Tim M. Williams

Attention-deficit hyperactivity disorder: treatment discontinuation in adolescents and young adults

BACKGROUND Symptoms of attention-deficit hyperactivity disorder (ADHD) are known to persist into adulthood in the majority of cases. AIMS To determine the prevalence of methylphenidate, dexamfetamine and atomoxetine prescribing and treatment discontinuation in adolescents and young adults. METHOD A descriptive cohort study using the UK General Practice Research Database included patients aged 15-21 years from 1999 to 2006 with a prescription for a study drug. RESULTS Prevalence of prescribing averaged across all ages increased 6.23-fold over the study period. Overall, prevalence decreased with age: in 2006, prevalence in males dropped 95% from 12.77 per 1000 in 15-year-olds to 0.64 per 1000 in 21-year-olds. A longitudinal analysis of a cohort of 44 patients aged 15 years in 1999 demonstrated that no patient received treatment after the age of 21 years. CONCLUSIONS The prevalence of prescribing by general practitioners to patients with ADHD drops significantly from age 15 to age 21 years. The fall in prescribing is greater than the reported age-related decrease in symptoms, raising the possibility that treatment is prematurely discontinued in some young adults in whom symptoms persist.

Broadband Cortical Desynchronization Underlies the Human Psychedelic State

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin—prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

Neural correlates of the LSD experience revealed by multimodal neuroimaging

Significance Lysergic acid diethylamide (LSD), the prototypical “psychedelic,” may be unique among psychoactive substances. In the decades that followed its discovery, the magnitude of its effect on science, the arts, and society was unprecedented. LSD produces profound, sometimes life-changing experiences in microgram doses, making it a particularly powerful scientific tool. Here we sought to examine its effects on brain activity, using cutting-edge and complementary neuroimaging techniques in the first modern neuroimaging study of LSD. Results revealed marked changes in brain blood flow, electrical activity, and network communication patterns that correlated strongly with the drug’s hallucinatory and other consciousness-altering properties. These results have implications for the neurobiology of consciousness and for potential applications of LSD in psychological research. Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin.

BACKGROUND Psilocybin is a classic psychedelic drug that has a history of use in psychotherapy. One of the rationales for its use was that it aids emotional insight by lowering psychological defences. AIMS To test the hypothesis that psilocybin facilitates access to personal memories and emotions by comparing subjective and neural responses to positive autobiographical memories under psilocybin and placebo. METHOD Ten healthy participants received two functional magnetic resonance imaging scans (2 mg intravenous psilocybin v. intravenous saline), separated by approximately 7 days, during which they viewed two different sets of 15 positive autobiographical memory cues. Participants viewed each cue for 6 s and then closed their eyes for 16 s and imagined re-experiencing the event. Activations during this recollection period were compared with an equivalent period of eyes-closed rest. We split the recollection period into an early phase (first 8 s) and a late phase (last 8 s) for analysis. RESULTS Robust activations to the memories were seen in limbic and striatal regions in the early phase and the medial prefrontal cortex in the late phase in both conditions (P<0.001, whole brain cluster correction), but there were additional visual and other sensory cortical activations in the late phase under psilocybin that were absent under placebo. Ratings of memory vividness and visual imagery were significantly higher after psilocybin (P<0.05) and there was a significant positive correlation between vividness and subjective well-being at follow-up (P<0.01). CONCLUSIONS Evidence that psilocybin enhances autobiographical recollection implies that it may be useful in psychotherapy either as a tool to facilitate the recall of salient memories or to reverse negative cognitive biases.

Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: an [11C]diprenorphine PET study.

The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [11C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls. Subjects underwent one [11C]diprenorphine PET scan in early abstinence from dependent alcohol use (approximately 2 weeks) and 2 months later if continuously abstinent. Global and regional [11C]diprenorphine volumes of distribution (VD) were increased in alcohol dependent patients compared with controls but did not reach significance. We demonstrated a correlation between global and regional [11C]diprenorphine VD and craving in alcohol dependent patients which persisted in the anterior cingulate cortex into extended abstinence. This confirms previous work showing increased opioid receptor availability in early abstinence from substances of abuse and correlation with craving suggesting that the opioid system plays a fundamental role in this phase of addiction.

Brain dopamine response in human opioid addiction

BACKGROUND Drugs of dependence cause dopamine release in the rat striatum. Human neuroimaging studies have shown an increase in dopamine in the equivalent region in response to stimulants and other drugs. AIMS We tested whether opioids provoke dopamine release and its relationship to the subjective experience. METHOD In two combined studies 14 heroin addicts on methadone maintenance treatment underwent two positron emission tomography brain scans of the dopamine system using [(11)C]-raclopride following an injection of placebo and either 50 mg intravenous diamorphine or 10 mg subcutaneous hydromorphone in a double-blind, random order design. RESULTS Both opioids produced marked subjective and physiological effects, but no measurable change in [(11)C]-raclopride binding. CONCLUSIONS The absence of a dopamine response to opioid agonists contrasts with that found with stimulant drugs and suggests dopamine may not play the same role in addiction to opioids. This questions the role of dopamine in the subjective experience of heroin in opioid addicts.

Estimation of the rate of pelvic inflammatory disease diagnoses: trends in England, 2000-2008.

Background: Pelvic inflammatory disease (PID) is difficult to define and diagnose; therefore, a standardized methodology for identifying and monitoring PID diagnoses is required. We estimated the rate of PID in general practice in England, and investigated variations by definition of PID, time, age, and geographical area. Methods: We analyzed the United Kingdom General Practice Research Database between 2000 and 2008. Definitions of “definite,” “probable,” and “possible” PID among female patients (aged 16 to 44 years) were determined according to medical codes that denoted diagnoses or symptoms indicative of PID. Diagnoses rates were calculated per 100,000 person-years (py). Trends were assessed using Poisson regression. Results: The rate of clinical PID diagnoses was 281/100,000 py (95% confidence interval [95% CI]: 277–286) for definite cases; 326/100,000 py (95% CI: 321–331) for definite and probable cases; and 1117/100,000 py (95% CI: 1107–1126) for definite, probable, and possible cases. During 2000 to 2008, the rate of definite/probable PID decreased by 10.4% per year (95% CI: 9.7–11.1; P < 0.001). Rates declined in all areas and among all age groups with greatest decline in women aged 16 to 19 years. Meanwhile, the rate of possible PID increased. Conclusions: The definition of PID used has a major effect on the rate and trends over time. There was heterogeneity in rates of definite/probable PID by age and region, but homogeneity with regard to a trend of declining rates. Ongoing monitoring of PID diagnoses, with standard case definitions, will contribute to the evaluation of chlamydia screening in England.

The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity

Background The compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals. Methods In a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level–dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week. Results Marked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects. Conclusions The MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug’s characteristic subjective effects arise from its modulation of spontaneous brain activity.

The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability.

This study sought to assess the tolerability of intravenously administered psilocybin in healthy, hallucinogen-experienced volunteers in a mock-magnetic resonance imaging environment as a preliminary stage to a controlled investigation using functional magnetic resonance imaging to explore the effects of psilocybin on cerebral blood flow and activity. The present pilot study demonstrated that up to 2 mg of psilocybin delivered as a slow intravenous injection produces short-lived but typical drug effects that are psychologically and physiologically well tolerated. With appropriate care, this study supports the viability of functional magnetic resonance imaging work with psilocybin.