Review Article | Open Access
Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use
Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal) and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed.
A body of literature over the past three decades has established cannabis use to be a significant risk factor for the onset and development of schizophrenia [1–5], with early onset of use (by age 15) believed to confer greater risk than later onset of use . In a comprehensive meta-analysis of prospective and population-based studies by Moore et al. , an increased risk of psychosis was found in individuals who had ever used cannabis, and a dose-response effect was yielded in which greater risk applied to people who used cannabis most frequently. The authors could not, however, draw a definitive causal link between cannabis use and psychosis on grounds that the studies were observational in nature, and no robust evidence supports the view that early-age onset of cannabis use might be more harmful than later-age onset of use. The increased risk of psychosis in people using cannabis from a younger age could indicate greater cumulative exposure to cannabis rather than a sensitive period of exposure.
The high prevalence of cannabis use in schizophrenia combined with observations that cannabis exacerbates the positive symptoms has driven research to investigate why cannabis is used so widely in this population. According to the self-medication hypothesis, there are beneficial effects of cannabis and cannabinoids on the symptoms of schizophrenia. Cross-sectional studies comparing users and nonusers have shown that cannabis use is associated with a reduction in negative symptoms [8–14]. Animal and human models have also suggested that cannabinoids possess antipsychotic properties [15–17]. One of these studies  involved a randomised, double-blind controlled trial in 42 patients with acute schizophrenia and found antipsychotic properties of cannabidiol (CBD) that were comparable to amisulpride. Other studies in which CBD has been administered to rats as well as healthy human volunteers have also demonstrated antipsychotic properties of CBD [16, 17].
These mixed findings on how cannabis or cannabinoids impact on the positive and negative symptoms of schizophrenia may in part be attributable to differences in methodology and research design. For example, studies have used different methods to measure cannabis exposure and assess outcome , and results are likely to be influenced by whether the studies were observational (prospective versus cross sectional) or experimental (direct drug administration by way of randomised controlled trials or other means). A range of other potential confounding factors are also likely to have contributed to the inconsistent results, particularly where observational designs were employed.
From a neuropsychological perspective, a paucity of research exists. Cannabis use, in some studies of schizophrenia, has been found to be associated with worse neuropsychological performance [18–20]. Conversely, cannabis has been suggested to improve neuropsychological functioning [21–25]. Only one of these studies  involved a randomised, double-blind, placebo-controlled trial, in which the effects of i.v. -tetrahydrocannabinol (THC) on cognition were studied in 13 stabilised schizophrenia patients and 22 healthy controls, 30 minutes after drug administration. All participants administered THC relative to their placebo baseline performance demonstrated cognitive impairments in domains such as memory and attention, and the schizophrenia group performed more poorly than the control group. Five of the remaining studies [19, 21–25] were cross sectional in nature in which current or past cannabis users with schizophrenia were compared to non current users or those without a past history of use; and one study  performed a correlational analysis examining the relationship between level of cannabis use over the preceding year and cognition in persons with a psychotic illness.
Again, the inconsistencies in the findings between these neuropsychological studies are likely to be at least, in part, attributable to methodological variability between the studies, as well as methodological limitations within each study (for full review, see Coulston et al. ). For example, different methods were used to measure cannabis exposure, as per the studies detailed earlier which assessed the clinical symptoms. All seven neuropsychological studies used only a single index to classify cannabis use, which does not adequately reflect the variable and fluctuating level of cannabis use that may occur over time in the schizophrenia population. In three instances [19, 22, 23], cannabis use was defined solely with respect to abuse/dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) . In one study , only the acute effects of cannabis were examined, whilst in another study , only the residual, longer-term effects of cannabis were examined in participants who had been abstinent for at least 28 days. Such indices of cannabis use fail to consider factors such as recency and frequency of use (beyond the acute intoxication phase), which have been found to impact on cognition in the normal population .
Other limitations in several of these neuropsychological studies, some of which are also relevant to those studies mentioned earlier that focused on the associations between cannabis use and the positive/negative symptoms, include absence of drug screening procedures prior to assessment, restricted range of cognitive functions assessed, minimal or no control of important confounding variables such as current and past history of other substance use (including caffeine and nicotine), and a range of demographic and medical/psychiatric variables (e.g., gender, level of education, premorbid IQ, early-age onset of psychosis, duration of mental illness, medications). Furthermore, several of these studies did not include a control group which limits interpretation of their findings, because it cannot be determined if the cognitive performance of the cannabis users was frankly impaired (i.e., fell below the normal range of performance) or, was in fact within the normal range of performance.
