Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics

Classic or serotonergic psychedelics (for example, psilocybin, LSD, mescaline, and the DMT-containing brew ayahuasca) produce profound alterations of perception, cognition and affect and have been used in ritual contexts for centuries. Although the pharmacology of individual compounds varies, these agents commonly act at serotonin 5HT2A receptors and can induce experiences ranging from enhanced imagery and introspection to mystical-type states. Interest in their clinical potential has resurged after decades of restricted research, with accumulating evidence suggesting therapeutic effects in depression and some substance-use disorders. Tófoli and colleagues set out to (1) review EEG, MEG, PET, SPECT and fMRI studies that have investigated the acute brain effects of classic psychedelics in humans, and (2) discuss the emerging evidence for their use as adjunctive treatments for addiction. The chapter emphasises findings from human neurophysiology and neuroimaging and considers possible neurobiological mechanisms that might underlie clinical effects.

The extracted text presents a narrative review of human EEG and brain‑imaging studies of classic psychedelics and of clinical and observational reports concerning therapeutic use for psychiatric and addictive disorders. No explicit, reproducible literature search strategy, inclusion/exclusion criteria, or formal systematic review methods are reported in the extracted text; the chapter instead synthesises representative EEG, PET, SPECT and fMRI studies alongside clinical and preclinical findings. Where available, the authors describe key experimental designs from primary studies (for example, double‑blind, placebo‑controlled crossover administrations of freeze‑dried ayahuasca or single‑dose psilocybin PET/fMRI experiments), and they report sample characteristics such as volunteer numbers, prior psychedelic experience, dosing regimens and timing of neurophysiological or imaging assessments. The review therefore combines results from controlled laboratory experiments, open‑label clinical reports, observational surveys of ritual users, animal models and early clinical trials to draw inferences about brain effects and potential therapeutic mechanisms.

Across modalities, a number of recurrent neurophysiological and neuroimaging findings are reported, although the literature remains patchy and sometimes inconsistent. EEG studies commonly show broad reductions in spectral power, particularly in the alpha and theta bands, and increases in peak frequency; some studies also report increased gamma activity. SPECT and PET investigations frequently observe increased cerebral blood flow (CBF) or glucose metabolism in brain regions involved in emotional processing, notably the anterior cingulate cortex (ACC) and insula. Functional MRI work often finds reduced activity and connectivity within hubs of the default mode network (DMN), particularly the posterior cingulate cortex (PCC)/precuneus, and pronounced effects on visual cortices and visual connectivity. Ayahuasca: Early ritual EEG studies in Santo Daime users (n = 11) found increased gamma power in left occipital‑temporal‑parietal electrodes with eyes closed; another EEG report in 12 experienced users showed increases in alpha and theta power predominately in occipital sites. In a double‑blind, placebo‑controlled crossover with encapsulated freeze‑dried ayahuasca (18 experienced volunteers), absolute EEG power decreased across bands (most prominently theta) whereas beta power increased; effects began 15–30 minutes after ingestion, peaked between 45 and 120 minutes, and returned to baseline by 4–6 hours. LORETA analyses after a high dose localized band power decreases to temporo‑parieto‑occipital junction and temporomedial/frontomedial regions. Polysomnography in a randomised crossover trial (22 healthy males) comparing ayahuasca (equivalent 1 mg/kg DMT) and D‑amphetamine found that ayahuasca did not subjectively impair sleep, both drugs reduced REM duration, but ayahuasca increased slow‑wave sleep power while amphetamine decreased it. An uncontrolled EEG study of 20 experienced users who ingested ayahuasca in natura reported a biphasic pattern: alpha power reduction at about 50 minutes and increases in slow and fast gamma at 75 and 125 minutes, with regional localisation predominantly left parieto‑occipital and frontotemporal; these EEG changes correlated with serum levels of DMT and β‑carbolines. A placebo‑controlled SPECT study (n = 15) scanned ~100–110 minutes post‑dose and showed increased CBF bilaterally in anterior insula, right ACC/frontomedial cortex and left amygdala/parahippocampal gyrus. fMRI work in ritual members reported increased activity in primary and higher visual cortices and parahippocampal and fusiform regions; other fMRI studies described decreased DMN activity and reduced functional connectivity between PCC/precuneus and other regions. Psilocybin: FDG‑PET studies (n ≈ 10) after oral psilocybin (15–20 mg) reported a global MRglu increase (~25%), most pronounced in frontomedial/ frontolateral cortices, ACC and temporomedial regions, with smaller increases in basal ganglia and sensorimotor/occipital cortices; frontal MRglu increases correlated with “psychotic‑like” symptoms in one study. EEG/MEG work found decreased parieto‑occipital alpha power and reductions in 1.5–20 Hz power within a network including anterior/posterior cingulate and parahippocampal regions; intensity of spiritual experience correlated with delta phase‑lagged synchronisation across retrosplenial, parahippocampal and lateral orbitofrontal sites. Intravenous psilocybin (2 mg) fMRI paradigms showed increased visual cortex activity and enhanced vividness of autobiographical memory imagery, with subsequent subjective well‑being correlating with imagery vividness. Arterial spin labelling studies linked decreased ACC/mPFC perfusion to subjective intensity and reported reduced mPFC–PCC coupling. Connectivity analyses indicate a general increase in global connectivity during the psychedelic state, characterised by many transient, low‑stability patterns and some novel persistent structures; compared with MDMA, psilocybin tends to increase between‑network resting‑state connectivity and to reduce differentiation between networks. Emotional‑processing studies reported attenuated amygdala reactivity to negative stimuli after psilocybin, with the degree of attenuation correlating with improved mood. Mescaline and LSD: A SPECT study of 12 males given 500 mg mescaline showed a hyperfrontality pattern 4.5 hours post‑dose, correlated with psychotomimetic symptoms. Early EEG LSD studies described decreased broadband power and increased peak frequencies, particularly frontal. More recent LSD imaging work reports increased visual cortex CBF, decreased visual cortex alpha power, expanded primary visual cortex functional connectivity and reductions in DMN connectivity. Therapeutic and observational findings: Historical clinical literature and contemporary studies suggest potential antidepressant and antiaddictive effects. An open‑label SPECT study in 17 patients with recurrent depression reported significant HAM‑D and MADRS reductions at 80 minutes after ayahuasca intake, sustained for 21 days; SPECT 8 hours post‑dose showed increased CBF in left nucleus accumbens, right insula and left subgenual area. In an open‑label trial of psilocybin for treatment‑resistant depression (n = 12), depressive symptoms were significantly reduced at 1 week and effects persisted at 3 months after a high dose. Early meta‑analysis of LSD trials suggested benefit for alcohol‑use disorders. Observational data from ritual ayahuasca users (Project Hoasca and larger surveys) are reported as showing lower rates of addiction and reduced drug abuse in members versus general population samples. Small workshops and preclinical models report reductions in addiction‑like behaviours, and an open‑label psilocybin study showed decreased drinking and 80% tobacco abstinence at 6 months in participating subjects.

