Effects of acute oral Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers

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Abstract

Reduced amplitudes of auditory evoked P300 are a robust finding in schizophrenic patients, indicating deficient attentional resource allocation and active working memory. Δ9-Tetrahydrocannabinol (Δ9-THC), the main active constituent of Cannabis sativa, has been known to acutely impair cognitive abilities in several domains, particularly in memory and attention. Given the psychotic-like effects of Δ9-THC, a cannabinoid hypothesis of schizophrenia has been proposed. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on P300 amplitude in 20 healthy volunteers (age 28.2 ± 3.1 years, 10 male) by comparing Δ9-THC and standardized cannabis extract containing Δ9-THC and cannabidiol (CBD). P300 waves were recorded during a choice reaction task. As expected, Δ9-THC revealed a significant reduction of P300 amplitude at midline frontal, central, and parietal electrodes. CBD has been known to abolish many of the psychotropic effects of Δ9-THC, but, unexpectedly, failed to demonstrate a reversal of Δ9-THC-induced P300 reduction. Moreover, there were no correlations between cannabinoid plasma concentrations and P300 parameters. These data suggest that Δ9-THC may lead to acute impairment of attentional functioning and working memory. It can be speculated whether the lack of effect of CBD may be due to an insufficient dose used or to an involvement of neurotransmitter systems in P300 generation which are not influenced by CBD.

Introduction

Cannabis sativa is one of the oldest and most frequently used illicit drugs (Rehm et al., 2005). Δ9-Tetrahydrocannabinol (Δ9-THC) has been identified as the major psychoactive constituent of C. sativa (Mechoulam and Gaoni, 1965). The activity of Δ9-THC is mediated by agonistic effects at the central cannabinoid (CB1) receptor (Matsuda et al., 1990), which is the only one known to be expressed in the brain. The highest density of CB1 receptors is observed in the cerebral cortex, basal ganglia, hippocampus, anterior cingulate cortex, and cerebellum. These brain regions are critically involved in the pathogenesis of schizophrenic disorders (Dean et al., 2001, Herkenham et al., 1990). A second cannabinoid receptor, CB2, is expressed in peripheral tissues, principally in the immune system (Munro et al., 1993). Following the discovery of specific cannabinoid receptors, at least five endogenous cannabinoids have been identified. Among these, anandamide is the most potent agent that behaves as a typical cannabimimetic compound (Devane et al., 1992). 11-OH-Δ9-Tetrahydrocannabinol (11-OH-THC) is the most important psychotropic metabolite of Δ9-THC with a similar spectrum of actions and similar kinetic profiles as the parent molecule. 11-nor-9-carboxy-THC (THC-COOH) is the most important non-psychotropic metabolite of Δ9-THC that possesses anti-inflammatory and analgesic properties by mechanisms similar to non-steroidal anti-inflammatory drugs (NSAIDs) (Grotenhermen, 2005).

A number of studies suppose a close relationship between cannabis use, the endogenous cannabinoid system, and schizophrenia (Leweke et al., 2004). There are several lines of evidence supporting such a hypothesis. First, acute administration of Δ9-THC to normal volunteers induced characteristic psychomotor alterations (Rodriguez de Fonseca et al., 1998), psychotic reactions (Johns, 2001), and cognitive impairments (Emrich et al., 1997, Jager et al., 2007) closely resembling the signs and symptoms of schizophrenia. Clinical signs of chronic cannabis use may also resemble negative symptoms of schizophrenic disorders, also discussed as the putative amotivational syndrome (Schwartz, 1987). Second, in schizophrenic patients, cannabis consumption has been found to worsen positive symptoms of schizophrenia (Turner and Tsuang, 1990) even when the patients are under a regular antipsychotic medication (Treffert, 1978). It also results in a poor outcome and liability to relapse (Martinez-Arevalo et al., 1994). Third, different epidemiological studies have shown that cannabis use can increase the risk for the development of schizophrenia (Andreasson et al., 1987, Arseneault et al., 2002, Miller et al., 2001, Van Os et al., 2002). Fourth, twofold higher endocannabinoid levels in cerebrospinal fluid of schizophrenic patients were found in comparison to non-schizophrenic controls (Leweke et al., 1999). And finally, two independent post-mortem studies have observed an increased density of CB1 receptors in the prefrontal cortex of schizophrenic patients (Dean et al., 2001, Zavitsanou et al., 2004) that is one of the dysfunctional areas in schizophrenia and a site of action for antipsychotic drugs (Thierry et al., 1978).