One of the most comprehensive cross-sectional neuropsychological studies to date  was conducted by considering all the limitations and range of potential confounds detailed above. The investigators found that cannabis use was associated with enhanced cognitive functioning, predominantly in the areas of attention, processing speed, and executive functioning, domains which rely heavily on prefrontal cortical networks.
Additional reasons for the discrepancies across the literature on the effects of cannabis use on symptomatology and cognition may pertain to the fact that separate and specialised groups of people with schizophrenia react differently to cannabis and other substances. Empirical literature indicates that systematic research on schizophrenia is difficult due to the disorder’s heterogeneity and different diagnostic conceptualisations , which would imply that the neurochemical imbalances in different brain regions are not equal in all persons. As such, the schizophrenia population is deemed pharmacologically heterogenous , in which case the interaction between cannabinoids, neurotransmitters, and antipsychotic treatments is likely to vary between individuals. Subsequently, a balanced neurochemical framework to conceptualise both the adverse and potential therapeutic use of cannabinoids for respective groups of the population would be useful for two reasons; first, in light of the new emerging literature supporting a therapeutic benefit for all symptoms, and second, in the context of relatively minimal research that has been conducted in the field of neuropsychology. Further, positing a more balanced neurochemical framework that perhaps underpins an aspect of the core pathophysiology of schizophrenia allows a reconceptualisation of aetiology and treatment of this complex disorder. In particular, a balanced framework promotes awareness that there may not be a unidirectional method of treatment for all subgroups of the population, thereby providing a foundation for novel approaches to investigating the basis of this neuropsychiatric condition.
This paper briefly outlines the neurochemical processes associated with schizophrenia and cannabis use in the normal population, with implications for the effects of cannabinoids on the positive and negative symptoms, as well as cognitive impairment.
2. Symptomatology in Schizophrenia and Neurotransmitter Systems
The effectiveness of conventional antipsychotic medications in alleviating positive symptoms is largely attributed to the blockade of dopamine transmission, especially in the mesolimbic system [32, 33]. Atypical antipsychotics are also believed to exert their therapeutic benefits on psychotic symptoms (in the same cerebral regions) via their antagonistic actions on serotonin, acetylcholine, and noradrenaline receptors [34–37], and via agonistic actions on GABA  and glutamate transmission . This suggests that in the unmedicated state, the positive symptoms of schizophrenia are, at least in part, attributable to hyperactivation of dopamine, serotonin, acetylcholine, and noradrenaline, and hypoactivity of GABA and glutamate in the mesolimbic and other subcortical regions.
Moreover, reduced prefrontal dopamine activity is associated with exaggerated striatal dopaminergic activity , which is thought to account for the negative symptoms and cognitive impairment. Negative symptoms and cognitive impairments have also been associated with decreased prefrontal acetylcholine, serotonin, noradrenaline, and glutamate [39–47]. The therapeutic action of atypical antipsychotics involves facilitating prefrontal neurotransmission across all of these neurotransmitter systems, except GABA [48–53]. This suggests that in the unmedicated state, the negative symptoms and cognitive impairments of schizophrenia are, at least in part, attributable to hypoactivity of dopamine, serotonin, acetylcholine, noradrenaline, and glutamate in the prefrontal region.
With respect to GABA, although direct enhancement of prefrontal activity would be a potential treatment for schizophrenia , atypical antipsychotics tend to exert their effect in the prefrontal cortex by inhibiting release of GABA from interneurons . This subsequently enhances prefrontal neurotransmitter activity. Dopamine and serotonin signalling, associated with antipsychotics, may therefore be responsible for the inhibition of GABAergic currents, and subsequent increase in prefrontal activity [56, 57].
3. The Endocannabinoid System
Cannabinoids exert their effect by binding to specific endogenous cannabinoid receptors  known as CB1 and CB2, which are located in the CNS and peripherally in the spleen and immune cells [59, 60]. The CB1 receptors are widely distributed in the brain including the cerebral cortex (especially the frontal and medial temporal lobes), limbic areas, basal ganglia, ventral tegmental area, thalamus, hypothalamus, cerebellum, and brainstem [58, 61–65].
CB1 receptors reside within the lipid membrane of the presynaptic neuron terminals, are modulated by the postsynaptic release of endocannabinoids (namely anandamide and 2-arachidonoyl glycerol), and are also influenced by exogenously consumed cannabinoids. CB1 receptors act as neuromodulators through coupling with intracellular G-proteins controlling cyclic adenosine monophosphate (c-AMP) formation and Ca2+ and K+ transport. In this respect, the cannabinoid system has important interactions with several neurotransmitter systems.
