Faculty Bibliography

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.

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.

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.

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.

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 microM) or by extraction from T. iboga (3.53 +/- 0.16 microM); ibogaine's principal metabolite noribogaine (2.86 +/- 0.68 microM); and voacangine (2.25 +/- 0.34 microM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 microM. 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 microM, 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.

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 039Hz, 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 (3.51-7.41Hz), 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 (1.56-3.12Hz), alpha (7.81-12.48Hz), beta (12.87-19.89Hz), and gamma (20.28-35.10Hz) 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.

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.

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 mu-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-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) 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]GTPgammaS 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]GTPgammaS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPgammaS 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.