Cannabidiol (CBD) is the second most abundant constituent of C. sativa. Preclinical evidence suggested neuroprotective and antipsychotic properties of CBD (Mechoulam et al., 2002, Roser et al., in press). In contrast to Δ9-THC, CBD has no psychoactive properties. CBD binds with low affinity to the orthosteric site on the CB1 receptor, but has been known to reduce several psychotropic effects of Δ9-THC via allosteric modification (Pertwee, 2008, Petitet et al., 1998). It is of note that CBD does not act only through this known cannabinoid receptor. The existence of various, not well characterized, new cannabinoid receptors has been suggested (Breivogel et al., 2001, Hajos et al., 2001, Monory et al., 2002). It is possible that CBD may be a ligand to one or more of these receptors. Recently, Ryberg et al. (2007) identified the receptor GPR55 as a novel cannabinoid receptor. The authors have found that CBD as well as CB1-agonistic exo- and endocannabinoids such as CP-55,940 and anandamide show ligand activity at this receptor. It is also possible that the effects of CBD are due to its inhibition of anandamide reuptake and enzymatic hydrolysis, and to its antioxidative effect mediated by an unknown receptor (Mechoulam et al., 2002).

The P300 wave is a cognitive event-related brain potential (ERP) component that reflects attentional resource allocation and active working memory (Polich, 1991). It is most commonly elicited in the context of an auditory ‘oddball’ experimental paradigm in which a sequence of repetitive standard stimuli is interrupted infrequently and unexpectedly by physically deviant (‘oddball’) stimuli, designated as the ‘target’. Subjects are instructed to indicate their perception of each target by making a button press or other response. The amplitude of the P300 is typically largest over the medial and parietal scalp locations, and its peak latency may occur between about 300 and 1000 ms after stimulus onset (Picton, 1992). The intracerebral origin of the P300 is poorly understood, but intracranial electrophysiological monitoring, low resolution electromagnetic tomography (LORETA) and functional magnetic resonance imaging (fMRI) studies have similarly detected multiple sources of P300-like ERP activity, including the hippocampus, thalamus, inferior parietal lobe, superior temporal gyrus, and prefrontal lobe (Halgren et al., 1980, Kiehl et al., 2001, Mulert et al., 2004, Smith et al., 1990, Stapleton and Halgren, 1987, Winterer et al., 2001, Yingling and Hosobuchi, 1984). Similarly, the neurochemical substrates of the P300 are unclear but presumably involve various neurotransmitter systems in the brain (Frodl-Bauch et al., 1999, Picton, 1992).

Reduced amplitudes of the auditory P300 response over the midline central and parietal scalp electrode locations are a robust finding in schizophrenia patients that have been replicated repeatedly with virtually uniform consistency (Blackwood et al., 1987, Braff, 1993, Bramon et al., 2004, Bramon et al., 2005, Duncan, 1988, Ford, 1999, Papageorgiou et al., 2004, Roth and Cannon, 1972). Moreover, a distinct left-smaller-than-right voltage asymmetry at temporal electrode sites has been observed (Jeon and Polich, 2001), a finding that is correlated with a decreased left superior temporal gyrus volume (McCarley et al., 1993). Additionally, schizophrenia patients often show a prolonged auditory P300 latency in comparison to healthy control subjects (O'Donnell et al., 1995), but this finding appears to be much more equivocal and less reliable. A recent meta-analysis reported a significant effect size of 0.59 for auditory P300 latency, compared with an effect size of 0.89 for auditory P300 amplitude (Jeon and Polich, 2003). There is evidence that reduced P300 amplitudes represent a trait marker of schizophrenia but reports about correlations between schizophrenic psychopathology, particularly positive symptomatology, and P300 amplitude indicate also a state character (Gallinat et al., 2001). Auditory P300 amplitude abnormalities have also been detected in schizophrenia patients at the initial and advanced stages of illness and remain detectable even in patients that were free of clinical symptoms or in relative remission (Ford et al., 1994, Juckel et al., 1996, Umbricht et al., 2006, Van der Stelt et al., 2005). It is of note that the P300 abnormalities in schizophrenia are not specific to this disorder. Reduced P300 amplitudes have also been observed in Alzheimer's disease (Polich et al., 1990), alcoholism (Hesselbrock et al., 2001), bipolar affective disorder (O'Donnell et al., 2004), and unipolar depression (Gangadhar et al., 1993).

Since CB1 CB1-agonistic endo- and exocannabinoids have been found to impair attention and working memory by interfering prefrontal and hippocampal areas (Iversen, 2003, Ranganathan and D'Souza, 2006, Solowij, 1998) similar to the cognitive dysfunctions seen in schizophrenia patients, we used the auditory P300 to study biological mechanisms of cannabis-induced psychotic states and schizophrenic conditions in normal subjects by comparing Δ9-THC and standardized cannabis extract that principally contains Δ9-THC and CBD. We expected group differences in the effects of Δ9-THC and cannabis extract with reduced P300 amplitudes under Δ9-THC predominantly at midline central and parietal electrodes, as observed in schizophrenia, and negative correlation coefficients between the plasma concentration of Δ9-THC and the P300 amplitude. Since CBD has been known to counteract several psychotropic effects of Δ9-THC, we expected less distinctive P300 deficits under cannabis extract.

Section snippets

Subjects

Twenty-seven healthy, right-handed, and normal hearing subjects were screened and randomised, from which twenty (10 male, 10 female, mean age 28.2 ± 3.1 years) finished the study according to the protocol. Two male and five female subjects were excluded from the analysis due to technical problems during the ERP recording, insufficient quality of the recording (mainly due to a small number of artifact free sweeps, see below), or hypersensitivity towards the study medication in terms of panic

Results

Intraindividual comparisons revealed significantly reduced P300 amplitudes at Fz, Cz and Pz under Δ9-THC vs. under placebo (Fz: F(1/19) = 3.432, p = 0.034; Cz: F(1/19) = 5.817, p = 0.015; Pz: F(1/19) = 5.593, p = 0.008, Table 1, Fig. 1). Similarly to the pure Δ9-THC, a significant reduction of P300 amplitudes under cannabis extract vs. under placebo was found at Cz (F(1/19) =5.817, p = 0.005) and Pz (F(1/19) = 5.593, p = 0.016), while a statistical tendency was observed at Fz (F(1/19) = 3.432, p = 0.064). Comparing

Discussion

The results of the present study demonstrate, as expected, that acute administration of the CB1 agonist Δ9-THC to healthy subjects is significantly associated with reduced auditory P300 amplitude at midline frontal, central, and parietal electrodes in comparison to placebo, reflecting deficient attentional resource allocation and working memory. These findings are in line with the findings obtained from P300 studies in schizophrenia patients (Bramon et al., 2005), and may confirm the hypothesis

Role of the funding source

Funding for this study was provided by the Institute for Clinical Research, Berlin, Germany. The Institute for Clinical Research had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Contributors

Patrik Roser, Georg Juckel and Jürgen Gallinat wrote the manuscript. Andreas M. Stadelmann and Georg Juckel designed the study and wrote the protocol. Patrik Roser and Jürgen Gallinat performed the experiments. Patrik Roser managed the literature searches. Patrik Roser and Johannes Rentzsch undertook the statistical analysis. Thomas Nadulski performed the pharmacokinetic analyses. All authors contributed to and have approved the final manuscript.

Conflict of interest

Georg Juckel is consultant and recipient of speaker honoraria from Janssen-Cilag, AstraZeneca, Lilly, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth. Jürgen Gallinat received honoraria from Bristol-Myers Squibb and AstraZeneca. All authors declare that they have no further conflicts of interest.

Acknowledgement

This study was supported by the Institute for Clinical Research, Berlin, Germany.

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      P300 generators have been primarily localized to the prefrontal cortex (P3a) and temporal-parietal junction (P3b) (67). Similar to MMN, P300 depends on NMDAR neurotransmission (68), but noradrenergic (69), dopaminergic (59), GABAergic (gamma-aminobutyric acidergic) (70), serotonin 5-HT2A (71), cholinergic muscarinic (72) and cannabinoid (73,74) receptors may also be involved. Both target P3b and novelty P3a amplitude reductions are well established in schizophrenia, especially during auditory tasks (29,30,75).

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