Cannabinoids augment potassium stimulated striatal dopamine efflux and subsequently dopamine release in the mesolimbic system (especially the nucleus accumbens), medial prefrontal cortex, midbrain regions, and substantia nigra [58, 66–74]. THC has been shown to facilitate stimulation of dopamine release in the medial forebrain bundle of the mesolimbic system at dose ranges pharmacologically relevant to human recreational use . As the positive symptoms of schizophrenia are related to elevated dopamine release, particularly in the mesolimbic system, cannabinoids have long been implicated in worsening the positive symptoms of schizophrenia [73, 75, 76].
In contrast to the effect of cannabinoids on dopamine release in the mesolimbic system, significant evidence exists for the CB1 receptor mechanism to play an important role in “dampening” neuroexcitability [59, 60, 77]. It has been demonstrated that in the cerebral cortex, serotonin activity is inhibited by cannabinoid receptor agonists (e.g., WIN 55,212 and CP-55,940) . Conversely, studies employing CB1 receptor antagonists (e.g., SR 141716A) have demonstrated increases in serotonin in various brain regions including the medial prefrontal cortex and nucleus accumbens .
Cannabinoids have been demonstrated to decrease acetylcholine release in the medial prefrontal cortex, hippocampus, and striatum [80–82]. Likewise, the CB1 receptor antagonist (SR 141716A) has resulted in an increase in acetylcholine in the medial prefrontal cortex and hippocampus [79, 83].
Noradrenaline activity in various areas of the brain including the hippocampus, cerebellum, hypothalamus, and cerebral cortex, has been inhibited by the cannabinoid receptor agonist (WIN 55,212) . This inhibition was subsequently attenuated by the cannabinoid receptor antagonist (SR 141716). Cannabinoid-inhibited release of noradrenaline has also been demonstrated in the hypothalamus and striatum [60, 85–87].
The CB1 receptor has been demonstrated to be present in high concentration at presynaptic terminals of glutaminergic synapses in the hippocampus and other areas of the brain . In general, activation of the CB1 receptor has been shown to inhibit glutamate release in the cerebellum, hippocampus, prefrontal cortex, and substantia nigra [77, 78, 89–91].
CB1 receptor mediated decreases in GABA has also been demonstrated in brain regions including the prefrontal cortex [78, 88, 92, 93], hippocampus [90, 94, 95], and subcortical regions including the basal ganglia [96–100].
4. Cannabinoids and Prefrontal Neurotransmission
Despite the general consensus that cannabinoids inhibit all major neurotransmitters (except dopamine) in various brain regions including the prefrontal cortex, a number of studies have supported the converse notion that cannabinoids in fact stimulate neurotransmission release in the prefrontal cortex [88, 92, 93].
An example of how neurotransmission of dopamine could be theoretically enhanced by cannabinoids in the prefrontal cortex is related to CB1 receptors being preferentially located on GABAergic interneurons in areas including the cerebral cortex, ventral tegmental area, and hippocampus . Cannabinoids such as THC decrease the excitability of GABA-ergic interneurons, and therefore, given GABA is the major inhibitory neurotransmitter in the CNS, disinhibition of dopamine and glutamate follows. Consequently, increases in the outflow of neurotransmission parallel the decrease in extracellular GABA.
As another example of how neurotransmission is theoretically enhanced by cannabinoids in the prefrontal cortex, studies have demonstrated that increased dopamine neurotransmission in the mesolimbic projections from the nucleus accumbens triggers an inhibition of GABA-ergic efferents to the basal forebrain. The process of inhibiting the release of GABA, in turn, decreases the inhibition of other neurotransmitters such as dopamine, acetylcholine, noradrenaline, and glutamate. A specific example of this process has been postulated where dopamine’s direct inhibitory effect on both glutamate and GABA-ergic activity leads to an increased excitability of cholinergic flow [46, 101].
Proceeding from these lines of reasoning, studies have demonstrated that in the prefrontal region, cannabinoids mediate increases in noradrenaline , acetylcholine [103, 104], and glutamate [92, 105]. With respect to serotonin and GABA, studies have demonstrated that cannabinoids mediate the inhibition of reuptake in cortical areas, which leads to their increase .
5. The Effects of Cannabis on Cognition and the Positive/Negative Symptoms of Schizophrenia
Table 1 presents a summary of the information discussed thus far. The grey arrows in the “Schizophrenia” columns represent the directions of neurotransmitter release in the unmedicated state of the disorder in both the prefrontal cortex and subcortical regions. As discussed above, the negative symptoms and cognitive impairments are generally conceptualised in terms of decreased neurotransmission of all six major systems in the prefrontal cortex, whilst the positive symptoms are generally thought to arise because of increased neurotransmission of dopamine, serotonin, acetylcholine and noradrenaline systems, and decreased neurotransmission of glutamate and GABA systems in subcortical regions.
