Steven Madonick

Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction

BACKGROUND Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. METHODS In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. RESULTS Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. CONCLUSIONS Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

Impaired prepulse inhibition of acoustic startle in schizophrenia

BACKGROUND Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. METHODS PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. RESULTS Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. CONCLUSIONS These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.

Enhanced Sensitivity to the Euphoric Effects of Alcohol in Schizophrenia

The purpose of this study was to determine whether schizophrenia was associated with alterations in alcohol response that might explain the elevated risk for AUDs in this population. In a randomized, double-blind, placebo-controlled, counter-balanced 3 test day laboratory study, the effects of alcohol were compared in 23 subjects with schizophrenia (without any previous alcohol use disorder (AUD) but with some alcohol exposure) and in 14 healthy subjects matched for age, gender, education, and lifetime exposure to alcohol. Standard alcohol drinks in a scheduled design were administered to produce blood alcohol levels of 0, 0.02–0.04 mg%, or 0.06–0.08 mg%. Schizophrenia symptoms, perceptual alterations, stimulant and depressant subjective effects of alcohol, and ‘high’ were measured before alcohol administration and at several post-drug time points. Verbal learning and recall, vigilance and distractibility, and motor function were assessed once per test day. Relative to healthy subjects, subjects with schizophrenia reported greater euphoria and stimulatory effects in response to alcohol. Alcohol produced small transient increases in positive psychotic symptoms and perceptual alterations without affecting negative symptoms. Alcohol also impaired several aspects of immediate and delayed recall, and vigilance, and distractibility. Schizophrenia patients showed increased euphoric and stimulatory responses to alcohol. These exaggerated positive responses to alcohol doses may contribute to the increased risk for AUDs associated with schizophrenia. The absence of ‘beneficial’ effects of alcohol does not support a self-medication hypothesis of alcohol use in schizophrenia.

Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism

The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.

Substance Abuse as a Risk Factor for Schizophrenia and Related Disorders

The concept that substance abuse might be a risk factor for schizophrenia and related disorders is somewhat controversial. It seems clear from clinical experience that substance abuse, often involving several potentially psychotogenic agents, may precede, for varying periods, the onset of psychosis. However, the interpretation of this phenomenom in retrospect is problematic. Some observers, for example, believe that drug use may be an attempt to self-medicate depression or other early symptoms of impending psychosis though much adolescent drug use seems to be related primarily to peer behavior. Most studies indicate that patients who first become psychotic after a period of substance abuse do not have atypical developmental histories and prominent negative symptoms, as do many adolescents who develop a chronic psychotic disorder. It may be that relapsing psychosis initiated by psychotogenic drug use, but not dependent upon continued use, is a partial phenocopy of schizophrenia and related disorders with primarily positive symptoms. However permanent a drug-initiated psychosis becomes, most investigators would agree that even temporary psychosis is neurobiologically harmful. Thus, ideas of reducing drug use as a risk factor for the major psychoses are worthy of consideration. How often does psychotogenic drug use precede the onset of first-episode psychosis? The answer to this question is critical if we are to entertain possibilities for primary prevention. In our initial study of first-episode patients who became psychotic after cannabis and/or lysergic acid diethylamide (LSD) use, all had started their drug use before being initially hospitalized for psychosis [1]. Alienbeck, Adamsson, & Engstrom [2] found that 69 percent of a sample of 1 12 patients with schizophrenia who used cannabis had started using the drug at least a year before the onset of psychosis. Linszer, Dingemans, & Lenior [3] reported cannabis use