Psilocybin sex-dependently reduces alcohol consumption in C57BL/6J mice.

The classical psychedelic psilocybin is of interest as a treatment for alcohol use disorder (AUD). This study investigated the effects of psilocybin on voluntary ethanol consumption in adult male and female C57BL/6J mice administered saline or psilocybin intraperitoneally as a single dose of 0.1, 0.5, 1.0 or 2.0 mg/kg and provided 20% ethanol utilizing a two-bottle choice alcohol drinking paradigm. Ethanol was provided continuously for 3 days immediately following the administration of psilocybin, then withheld for 2 days, and then provided continuously for two subsequent additional days. A multilevel model (MLM) for repeated measures was used to compare ethanol consumption and preference in psilocybin-treated groups versus controls. Ethanol consumption and preference were reduced in male mice during the 3-day interval that immediately followed psilocybin administration. The effect of psilocybin on ethanol consumption was dose-related and was consistent across the 3-day interval at dosages of 0.5 mg/kg or greater. Psilocybin had no effect on consumption or preference when ethanol was subsequently reintroduced after 2 days of withdrawal. In contrast to males, psilocybin had no significant effect on ethanol consumption or preference in female mice at any dosage or time point. The lack of an effect of psilocybin on quinine preference, and its limited interaction with locomotor activity indicated that the observed reduction in voluntary ethanol consumption was not attributable to altered taste perception or motor effects. Total fluid consumption was increased in males at some time points and psilocybin dosages and unchanged in females, and the absence of any decrease in either group at any time point indicated that the observed reduction in ethanol consumption was not mediated by nonspecific effects on consummatory behavior. The finding of a sex-dependent effect of psilocybin on ethanol consumption suggests that the C57BL/6J mouse may provide a useful experimental approach to modeling sex differences in vulnerability to AUD in addition to investigation of the neurobiological basis of the effect of classical psychedelics on alcohol drinking behavior.

Case Report: Famotidine for Neuropsychiatric Symptoms in COVID-19.

Famotidine is of interest as a possible treatment for COVID-19, with effects on disease-related symptoms and survival reported in observational and retrospective studies, as well as in silico predictions of binding to potential SARS-CoV-2 drug targets. Published studies of famotidine for COVID-19 have focused on acute illness, and none have reported on neuropsychiatric symptoms. This case study reports on an 18-year-old man who sought psychiatric treatment for depression and anxiety, disruptive interpersonal conflicts, and impairments in attention and motivation following mildly symptomatic illness with COVID-19. The neuropsychiatric symptoms, which had been present for 16 weeks at the time of the initial evaluation represented a significant departure from the patient's previous behavioral baseline. The patient had no prior psychiatric history preceding his illness with COVID-19, and no history of any prior treatment with psychopharmacological medications. Famotidine 20 mg twice daily administered orally was begun without any additional medications. At 1-week follow-up the patient was much improved. Improvement was sustained through 12 weeks of follow-up during which the patient continued to take famotidine without apparent side effects. With progression of the COVID-19 pandemic it has become evident that persistent disease-related symptoms may follow acute COVID-19 and may include neuropsychiatric symptoms. Controlled clinical research on famotidine for COVID-19 should follow, as well as the development of valid and reliable research diagnostic criteria to define and operationalize the features of a putative COVID-19 neuropsychiatric residual.

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice.

There is a substantive clinical literature on classical hallucinogens, most commonly lysergic acid diethylamide (LSD) for the treatment of alcohol use disorder. However, there has been no published research on the effect of LSD on alcohol consumption in animals. This study evaluated the effect of LSD in mice using a two-bottle choice alcohol drinking paradigm. Adult male C57BL/6J mice were exposed to ethanol to develop preference and divided into three groups of equal ethanol consumption, and then treated with single intraperitoneal injection of saline or 25 or 50 µg/kg LSD and offered water and 20% ethanol. The respective LSD-treated groups were compared to the control group utilizing a multilevel model for repeated measures. In mice treated with 50 µg/kg LSD ethanol consumption was reduced relative to controls (p = 0.0035), as was ethanol preference (p = 0.0024), with a group mean reduction of ethanol consumption of 17.9% sustained over an interval of 46 days following LSD administration. No significant effects on ethanol consumption or preference were observed in mice treated with 25 µg/kg LSD. Neither total fluid intake nor locomotor activity in the LSD-treated groups differed significantly from controls. These results suggest that classical hallucinogens in the animal model merit further study as a potential approach to the identification of targets for drug discovery and investigation of the neurobiology of addiction.

Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes.

BACKGROUND: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. OBJECTIVES: To study outcomes following opioid detoxification with ibogaine. METHODS: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. RESULTS: SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. CONCLUSION: Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.

hERG Blockade by Iboga Alkaloids.

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

OBJECTIVE: The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of µ-opioid receptor (MOR)-related G proteins by iboga alkaloids. METHODS: Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. RESULTS AND SIGNIFICANCE: In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

Childhood abuse and EEG source localization in crack cocaine dependence.

Fourteen subjects with histories of sexual and/or physical abuse in childhood and 13 matched control subjects were selected from a consecutive series of clients in residential treatment for crack cocaine dependence. Standardized low-resolution electromagnetic brain tomography (sLORETA) was used to estimate the source generators of the EEG in a cortical mask with voxel z-scores referenced to normative data at frequency intervals of 039 Hz, with nonparametric permutation to correct by randomization for the number of comparisons and the intercorrelations and variance of distribution of voxel values. Subjects with histories of abuse in childhood had significantly greater EEG power than controls in the theta frequency range (3.51-7.41 Hz), with greatest differences in the 3.90-Hz band distributed mainly in the parahippocampal, fusiform, lingual, posterior cingulate, and insular gyri. The groups did not differ significantly with regard to delta (1.56-3.12 Hz), alpha (7.81-12.48 Hz), beta (12.87-19.89 Hz), and gamma (20.28-35.10 Hz) frequency power. In excess, theta EEG power, a bandwidth of transactions among hippocampus and amygdala and paralimbic and visual association cortex, may be a correlate of childhood exposure to abuse.

Neuroinflammation and psychiatric illness.

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.

Emotion processing bias and age of seizure onset among epilepsy patients with depressive symptoms.

The current study examined whether mood-congruent biases in emotion processing extend to epilepsy patients with depressive symptoms and the potentially moderating effects of age of seizure onset on these biases. In addition, we examined associations between depression (Beck Depression Inventory - 2nd Edition; BDI-II) and quality of life (Quality of Life in Epilepsy - 10-item questionnaire; QOLIE-10). Data from 101 epilepsy patients were analyzed, including 61 females and 40 males. Measures included the Comprehensive Affect Testing System - Abbreviated (CATS-A), from which indices of mood-congruent bias were derived. A significant interaction between BDI-II raw scores and age of seizure onset was found for mood-congruent bias scores in the facial affect modality (ß=-0.24, p<.03). Beck Depression Inventory - 2nd Edition raw scores were significantly and positively correlated with quality of life (QOLIE-10; r=.69, p<.01). Results of the current study show that epilepsy patients with an early age of seizure onset may be most at risk for mood-congruent biases when experiencing depressive symptoms and that such symptoms have real-world implications for quality of life for persons living with epilepsy.

Fatalities temporally associated with the ingestion of ibogaine.

Ibogaine is a naturally occurring psychoactive plant alkaloid that is used globally in medical and nonmedical settings for opioid detoxification and other substance use indications. All available autopsy, toxicological, and investigative reports were systematically reviewed for the consecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteen individuals (15 men, four women between 24 and 54 years old) are known to have died within 1.5-76 h of taking ibogaine. The clinical and postmortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardiovascular, and/or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequate postmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine.

Ibogaine and the inhibition of acetylcholinesterase.

ETHNOPHARMACOLOGICAL RELEVANCE: Ibogaine is a psychoactive monoterpine indole alkaloid extracted from the root bark of Tabernanthe iboga Baill. that is used globally in medical and nonmedical settings to treat drug and alcohol addiction, and is of interest as an ethnopharmacological prototype for experimental investigation and pharmaceutical development. The question of whether ibogaine inhibits acetylcholinesterase (AChE) is of pharmacological and toxicological significance. MATERIALS AND METHODS: AChE activity was evaluated utilizing reaction with Ellman's reagent with physostigmine as a control. RESULTS: Ibogaine inhibited AChE with an IC(50) of 520±40 µM. CONCLUSIONS: Ibogaine's inhibition of AChE is physiologically negligible, and does not appear to account for observations of functional effects in animals and humans that might otherwise suggest the possible involvement of pathways linked to muscarinic acetylcholine transmission.

Emotional recognition in depressed epilepsy patients.