The authors interpret convergent findings across EEG, PET/SPECT and fMRI as indicating that classic psychedelics produce reproducible changes in brain dynamics: broad reductions in spectral power (notably alpha and theta), increases in certain higher‑frequency bands, increased perfusion/metabolism in emotion‑related regions (ACC, insula) and decreased activity or connectivity in DMN hubs such as the PCC/precuneus. They emphasise strong and consistent effects on visual cortex function and connectivity and note that changes in network differentiation and transient increases in global connectivity may characterise the psychedelic state. Tófoli and colleagues situate these neural effects within therapeutic contexts, arguing that observed changes—particularly DMN modulation, influences on regions implicated in affect and interoception, and rapid increases in markers such as BDNF—provide plausible mechanisms for antidepressant and antiaddictive effects. They caution, however, that the relationship between DMN effects and addiction is complex: whereas alcohol dependence has been linked to DMN hyperconnectivity, many addictive drugs show reduced DMN connectivity, so simple models are premature. Molecularly, the chapter highlights evidence that psychedelics may upregulate BDNF and can modulate dopamine systems indirectly via serotonergic mechanisms; DMT’s action at sigma‑1 receptors is noted as another potentially relevant pathway. Key limitations acknowledged by the authors include gaps and contradictions in the literature, limited standardisation of substance preparations and dosing (notably for complex brews such as ayahuasca), small sample sizes, a mixture of controlled and open‑label designs, and difficulty dissociating direct pharmacological brain effects from psychological or contextual factors. They also point out the need to better characterise visual phenomena (true hallucinations versus imagery facilitation) and to refine understanding of which aspects of neurophysiological change are therapeutically relevant. Implications discussed include the need for more rigorous, controlled imaging and electrophysiology studies, careful study of clinical populations (for example, alcohol‑dependent patients), and consideration of how ritual, spiritual and psychotherapeutic contexts interact with neurobiological effects to produce lasting clinical benefit.