The Ups and Downs of 3,4-Methylenedioxymethamphetamine: Linking Subjective Effects to Spontaneous Brain Function.

Psychoactive drugs, especially drugs with so-called psyche-delic properties, exert profound effects on sensory perception,cognition, and emotion by modulating target neurotransmittersystems. The compound 3,4-methylenedioxymethampheta-mine (MDMA) exerts stimulant and psychedelic effects throughits actions on dopamine, norepinephrine, and serotonin(5-hydroxytryptamine, [5-HT]) transporters, by inhibiting theirreuptake and stimulating their release. In addition to producingeuphoria and positive mood, MDMA appears to produceunique “prosocial” or “empathogenic” feelings. These effectsdistinguish MDMA from other stimulant and hallucinogenicdrugs and are believed to be driven by its greater action at the5-HT transporter. In humans, our understanding of thesesubjective and interoceptive effects has relied mainly onreports from users and a few controlled laboratory studies.A fundamental question—where and how MDMA and otherpsychedelic drugs exert their effects in the human brain—remains largely unanswered.In this issue of Biological Psychiatry, Carhart-Harris et al.(1)address this knowledge gap by employing two modes offunctional magnetic resonance imaging (fMRI), arterial spinlabeling to measure cerebral blood ﬂow (CBF) and resting-state functional connectivity (RSFC) to measure region-to-region coupling of spontaneous activity after a single dose ofMDMA or placebo in a double-blind, balanced-order design inhealthy experienced users. Behaviorally, MDMA induced“intense” and positive mood effects. For RSFC analyses, theauthors used a seed-based approach to examine brain con-nectivity with the ventromedial prefrontal cortex (PFC), hippo-campus, and amygdala as representative paralimbic/limbicnodes of socioemotional functioning. The CBF in the medialtemporal lobe, thalamus, inferior visual cortex, and somato-sensory cortex was decreased by MDMA. It also increasedRSFC between amygdala and hippocampus and decreasedRSFC between midline cortical regions, medial PFC, andmedial temporal lobe. It decreased RSFC between ventrome-dial PFC and posterior cingulate cortex and between medialPFC and hippocampus. These neural effects of MDMA wererelated to self-reports: subjective intensity of drug effects wascorrelated with a reduction in hippocampus and amygdalaCBF, and drug intensity and positive mood were correlated attrend level with RSFC within the ventromedial PFC, hippo-campus, and amygdala network.By examining MDMA effects on brain function in relation toits behavioral effects, this study takes an important step,adding valuable mechanistic insight into where in the brainMDMA exerts its potent psychoactive effects. This studycritically begins to provide a brain-based framework (perfusionand connectivity) to help explain the unique prosocial orempathogenic effects of MDMA. The ﬁndings may help us tounderstand its appeal in nonmedical contexts as well as itspotential use as an adjunct to psychotherapy. The studyhighlights some scientiﬁc challenges for pharmacoimagingstudies more generally and points to important and muchneeded avenues for future research. We note some key issuesin methods and interpretation and future directions raised byCarhart-Harris et al. First, how can we relate the mood andneural (fMRI) effects of drugs to their underlying neurochemicalmechanisms of action? Second, can we advance our under-standing of the neural targets of drug action by comparingMDMA with the psychedelic, prosocial, and mood-elevatingeffects of other psychoactive drugs? Third, how do the acuteeffects of drugs on mood and brain function relate to theireffects on sensory, cognitive, emotional, and social function?Task-dependent and task-independent (i.e., resting state)fMRI scans provide important data about regional and circuit-wide CBF and functional activation and connectivity. However,fMRI provides no direct information about the neurochemicalmechanisms that underlie these changes. Carhart-Harris et al.use existing knowledge of the predominant pharmacologicmechanism of action of MDMA on 5-HT transporters, regionaldistribution of 5-HT receptor systems in the brain, and priorevidence of serotoninergic effects on brain function andsubjective effects to attribute the CBF and RSFC brainchanges by MDMA to 5-HT actions. However, MDMA alsodirectly and indirectly acts on other monoamines, which couldcontribute to the observed effects. Novel approaches areneeded to link brain function changes to modulation ofspeciﬁc neurotransmitters to identify the receptor and mole-cular mechanisms that underlie the effects of a drug. Thisissue applies broadly to pharmacologic challenge studies thatuse fMRI techniques to investigate brain and behavior. Studiesincorporating in vivo and dynamic measures of endogenouslevels or release of neurotransmitters at the synapse (e.g.,positron emission tomography with arterial spin labeling orRSFC fMRI (2)) will address these knowledge gaps as tech-nological and conceptual advances in this emerging area tiethe magnetic resonance imaging–based measures to speciﬁcneurotransmitter function.On a related note, advances in neuroimaging analysespermit the study of drug effects on brain function at thenetwork, rather than regional, level (3). These new approaches