The current study examined the relationship between emotional recognition and depression using the Minnesota Multiphasic Personality Inventory, Second Edition (MMPI-2), in a population with epilepsy. Participants were a mixture of surgical candidates in addition to those receiving neuropsychological testing as part of a comprehensive evaluation. Results suggested that patients with epilepsy reporting increased levels of depression (Scale D) performed better than those patients reporting low levels of depression on an index of simple facial recognition, and depression was associated with poor prosody discrimination. Further, it is notable that more than half of the present sample had significantly elevated Scale D scores. The potential effects of a mood-congruent bias and implications for social functioning in depressed patients with epilepsy are discussed.

Postictal psychosis in partial epilepsy: a case-control study.

OBJECTIVE: Divergent findings among prior studies on correlates of risk for postictal psychosis (PIP) suggest the value of a controlled study involving a relatively large number of patients. METHODS: The study population consisted of a consecutive series of 59 patients with partial epilepsy and a history of PIP, and 94 control patients with partial epilepsy and no history of PIP evaluated as inpatients with video-electroencephalography. The groups did not differ significantly regarding demographic features. Exact tests yielded a subset of variables and a tentative interpretation that were evaluated further utilizing principal components analysis and logistic regression. RESULTS: PIP was associated with extratemporal versus temporal (p = 0.036) or undetermined (p = 0.001) localization of seizure onset, bilateral interictal epileptiform activity (p = 0.017), secondary generalization (p = 0.049), and history of encephalitis (p = 0.018). Interictal slow activity was more frequently absent in control patients (p = 0.045). PIP was associated with family histories of psychiatric disorders (p = 0.007) and epilepsy (p = 0.042), which themselves were significantly intercorrelated (r = 0.225; p = 0.006). Age of onset or duration of epilepsy and lateralized electroencephalographic or magnetic resonance imaging asymmetries did not differ significantly between control and PIP groups. The analysis indicated four underlying domains of risk for PIP: ambiguous/extratemporal localization, family neuropsychiatric history, abnormal interictal electroencephalographic activity, and encephalitis. Each unit increase on a simple additive scale composed of 9 dichotomous independent variables multiplied the odds ratio for PIP by 1.71 (95% confidence interval, 1.36-2.15; p < 0.0001). INTERPRETATION: PIP in partial epilepsy is associated with relatively broadly and bilaterally distributed epileptogenic networks, genetic determinants of psychiatric disorders and seizures, and encephalitis.

Localizing epileptogenic regions in partial epilepsy using three-dimensional statistical parametric maps of background EEG source spectra.

This preliminary study sought to localize epileptogenic regions in patients with partial epilepsy by analysis of interictal EEG activity utilizing variable resolution electromagnetic tomography (VARETA), a three-dimensional quantitative electroencephalographic (QEEG) frequency-domain distributed source modeling technique. The very narrow band (VNB) spectra spanned the frequency range 0.39 Hz to 19.1 Hz, in 0.39 Hz steps. These VNB spectra were compared to normative data and transformed to provide Z-scores for every scalp derivation, and the spatial distributions of the probable EEG generators of the most abnormal values were displayed on slices from a probabilistic MRI atlas. Each voxel was color-coded to represent the significance of the deviation relative to age appropriate normative values. We compared the resulting three-dimensional images to the localization of epileptogenic regions based on invasive intracranial EEG recordings of seizure onsets. The VARETA image indicated abnormal interictal spectral power values in regions of seizure onset identified by invasive monitoring, mainly in delta and theta range (1.5 to 8.0 Hz). The VARETA localization of the most abnormal voxel was congruent with the epileptogenic regions identified by intracranial recordings with regard to hemisphere in all 6 cases, and with regard to lobe in 5 cases. In contrast, abnormal findings with routine EEG agreed with invasive monitoring with regard to hemisphere in 3 cases and with regard to lobe in 2 cases. These results suggest that analysis of background interictal EEG utilizing distributed source models should be investigated further in clinical epilepsy.

The ibogaine medical subculture.

