New Psychedelic Entactogens: Designer Drugs Produce Designer Effects

Entactogens Explained: History, Phenomenology, and Development as Medicines

Entactogens, sometimes called empathogens, are a class of drugs that increase empathy, reactivity to social emotions, create a sense of openness and euphoria, and produce a range of perceptual effects.^1-3 Though somewhat similar to the subjective effects from psychedelics and amphetamines, the alterations in sensation, emotion, and social cognition associated with use of entactogens is unique.^1-4 The prototypical entactogen is 3,4-methylenedioxymethamphetamine (MDMA), with a long history as a research chemical, most notorious reputation as a recreational drug, and the clearest and closest case for potential medical use today.^1-6

MDMA-assisted psychotherapy for people with post-traumatic stress disorder (PTSD) is in advanced, Phase 3 clinical trials.^6-9 These trials, sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), demonstrate that MDMA-assisted therapy profoundly improves PTSD symptoms in this clinical population, which classically does not respond well to traditional pharmacotherapies.^1,6-9 Indeed, about ⅔ of PTSD patients were deemed to have lost their diagnosis after 3 MDMA-assisted therapy sessions.^1,6-9 MAPS anticipates FDA approval of MDMA-assisted psychotherapy for treatment of PTSD within a year or two.^1,6,9

Although these therapeutic effects of MDMA are promising, adverse effects related to cardiovascular function in certain high-risk populations remains a concern, as do some (conflicting and likely exaggerated) reports about neurotoxicity of MDMA after repeated doses.^1,4,10-13 Drug sponsors like MAPS that are responsible for overseeing the clinical trials for MDMA-assisted psychotherapy have also yet to adequately respond to recent, serious allegations of ethical and clinical misconduct. These violations pertain to appropriate boundaries between clinicians and subjects during MDMA-assisted therapy sessions, and are especially concerning because MDMA engenders a state of increased suggestibility and vulnerability in subjects that may facilitate the risk as well as increase the damage it does to patients.^14,15

Further, the current designation of MDMA as a Schedule I compound limits the ability for researchers to study its mechanism of action or therapeutic effects, in either clinical populations or preclinical animal models.^1,6  Thus, there is a need to synthesize and profile compounds with similar structures to MDMA in order to determine if they are suitable for preclinical research on entactogens.^1,16,17 Designer entactogens could theoretically be tweaked or tailored to produce new types of effects on molecular targets or reduce unwanted side-effects in the rest of the body.^1,16,17 Moreover, unscheduled, rationally-designed analogs of MDMA may also help establish new indications for entactogenic drugs in psychiatry.^1,16,17

Sulfur, So Good: Rationale and Approach for Investigating APBTs

Although there are now many analogs of MDMA with plausible entactogenic effects under investigation, a family of compounds called (2-aminopropyl)benzofurans (APBs) is among the newest of these.^1,16,17 Studies of APBs and earlier forerunners like (2-aminopropyl)indoles (APIs) indicated that they demonstrate entactogenic effects but may not have addressed concerns about whether or not these new drugs have lower abuse potential or are more effective and safe than MDMA.^1-6,16,17

An even newer group of compounds based on the APB scaffold modified with sulfur instead of oxygen on one of its rings has recently been synthesized, known as  (2-Aminopropyl)benzo[β]thiophene (APBTs) (Figure 1).^1,16-18 Until recently, APBTs had not been screened for pharmacological targets, mechanism of action, or physiological and behavioral effects in animals.^1,16-18 In the present study, Rudin and colleagues set out to characterize the pharmacological profile and behavioral effects of APBTs in mice, using biochemical techniques and mouse behavioral models to establish the various drug effects and responses to different doses.¹⁸

Figure 1. Chemical structures of MDMA (blue), the parent entactogen compound used as a template, and 5-substituted isomers of APB (green) and APBT (brown). Asterisks denote chemical substitutions in designer MDMA analogs. Adapted from Rudin et al. 2021 by Daniel Lustberg.¹⁸

Summary and Integration of Major Findings

1. Like MDMA and earlier entactogen analogs (APIs, APBs), new APBTs are reuptake inhibitors and releasing agents for the monoamine neurotransmitters serotonin (5-HT), dopamine (DA), and norepinephrine (NE) through actions on monoamine transporters.^1,5,18
2. Similar to psychedelics, APBTs are potent agonists of 5-HT₂ receptors and induce head-twitch responses in mice, suggesting they would elicit  “hallucinogenic” effects in people.^18,19
3. Unlike MDMA, APBs, or stimulants, APBTs do not increase motor activity in a familiar cage. In addition, APBTs do not cause obvious behavioral abnormalities across a range of doses.^18,20
4. Like APB parent compounds, high doses of APBTs were associated with profound decreases in body temperature in mice not observed for MDMA. Interestingly, psychedelics produce mixed effects on body temperature while MDMA more reliably increases it.^1-5,18-20

Entactogens Enhanced: Future Directions for Research and Medicine

Rudin and colleagues demonstrated that several structural analogs of the novel APBT family have similar pharmacological and behavioral profiles to both entactogens (like MDMA) and psychedelics (like psilocybin).¹⁸ Further, despite appreciable effects on the release of the neurotransmitters NE and DA, APBTs differ from MDMA and stimulants in their absence of increased motor activity.^18,20 Because classical stimulants (e.g., amphetamine, cocaine) and MDMA increase locomotion and are rewarding in animal models, it is possible that the unique “entactodelic” pharmacology of APBTs reduces abuse potential, as other classical psychedelics do not show high abuse potential.^1,6,18,20 Although the arrival of a new drug class with simultaneous qualities of entactogens and psychedelics is certainly exciting and further preclinical studies on behavioral effects of these compounds are warranted, caution should also be employed on the toxicity side of drug development. APBs and APBTs produced appreciable loss of body temperature, which could be explained by restriction of blood vessels or dysregulation of central temperature homeostatic centers in the brain.^18,19 Thus, it is still not yet clear if APBTs would be any safer than MDMA, nor less or more effective at achieving therapeutic effects in clinical populations of psychiatric disease and associated animal models.

Daniel Lustberg, PhD

Danny Lustberg received his PhD in Molecular & Systems Pharmacology from Emory University in 2022. He is currently a postdoctoral researcher at Emory University, studying the role of the central noradrenergic system in stress-related psychiatric diseases, including anxiety disorders and OCD.

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