LSD enhances suggestibility in healthy volunteers.

RATIONALE: Lysergic acid diethylamide (LSD) has a history of use as a psychotherapeutic aid in the treatment of mood disorders and addiction, and it was also explored as an enhancer of mind control. OBJECTIVES: The present study sought to test the effect of LSD on suggestibility in a modern research study. METHODS: Ten healthy volunteers were administered with intravenous (i.v.) LSD (40-80 µg) in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale (CIS) and a mental imagery test (MIT). CIS and MIT items were split into two versions (A and B), balanced for 'efficacy' (i.e. A ≈ B) and counterbalanced across conditions (i.e. 50 % completed version 'A' under LSD). The MIT and CIS were issued 110 and 140 min, respectively, post-infusion, corresponding with the peak drug effects. RESULTS: Volunteers gave significantly higher ratings for the CIS (p = 0.018), but not the MIT (p = 0.11), after LSD than placebo. The magnitude of suggestibility enhancement under LSD was positively correlated with trait conscientiousness measured at baseline (p = 0.0005). CONCLUSIONS: These results imply that the influence of suggestion is enhanced by LSD. Enhanced suggestibility under LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role. That cued imagery was unaffected by LSD implies that suggestions must be of a sufficient duration and level of detail to be enhanced by the drug. The results also imply that individuals with high trait conscientiousness are especially sensitive to the suggestibility-enhancing effects of LSD.

Innovative solutions to novel drug development in mental health.

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

The effects of elevated endogenous GABA levels on movement-related network oscillations.

The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation-inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15-30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta-ERD) and movement-related gamma synchronisation (MRGS) (60-90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated.

Hypothermic responses to infection are inhibited by alpha2-adrenoceptor agonists with possible clinical implications.

BACKGROUND: alpha(2)-Adrenoceptor agonists are currently used as primary sedative agents in high dependency patients who are at high risk of sepsis. Clinical surveillance of such patients relies in part on their ability to mount appropriate responses to infection, in particular thermal responses. Thermoregulatory responses to infection are well studied in the rat and in this species, and humans, infection can induce febrile, hypothermic, or mixed hypothermic and febrile responses. The involvement of noradrenergic systems in thermal responses to infection prompted the hypothesis that ligands that act on adrenoceptors may interfere with the normal thermal responses to infection. METHODS: In this study on rats, the effect of infusion of the selective alpha(2)-agonist, mivazerol, on hypothermic and plasma corticosterone responses induced by bacterial lipopolysaccharide (LPS) was investigated. RESULTS: Clinically effective doses of mivazerol (4.8 and 10 microg kg(-1) h(-1)) had no effect on body temperature alone. However, mivazerol significantly inhibited the typical thermoregulatory response to bacterial LPS in a dose-dependent manner. This effect was mimicked by the selective alpha(2)-agonist, UK14304-18 (6 microg kg(-1) h(-1)), and antagonized by the alpha(2)-antagonist, RX811059A (7 microg kg(-1) h(-1)). The alpha(2)-ligands had no effect on basal or LPS-induced corticosterone levels. CONCLUSIONS: These data suggest that early thermoregulatory responses to infection can be selectively antagonized by ligands that activate alpha(2)-adrenoreceptors. High dependency patients receiving alpha(2)-adrenoceptor agonists may not be capable of mounting a normal thermal response to infecting organisms and clinical monitoring using core temperature to detect infection may therefore be unreliable in these vulnerable patients.

Vitamin C, Mood and Cognitive Functioning in the Elderly.

The present study examined the effects of anti-oxidant vitamin supplementation on mood and cognitive functioning in 205 volunteers (110 females, 95 males; age range: 60-80 years). In this randomised, double-blind, placebo-controlled study, the volunteers received either anti-oxidant supplementation (daily dosage 12mg/d ß-carotene, 400 mg/d α-tocopherol and 500mg/d ascorbic acid) or placebo. The volunteers were followed up for 12 months. Vitamin levels were assessed from plasma samples. The primary outcome measures were subjective mood, self-reported cognitive failures, and measures of intelligence. These were measured at 4, 8 and 12 months. There were very few significant differences between the placebo and vitamin groups. Analysis of the effects of changes in vitamin levels on mood and cognition revealed significant effects of changes in vitamin C but not the other anti-oxidants. Increases in vitamin C were associated at 12 months with more positive mood, greater improvements in global assessments of intellectual functioning and a reduction in everyday errors of memory, attention and action. These effects were greatest for those volunteers who had a more negative mood and lower levels of cognitive function at baseline. Overall, results support earlier findings based on examination of dietary intake.