The black arrows in the “Atypical antipsychotic treatment” columns represent how these medications are purported to ameliorate the symptoms and cognitive impairments of schizophrenia. Specifically, atypical antipsychotics are postulated to ameliorate the negative symptoms and cognitive impairment by stimulating neurotransmission in the prefrontal cortex (of all neurotransmitters except GABA), and are thought to ameliorate the positive symptoms by inhibiting dopamine, serotonin, acetylcholine, and noradrenaline, and by increasing glutamate and GABA in subcortical regions.
Of pertinent interest to this review is the theoretical amelioration and/or exacerbation of the symptoms and cognitive impairments of schizophrenia that cannabis use may produce. As Table 1 shows, cannabis in the normal population leads to excitation of dopamine in the prefrontal cortex. However, what remains relatively less certain is whether cannabis leads to excitation or inhibition of the other five major neurotransmitters in the prefrontal cortex (i.e., serotonin, acetylcholine, noradrenaline, glutamate, and GABA), given that evidence for both modes of action have been presented. Hence, the postulated effect of cannabis on these five systems is indicated by both grey and black arrows.
Consequently, looking at the “Schizophrenia (unmedicated)” and “Cannabis use” columns in conjunction, Table 1 shows that although cannabis has the potential to exacerbate the negative symptoms and cognitive impairments of schizophrenia via contributing further to the “hypofrontal” nature of the disorder, cannabis also has a therapeutic potential by facilitating neurotransmission (at least in the dopaminergic system) in the prefrontal cortex. In line with the latter perspective, research has demonstrated enhanced cognitive performance in schizophrenia with comorbid cannabis use [21–25, 29], which may be attributable to stimulation of prefrontal neurotransmission.
In subcortical regions, Table 1 shows that cannabis use is associated with excitation of dopamine and inhibition of all the other five major neurotransmitters (i.e., serotonin, noradrenaline, acetylcholine, glutamate, and GABA). Hence, cannabis has the potential to counteract increased levels of serotonin, acetylcholine, and noradrenaline that occur in subcortical regions in untreated schizophrenia and thus, provide an antipsychotic therapeutic effect. However, excitation of dopamine and inhibition of glutamate and GABA in subcortical regions produced by cannabis use may augment the dysregulation that occurs in these three systems in untreated schizophrenia, and possibly exacerbate the positive symptoms.
6. Summary and Conclusion
Cannabis use in the schizophrenia population has been shown to worsen the prognosis and increase the burden of the disorder. However, evidence exists for a subgroup of the population to suggest that cannabinoids have therapeutic effects on the negative and positive symptoms, as well as cognitive impairments. Although this evidence is not conclusive and requires further research and replication, a more comprehensive and broad-based neurochemical framework has been presented in this paper, offering an explanation for the potentially therapeutic effects of cannabinoids in addition to its adverse effects.
Whilst the neurochemical effects of cannabinoids are complex, cannabinoids appear to have at least in part, a “restorative” effect on neurotransmitter dysfunctions in schizophrenia, which may underpin the biological substrate of the therapeutic effects cannabis has been demonstrated to have in recent studies.
In the context of recent research by Coulston et al. , future studies need to establish which subgroups of schizophrenia most benefit from cannabinoids as a putative “treatment”; which subgroups demonstrate nil or minimal exacerbation of positive symptoms in the context of cannabis use, or indeed, which subgroups may experience antipsychotic effects of cannabis; how such a treatment may complement or interact with standard antipsychotics and other psychiatric treatments; what constitutes an effective quantity or dose of cannabinoids to exert a beneficial impact on cognition; what precise frequency of administration would be required; how long the effects of cannabinoids last on cognition following a recent dose; how such a treatment may generalise to other domains of real-life functioning such as employment and social settings (and in particular, cognitive processes required to function well in these settings); and whether such a treatment can be generalised to older age groups. Methods by which future research could proceed to address these questions include randomised, double-blind, controlled drug trials.
Clearly there are many questions that need to be addressed and the use of further randomised, double-blind studies is necessary to establish the effects of cannabis across the domains of cognition, mood, and mentation. However, given the prevalence of cannabis use and its integral role in the clinical manifestation of psychosis, this is an area for future research, and reconceptualising our neurochemical understanding is perhaps a useful first step. In this context, the consideration, appraisal, and rigorous testing of novel models are necessary, and are likely to advance our understanding.