AIM OF THE STUDY: Ibogaine is a naturally occurring psychoactive indole alkaloid that is used to treat substance-related disorders in a global medical subculture, and is of interest as an ethnopharmacological prototype for experimental investigation and possible rational pharmaceutical development. The subculture is also significant for risks due to the lack of clinical and pharmaceutical standards. This study describes the ibogaine medical subculture and presents quantitative data regarding treatment and the purpose for which individuals have taken ibogaine. MATERIALS AND METHODS: All identified ibogaine "scenes" (defined as a provider in an associated setting) apart from the Bwiti religion in Africa were studied with intensive interviewing, review of the grey literature including the Internet, and the systematic collection of quantitative data. RESULTS: Analysis of ethnographic data yielded a typology of ibogaine scenes, "medical model", "lay provider/treatment guide", "activist/self-help", and "religious/spiritual". An estimated 3414 individuals had taken ibogaine as of February 2006, a fourfold increase relative to 5 years earlier, with 68% of the total having taken it for the treatment of a substance-related disorder, and 53% specifically for opioid withdrawal. CONCLUSIONS: Opioid withdrawal is the most common reason for which individuals took ibogaine. The focus on opioid withdrawal in the ibogaine subculture distinguishes ibogaine from other agents commonly termed "psychedelics", and is consistent with experimental research and case series evidence indicating a significant pharmacologically mediated effect of ibogaine in opioid withdrawal.

Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports.

BACKGROUND: Clinical trial data provide an approach to the investigation of the effects of psychopharmacological agents, and psychiatric disorders themselves, on seizure threshold. METHODS: We accessed public domain data from Food and Drug Administration (FDA) Phase II and III clinical trials as Summary Basis of Approval (SBA) reports that noted seizure incidence in trials of psychotropic drugs approved in the United States between 1985 and 2004, involving a total of 75,873 patients. We compared seizure incidence among active drug and placebo groups in psychopharmacological clinical trials and the published rates of unprovoked seizures in the general population. RESULTS: Increased seizure incidence was observed with antipsychotics that was accounted for by clozapine and olanzapine, and with drugs indicated for the treatment of OCD that was accounted for by clomipramine. Alprazolam, bupropion immediate release (IR) form, and quetiapine were also associated with higher seizure incidence. The incidence of seizures was significantly lower among patients assigned to antidepressants compared to placebo (standardized incidence ratio = .48; 95% CI, .36- .61). In patients assigned to placebo, seizure incidence was greater than the published incidence of unprovoked seizures in community nonpatient samples. CONCLUSIONS: Proconvulsant effects are associated with a subgroup of psychotropic drugs. Second-generation antidepressants other than bupropion have an apparent anticonvulsant effect. Depression, psychotic disorders, and OCD are associated with reduced seizure threshold.

Correlation of PET and qEEG in normal subjects.

Positron emission tomography (PET) and quantitative electroencephalography (qEEG) were obtained in 15 normal male subjects with eyes closed at rest. Correlations between qEEG variables and regional metabolism were examined as an approach to investigating the metabolic and neuroanatomical basis of the generation of the EEG. Analogous to the neurometric approach to qEEG, a normative 2-fluoro-deoxyglucose voxel data base was developed for the PET image. The PET image was transformed to an idealized cylindrical set of coordinates to allow registration with the Talairach stereotactic atlas. PET regions of interest for the thalamus, the left and right temporal lobes, the medial frontal cortex and the dorsolateral prefrontal cortex were defined using Talairach coordinates and correlated to the QEEG. Salient findings included a negative correlation of thalamic metabolism to alpha power and a positive correlation of medial frontal cortical metabolism to delta EEG power. The significance of these findings is discussed with reference to the existing literature on the physiology of the generation of the EEG.

Nonepileptic seizures treatment workshop summary.

In May 2005, an international, interdisciplinary group of researchers gathered in Bethesda, MD, USA, for a workshop to discuss the development of treatments for patients with nonepileptic seizures (NES). Specific subgroup topics that were covered included: pediatric NES; presenting the diagnosis of NES, outcome measures for NES trials; classification of NES subtypes; and pharmacological treatment approaches and psychotherapies. The intent was to develop specific research strategies that can be expanded to involve a large segment of the epilepsy and psychiatric treatment communities. Various projects have resulted from the workshop, including the initial development of a prospective randomized clinical trial for NES.

Obsessive-compulsive symptoms in patients with temporal lobe epilepsy.

The goals of this work were to: (1) determine the prevalence of clinically significant obsessive-compulsive (OC) symptoms in patients with temporal lobe epilepsy (TLE), (2) characterize the differences in self-reported OC symptoms in patients with TLE and a normative control group, and (3) compare the severity of OC symptoms in right and left hemisphere TLE patients. Patients with TLE (n=30) were administered the Obsessive-Compulsive Inventory (OCI). As a group, patients with TLE had a higher prevalence of OC symptoms than the nonpatient normative sample. In addition, TLE patients exhibited elevated scores on all but 3 of the 16 OCI scales and subscales. There were no reliable differences in OC symptoms in patients with right versus left hemisphere seizure foci, although the right hemisphere patients tended to score higher on both scales of the OCI.