Integrating the cognitive and physiological aspects of craving.

'Craving is generally considered a significant factor in opiate addiction that is associated with drug-dependence and in relapse to drug use after treatment'-ARC expert consensus (Pickens and Johanson, Drug and Alcohol Dependence 30: 127-131). There are however difficulties in defining craving and urges to use drugs and in associating craving with drug use and relapse. Tiffany [Psychological Review 97(2): 147-168] has reviewed a considerable number of studies that associated reports of craving with consumption measures of drugs and revealed only an overall modest correlation of 0.4. These findings call into question the general assumption that subjective cravings are invariably associated with drug use. Furthermore, it led to Tiffany's provocative argument that cravings are not necessary for drug use. We have addressed these issues by using a range of complementary techniques derived from research in related fields such as the cognitive psychology of anxiety and depression, physiological response measurements and positron emission tomography (PET) neuro-imaging. Initially we developed computerized assessments to probe cognitive dysfunction in addiction that related to biased processing of automatic thoughts and beliefs about craving and drug use in opiate-dependent subjects and alcoholics. Subsequently in an attempt to develop a reliable method of inducing craving we explored an imagery-based technique that relied on the memory of craving experiences. These experiments were conducted both in opiate addicts who had achieved abstinence and in those undergoing detoxification. Finally, we have begun a study to understand the neural mechanisms of craving using imagery-based procedures at the same time as performing PET studies of regional blood flow using the O15-labelled water technique.

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on food and water intake in the rat.

1. Idazoxan (1, 3, 10 mg kg-1, i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2. The more selective and specific alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg kg-1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3. The peripherally acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect RX811059 and RX821002 on food intake contrasts with the large dose-related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.

Low affinity hypothalamic [3H]mazindol binding: a probe for hypothalamic body weight regulation?

It has been previously suggested that low affinity [3H]mazindol binding in the hypothalamus correlates with body weight and obesity. Low affinity [3H]mazindol binding in hypothalamic crude synaptosome preparations was carried out in normoglycemic obese mice (C57 B1/6J ob/ob) as well as in their lean littermates (C57 B1/6J +/?). NIH Swiss mice were used as additional controls. Furthermore the effect on this binding site of repeated electroconvulsive shock (ECS), a treatment known to change body weight gain, was studied in rats. Neither Bmax nor Kd were altered in obese mice compared with their lean littermates or NIH Swiss mice. The obese mice had a significantly greater body weight and weight gain than either control group. Once-daily ECS over 10 days (which significantly reduced weight gain in rats) did not change binding parameters for [3H]mazindol in hypothalami. The present data do not appear to support the hypothesis that this low affinity binding site has a physiological function in the control of body weight and obesity, at least in the examined paradigm.

Comparison of the effects of chronic desmethylimipramine administration on alpha 2- and beta-adrenoceptors in different regions of rat brain.

The effects of ten once-daily injections of desmethylimipramine (10 mg/kg i.p.) on alpha 2- and beta-adrenoceptor binding were investigated in the rat cortex, hippocampus and hypothalamus. [3H]clonidine and [3H]dihydroalprenolol were used as ligands for alpha 2- and beta-adrenoceptors, respectively. Twenty-four hours after the last injection, the density of beta-adrenoceptors was reduced in all regions studied. In contrast, there was no change in alpha 2-adrenoceptor binding in the cortex, while increased binding was found in the hypothalamus. The effects of desmethylimipramine are discussed in relation to those of other antidepressant treatments.

Comparison of the effects of repeated electroconvulsive shock on alpha 2- and beta-adrenoceptors in different regions of rat brain.

The effects of ten, once-daily electroconvulsive shocks on alpha 2 and beta-adrenoceptor binding were investigated in the rat cortex, hippocampus, hypothalamus and cerebellum. [3H]Clonidine and [3H]dihydroalprenolol were used as radioligands for alpha 2 and beta-adrenoceptors respectively. Twenty-four hours after the last shock, the density of beta-adrenoceptors was reduced in the cortex and hippocampus, but not in the hypothalamus or cerebellum. There was no change in the apparent affinity of the beta-receptors in any of the regions studied. Alpha 2-adrenoceptor density was reduced in all the regions studied (cortex, hippocampus, hypothalamus) with, again, no change in their apparent affinity. It is concluded that the effects of electro-convulsive shock on alpha 2 and beta-adrenoceptors show regional variation; possible reasons for this variation are discussed.