To date, there is no evidence for gross morphological and structural changes in brain following short-term or long-term marijuana smoking. Although this has been investigated over many years, of particular interest here are studies that have utilised modern imaging techniques such as magnetic resonance imaging (MRI). There were no regional or global changes in brain tissue volume or composition in cannabis users (Block et al. 2000). More subtle changes can be determined through post-mortem analysis using radiolabelled compounds, or measurement of endocannabinoid levels. Such work showed reduced cannabinoid binding in caudate and hippocampus of Alzheimer's brains (Westlake et al. 1994), and in normal ageing (Biegon and Kerman 1995). No such studies have been reported on chronic marijuana smokers yet.
Alterations in brain function following acute and chronic use of cannabis is nevertheless detectable using cerebral blood flow (CBF) measurements such as positron emission tomography (PET) and multi-site EEG. Although very impor tant for the understanding of brain regions associated with behavioural changes, CBF measurements are not ideal for determination of marijuana-induced changes in brain function (Mathew and Wilson 1991; also see chapter by Lindsey et al. in this handbook). This is mainly due to contaminating effects of cannabis on vascular smooth muscles and altered vasomotor tone, but also due to alterations in respiration and general circulation (for details see chapter by Pacher et al. in this volume). Since such circulation-related effects cannot be controlled for properly, they may lead to increased variability and make interpretations of CBF studies in marijuana users difficult. Fortunately, there is no conclusive evidence to suggest these peripheral effects impact significantly on blood circulation in brain. PET, for instance, makes use of a radiotracer (11C, 13N or 15O) followed by reconstruction of tomographic slices depicting isotope concentrations in different brain regions. A shortcoming of PET is, however, its low resolution. Areas of less than 2 mm cannot be resolved properly. As with psychological testing, results of PET tests have been ambiguous; some reported decreased CBF, others increased CBF; some found no difference (see Wilson and Mathew, 2002 for review). Yet, it remains elusive as to why this variability is observed.
Collectively, data from CBF studies confirm the contention that alterations in brain function predominate in areas with high levels of cannabinoid receptor sites (Pertwee 1997). However, global marijuana intoxication will induce multiple effects at the same time, making it difficult to correlate any particular effect and CBF change. Overall, it has been found that chronic cannabis users have a lower resting level of brain blood flow than controls and that marijuana smoking or intravenous administration increases CBF in most cortical areas in a dose- and time-dependent manner (Wilson and Mathew 2002). Increases in CBF peaked at 30 min and returned to near-baseline levels 2 h after smoking. Subcortical areas including basal ganglia, thalamus, hippocampus and amygdala showed reduced CBF relative to placebo and both hemispheres were affected to the same extent. In addition, cere-bellar blood flow increased by at least 1 standard error of the mean in about 60% of subjects. It should be obvious from these results that systemic administration of marijuana may not help to resolve the question as to what the function of individual subpopulations of receptors located in specific brain areas might be. CBF will provide important information as to global changes related to drug treatment.
An interesting approach in utilising PET is its combination with cognitive tasks. While subjects perform verbal memory recall tasks, they are monitored in the scanner. Relative to controls, frequent marijuana users presented with reduced memory-related blood flow in prefrontal cortex, but increased CBF in hippocampus and cerebellum (Block et al. 2002). These alterations were paralleled by an increased recency effect, suggesting that users rely on short-term memory and thus fail in multiple trial learning tasks, while control subjects encode and retrieve episodic memory. Consequently, it may be argued that chronic marijuana use leads to a reconfiguration of memory processing. Reductions in prefrontal CBF are consistent with deficits in working memory.
Another functional approach is the use of multiple recording sites on the skull to detect global changes in cortical activity through EEG. Event-related potentials (ERPs) derived from EEGs recorded during complex cognitive tasks have been recorded in a number of studies by Solowij and colleagues (see Solowij 1998 for review). Collectively, data in this area can be summarised as follows. Independent of frequency of marijuana smoking, ERPs in frontal regions progressively decline with thenumberofyearsofuse. Thissuggestsaphysiologicalmechanismforthere-duced ability to focus attention and filter out irrelevant information. Interestingly, the deficit was maintained even after several months of abstinence. The speed of information processing can be measured as positive wave at 300 ms (P300) of the ERP. Similar to reaction times, P300 was impaired with increasing frequency and length of marijuana use. Long-term marijuana use manifests in elevated absolute power and interhemispheric coherence of alpha and theta rhythm of the EEG (Struve et al.1994) and reduces the P50 auditory sensory gating response (Patrick et al. 1999).
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