are either similar to that of MDMA, or biased in favor of DAT inhibition. Selectivity for DAT over SERT is associated with greater reinforcing effectiveness in drug self-administration studies (Roberts et al., 1999; Lile et al., 2003; Wee et al., 2005; Gannon et al., 2018a), suggesting that both enantiomers of 6-MABB would likely maintain contingent responding, with the R enantiomer (the most DAT-biased of the four drugs) potentially exhibiting strong reinforcing effects. However, reinforcing effects of MDMA itself are marginal and highly variable in rodents as compared with other amphetamine analogs (De La Garza et al., 2007; Schenk, 2009), so any conclusion about the capacity of a substance to support contingent responding based solely on an MDMA-like profile of monoamine transporter interaction would not be especially compelling. The finding that the S isomers of the benzofurans are fully effective releasers at all three monoamine transporters, while the R isomers are only effective 5-HT releasers is interesting, but it is again unclear how this might translate to psychostimulant-like abuse liability. It is important to note that a previous report with pentylone — a synthetic cathinone analog with structural similarities to MDMA – showed that it was the most robustly self-administered compound in the series studied despite being the weakest compound in terms of its capacity to release dopamine (Dolan et al., 2018). It is also concerning that methylone — another synthetic cathinone analog with structural similarities to MDMA, which exhibits a strong capacity to provoke 5-HT release through the SERT (Baumann et al., 2013; Eshleman et al., 2013; Simmler et al., 2013) — elicits significant toxicity and lethality when it is self-administered by rats (Gannon et al., 2018b, 2019).

It will be critical to evaluate the safety profile of novel MDMA-like drugs as they advance toward therapeutic use, and based on the present data this is certainly the case for 5-MABB and 6-MABB. Indeed, illicit use of novel “benzo furies” (get the title now?) is associated with significant toxicity, including death (King and Corkery, 2018; Roque Bravo et al., 2019; Theofel et al., 2021). Nevertheless, better treatments for intractable neuropsychological conditions ranging from post-traumatic stress disorder to depression to social anxiety are needed, and the unique pharmacology of MDMA-like drugs appears to offer viable therapeutic options. Studies like this one pave the way for further drug development efforts and showcase the utility of interdisciplinary pharmacology as a translational science with real-world clinical relevance.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Fantegrossi, Gannon.

FootnotesReceived February 14, 2024.Accepted March 20, 2024.

W.E.F. receives research funds and salary support from a contract between PharmAla Biotech and UAMS. PharmAla is a for-profit company working to develop novel MDMA-like therapeutics. PharmAla did not participate in the writing of this Viewpoint, or in the decision to submit it for publication.

dx.doi.org/10.1124/jpet.124.002183.

AbbreviationsDATdopamine transporter5-MABB5-(2-methylaminobutyl)benzofuranMDMA3, 4-methylenedioxymethamphetamine6-MABB6-(2-methylaminobutyl)benzofuranSERTserotonin transporterCopyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics