These results provide further evidence that use of ecstasy may be associated with impairment of memory and of serotonergic function. These findings are compatible with neurotoxicity of ecstasy as shown in animals.

The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that D9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D 2 /D 3 receptor tracer [ 11 C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [11 C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

MDMA (3,4-methylenedioxymethamphetamine or "ecstasy") is a recreationally used drug with remarkable and characteristic prosocial effects. In spite of abundant attention in the scientific literature, the mechanism of its prosocial effects has not been elucidated in humans. Recently, research in animals has suggested that the neuropeptide oxytocin may induce these effects. In a double blind, randomized, crossover, and placebo-controlled study in 15 healthy volunteers we assessed blood oxytocin and MDMA concentrations and subjective prosocial effects after oral administration of 100 mg MDMA or placebo. MDMA induced a robust increase of blood oxytocin concentrations and an increase of subjective prosocial feelings. Within subjects, the variations in these feelings were significantly and positively correlated with variation in oxytocin levels, and the correlations between these feelings and oxytocin were significantly stronger than those between these feelings and blood MDMA levels. MDMA induces oxytocin release in humans, which may be involved in the characteristic prosocial effects of ecstasy.

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose-response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose ( r 2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.

Maladaptive dopaminergic mediation of reward processing in humans is thought to underlie multiple neuropsychiatric disorders, including addiction, Parkinson's disease, and schizophrenia. Mechanisms responsible for the development of such disorders may depend on individual differences in neural signaling within large-scale cortico-subcortical circuitry. Using a combination of functional neuroimaging and pharmacological challenges in healthy volunteers, we identified opposing dopamine agonistic and antagonistic neuromodulatory effects on distributed functional interactions between specific subcortical regions and corresponding neocortical "resting-state" networks, known to be involved in distinct aspects of cognition and reward processing. We found that, relative to a placebo, levodopa and haloperidol challenges, respectively, increased or decreased the functional connectivity between (1) the midbrain and a "default mode" network, (2) the right caudate and a right-lateralized frontoparietal network, and (3) the ventral striatum and a fronto-insular network. Further, we found drug-specific associations between brain circuitry reactivity to dopamine modulation and individual differences in trait impulsivity, revealing dissociable drug-personality interaction effects across distinct dopamine-dependent cortico-subcortical networks. Our findings identify possible systems underlying pathogenesis and treatment efficacy in disorders of dopamine deficiency.