Hinderk M. Emrich

The Pharmacology of Lysergic Acid Diethylamide: A Review

Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so‐called “experimental psychosis” by altering neurotransmitter system and in psychotherapeutic procedures (“psycholytic” and “psychedelic” therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho‐) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

Comorbidity of alcohol and substance dependence with attention-deficit/hyperactivity disorder (ADHD).

AIMS Attention-deficit/hyperactivity disorder (ADHD) is of great clinical importance not only because of its high prevalence but also due to the frequent comorbid illnesses that are connected with this disorder. Several studies were able to demonstrate that ADHD constitutes a significant risk factor for the exacerbation of habit-forming illnesses, i.e. addictions. METHODS We conducted a study on 152 adult patients with alcohol dependence (n = 91) or multiple substance addiction (n = 61) to determine whether or not these patients were affected by ADHD. For retrospective assessment of childhood ADHD, the WURS-k was used as well as the DSM-IV symptom checklist for ADHD. The CAARS was used to assess the persisting symptoms of ADHD in adults. RESULTS 20.9% (WURS-k) or 23.1% (DSM-IV diagnostic criteria) of the alcohol-dependent patients showed evidence of retrospective ADHD affliction in childhood. With the help of CAARS, ADHD was proved to be persistent in 33.3% of the adult patients. In the group of substance-addicted patients 50.8% (WURS-k) and 54.1% (DSM-IV) presented with diagnostic criteria for ADHD in childhood and 65.5% (CAARS) showed evidence of ADHD persisting in adulthood. CONCLUSIONS These results reveal that habit-forming illnesses can be associated with a high comorbidity with ADHD, expressed in the form of alcohol abuse and also in consumption of illegal drugs. The results underline the great importance of early and adequate diagnostics and therapy of ADHD for the prevention of habit-forming illnesses.

Prefrontal and anterior cingulate cortex abnormalities in Tourette Syndrome: evidence from voxel-based morphometry and magnetization transfer imaging

BackgroundPathophysiological evidence suggests an involvement of fronto-striatal circuits in Tourette syndrome (TS). To identify TS related abnormalities in gray and white matter we used optimized voxel-based morphometry (VBM) and magnetization transfer imaging (MTI) which are more sensitive to tissue alterations than conventional MRI and provide a quantitative measure of macrostructural integrity.MethodsVolumetric high-resolution anatomical T1-weighted MRI and MTI were acquired in 19 adult, unmedicated male TS patients without co-morbidities and 20 age- and sex-matched controls on a 1.5 Tesla neuro-optimized GE scanner. Images were pre-processed and analyzed using an optimized version of VBM in SPM2.ResultsUsing VBM, TS patients showed significant decreases in gray matter volumes in prefrontal areas, the anterior cingulate gyrus, sensorimotor areas, left caudate nucleus and left postcentral gyrus. Decreases in white matter volumes were detected in the right inferior frontal gyrus, the left superior frontal gyrus and the anterior corpus callosum. Increases were found in the left middle frontal gyrus and left sensorimotor areas. In MTI, white matter reductions were seen in the right medial frontal gyrus, the inferior frontal gyrus bilaterally and the right cingulate gyrus. Tic severity was negatively correlated with orbitofrontal structures, the right cingulate gyrus and parts of the parietal-temporal-occipital association cortex bilaterally.ConclusionOur MRI in vivo neuropathological findings using two sensitive and unbiased techniques support the hypothesis that alterations in frontostriatal circuitries underlie TS pathology. We suggest that anomalous frontal lobe association and projection fiber bundles cause disinhibition of the cingulate gyrus and abnormal basal ganglia function.

High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients.

Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in major depression. In order to investigate the therapeutic efficacy of rTMS in psychotic patients, 12 participants (four women, eight men) with schizophrenia according to DSM-IV criteria, aged 25 to 63 years (mean (± s.d) 40.4 ± 11.0), were enrolled in the study. Following a double-blind crossover design, patients were treated at random with 2 weeks of daily left prefrontal rTMS (20 2 s 20 Hz stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. The Brief Psychiatric Rating Scale decreased under active rTMS (p < 0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly. Prefrontal rTMS might be effective in the non-pharmacological treatment of psychotic patients.

Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia

Highlighting the association between schizophrenia and Cannabis sativa and the endogenous cannabinoid receptor system, respectively, two opposite aspects are of major relevance. On the one hand, cannabis is the most widely used illegal drug. There is substantial evidence that cannabis has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. This risk seems to be increased in genetically predisposed people and may depend on the amount of cannabis used. On the other hand, during the last few years, an endogenous cannabinoid receptor system (including two known cannabinoid [CB1 and CB2] receptors and five endogenous ligands) has been discovered. There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia (e.g., increased density of CB1 receptor binding and increased levels of cerebrospinal fluid endocannabinoid anandamide). Accordingly, beside the ‘dopamine hypothesis’ of schizophrenia, a ‘cannabinoid hypothesis’ has been suggested. Interestingly, there is a complex interaction between the dopaminergic and the endocannabinoid receptor system. Thus, agents that interact with the cannabinoid receptor system, such as the nonpsychoactive cannabidiol, might be beneficial in the treatment of psychosis.

Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence.

It is known from clinical studies that some patients attempt to cope with the symptoms of post-traumatic stress disorder (PTSD) by using recreational drugs. This review presents a case report of a 19-year-old male patient with a spectrum of severe PTSD symptoms, such as intense flashbacks, panic attacks, and self-mutilation, who discovered that some of his major symptoms were dramatically reduced by smoking cannabis resin. The major part of this review is concerned with the clinical and preclinical neurobiological evidence in order to offer a potential explanation of these effects on symptom reduction in PTSD. This review shows that recent studies provided supporting evidence that PTSD patients may be able to cope with their symptoms by using cannabis products. Cannabis may dampen the strength or emotional impact of traumatic memories through synergistic mechanisms that might make it easier for people with PTSD to rest or sleep and to feel less anxious and less involved with flashback memories. The presence of endocannabinoid signalling systems within stress-sensitive nuclei of the hypothalamus, as well as upstream limbic structures (amygdala), point to the significance of this system for the regulation of neuroendocrine and behavioural responses to stress. Evidence is increasingly accumulating that cannabinoids might play a role in fear extinction and antidepressive effects. It is concluded that further studies are warranted in order to evaluate the therapeutic potential of cannabinoids in PTSD.

Genuine and drug-induced synesthesia: A comparison

Despite some principal similarities, there is no systematic comparison between the different types of synesthesia (genuine, acquired and drug-induced). This comprehensive review compares the three principal types of synesthesia and focuses on their phenomenological features and their relation to different etiological models. Implications of this comparison for the validity of the different etiological models are discussed. Comparison of the three forms of synesthesia show many more differences than similarities. This is in contrast to their representation in the literature, where they are discussed in many respects as being virtually similar. Noteworthy is the much broader spectrum and intensity with the typical drug-induced synesthesias compared to genuine and acquired synesthesias. A major implication of the phenomenological comparison in regard to the etiological models is that genuine and acquired synesthesias point to morphological substrates, while drug-induced synesthesia appears to be based on functional changes of brain activity.

Target evaluation processing and serum levels of nerve tissue protein S100B in patients with remitted major depression

Selective attention processes (N2 and P3 components of event-related potentials (ERPs)) have been shown to be impaired in depressed patients but findings have been mixed. Part of this variability might be explained by neurobiological factors. ERPs (Go/Nogo paradigm) were investigated in patients with remitted major depression in relation to S100B. S100B, an astroglial protein with neuroplastic properties, has been shown to be increased in depression. Its pathophysiologic role in depression, however, is not yet sufficiently understood. Patients with increased S100B serum levels (n=6) showed a normal N2- and P3-amplitude in contrast to a reduced N2- and P3-amplitude in patients with normal S100B serum levels (n=6). These findings provide evidence of a correlation between S100B levels and attentional processes in patients with recurrent depression and further substantiate S100Bs role as a marker in the course of affective disorders.

Disinhibited feedback as a cause of synesthesia: evidence from a functional connectivity study on auditory-visual synesthetes.

In synesthesia, certain stimuli to one sensory modality lead to sensory perception in another unstimulated modality. In addition to other models, a two-stage model is discussed to explain this phenomenon, which combines two previously formulated hypotheses regarding synesthesia: direct cross-activation and hyperbinding. The direct cross-activation model postulates that direct connections between sensory-specific areas are responsible for co-activation and synesthetic perception. The hyperbinding hypothesis suggests that the inducing stimulus and the synesthetic sensation are coupled by a sensory nexus area, which may be located in the parietal cortex. This latter hypothesis is compatible with the disinhibited feedback model, which suggests unusual feedback from multimodal convergence areas as the cause of synesthesia. In this study, the relevance of these models was tested in a group (n=14) of auditory-visual synesthetes by performing a functional connectivity analysis on functional magnetic resonance imaging (fMRI) data. Different simple and complex sounds were used as stimuli, and functionally defined seed areas in the bilateral auditory cortex (AC) and the left inferior parietal cortex (IPC) were used for the connectivity calculations. We found no differences in the connectivity of the AC and the visual areas between synesthetes and controls. The main finding of the study was stronger connectivity of the left IPC with the left primary auditory and right primary visual cortex in the group of auditory-visual synesthetes. The results support the model of disinhibited feedback as a cause of synesthetic perception but do not suggest direct cross-activation.

Glia in the cytokine-mediated onset of depression: fine tuning the immune response

Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system’s (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted.