Rationale Classical psychedelics, including psilocybin and lysergic acid diethylamide (LSD), are under investigation as potential therapeutic agents in psychiatry. Whereas most studies utilize relatively high doses, there are also reports of beneficial effects of "microdosing," or repeated use of very low doses of these drugs. The behavioral and neural effects of these low doses are not fully understood. Objectives To examine the effects of LSD (13 μg and 26 μg) versus placebo on resting-state electroencephalography (EEG) and event-related potential (ERP) responses in healthy adults. Methods Twenty-two healthy men and women, 18 to 35 years old, participated in 3 EEG sessions in which they received placebo or LSD (13 μg and 26 μg) under double-blind conditions. During each session, participants completed drug effect and mood questionnaires at hourly intervals, and physiological measures were recorded. During expected peak drug effect, EEG recordings were obtained, including resting-state neural oscillations in scalp electrodes over default mode network (DMN) regions and P300, N170, and P100 ERPs evoked during a visual oddball paradigm. Results LSD dose-dependently reduced oscillatory power across delta, theta, alpha, beta, and gamma frequency bands during both eyes closed and eyes open resting conditions. During the oddball task, LSD dose-dependently reduced ERP amplitudes for P300 and N170 components and increased P100 latency. LSD also produced dose-related increases in positive mood, elation, energy, and anxiety and increased heart rate and blood pressure. On a measure of altered states of consciousness, LSD dose-dependently increased Blissful State, but not other indices of perceptual or sensory effects typical of psychedelic drugs. The subjective effects of the drug were not correlated with the EEG measures. Conclusions Low doses of LSD produced broadband cortical desynchronization over the DMN during resting state and reduced P300 and N170 amplitudes, patterns similar to those reported with higher doses of psychedelics. Notably, these neurophysiological effects raise the possibility that very low doses of LSD may produce subtle behavioral and perhaps therapeutic effects that do not rely on the full psychedelic experience.

Methamphetamine (MA) abuse remains an urgent public health problem. Understanding how the drug affects brain function will help to identify how it leads to abuse and dependence. Previous studies indicate that MA and other stimulants have complex effects on resting state functional connectivity. Here, we used a hypothesis-free approach to examine the acute effects of MA (20 mg oral) versus placebo on neural connectivity in healthy adults. Using networks identified by an independent component analysis with placebo data, we examined the effects of MA on connectivity within and between resting state networks. The drug did not significantly alter connectivity within networks. MA did alter connectivity between some networks: it increased connectivity between both the thalamus and cerebellum to sensorimotor and middle temporal gyrus. However, MA decreased connectivity between sensorimotor and middle temporal gyrus networks. MA produced its expected subjective effects, but these were not significantly related to connectivity. The findings extend our knowledge of how MA affects connectivity, by reporting that it affects between-network connectivity but not within-network connectivity. Future studies with other behavioral measures may reveal relationships between the neural and behavioral actions of the drug.