- S. Andréasson, P. Allebeck, A. Engström, and U. Rydberg, “Cannabis and schizophrenia. A longitudinal study of Swedish conscripts,” Lancet, vol. 2, no. 8574, pp. 1483–1486, 1987.
- D. M. Fergusson, L. J. Horwood, and N. R. Swain-Campbell, “Cannabis dependence and psychotic symptoms in young people,” Psychological Medicine, vol. 33, no. 1, pp. 15–21, 2003.
- P. A. Silva and W. R. Stanton, From Child to Adult: The Dunedin Multidisciplinary Health and Development Study, Oxford University Press, Auckland, UK, 1996.
- J. Van Os, M. Bak, M. Hanssen, R. V. Bijl, R. De Graaf, and H. Verdoux, “Cannabis use and psychosis: a longitudinal population-based study,” American Journal of Epidemiology, vol. 156, no. 4, pp. 319–327, 2002.
- S. Zammit, P. Allebeck, S. Andréasson, I. Lundberg, and G. Lewis, “Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study,” British Medical Journal, vol. 325, no. 7374, pp. 1199–1201, 2002.
- L. Arseneault, M. Cannon, R. Poulton, R. Murray, A. Caspi, and T. E. Moffitt, “Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study,” British Medical Journal, vol. 325, no. 7374, pp. 1212–1213, 2002.
- T. H. Moore, S. Zammit, A. Lingford-Hughes et al., “Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review,” Lancet, vol. 370, no. 9584, pp. 319–328, 2007.
- G. Bersani, V. Orlandi, S. Gherardelli, and P. Pancheri, “Cannabis and neurological soft signs in schizophrenia: absence of relationship and influence on psychopathology,” Psychopathology, vol. 35, no. 5, pp. 289–295, 2002.
- G. Bersani, V. Orlandi, G. D. Kotzalidis, and P. Pancheri, “Cannabis and schizophrenia: impact on onset, course, psychopathology and outcomes,” European Archives of Psychiatry and Clinical Neuroscience, vol. 252, no. 2, pp. 86–92, 2002.
- M. T. Compton, A. C. Furman, and N. J. Kaslow, “Lower negative symptom scores among cannabis-dependent patients with schizophrenia-spectrum disorders: preliminary evidence from an African American first-episode sample,” Schizophrenia Research, vol. 71, no. 1, pp. 61–64, 2004.
- M. T. Compton, N. E. Whicker, and K. M. Hochman, “Alcohol and cannabis use in urban, African American, first-episode schizophrenia-spectrum patients: associations with positive and negative symptoms,” Journal of Clinical Psychiatry, vol. 68, no. 12, pp. 1939–1945, 2007.
- C. Dubertret, I. Bidard, J. Adès, and P. Gorwood, “Lifetime positive symptoms in patients with schizophrenia and cannabis abuse are partially explained by co-morbid addiction,” Schizophrenia Research, vol. 86, no. 1–3, pp. 284–290, 2006.
- V. Peralta and M. J. Cuesta, “Influence of cannabis abuse on schizophrenic psychopathology,” Acta Psychiatrica Scandinavica, vol. 85, no. 2, pp. 127–130, 1992.
- P. D. Skosnik, S. Park, L. Dobbs, and W. L. Gardner, “Affect processing and positive syndrome schizotypy in cannabis users,” Psychiatry Research, vol. 157, no. 1–3, pp. 279–282, 2008.
- F. M. Leweke, D. Koethe, C. W. Gerth et al., “Cannabidiol as an antipsychotic agent,” European Psychiatry, vol. 22, supplement 1, p. S21, 2007.
- A. W. Zuardi, J. A. S. Crippa, J. E. C. Hallak, F. A. Moreira, and F. S. Guimarães, “Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug,” Brazilian Journal of Medical and Biological Research, vol. 39, no. 4, pp. 421–429, 2006.
- A. W. Zuardi, J. A. Rodrigues, and J. M. Cunha, “Effects of cannabidiol in animal models predictive of antipsychotic activity,” Psychopharmacology, vol. 104, no. 2, pp. 260–264, 1991.
- D. C. D'Souza, W. M. Abi-Saab, S. Madonick et al., “Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction,” Biological Psychiatry, vol. 57, no. 6, pp. 594–608, 2005.
- F. Liraud and H. Verdoux, “Effect of comorbid substance use on neuropsychological performance in subjects with psychotic or mood disorders,” Encephale, vol. 28, no. 2, pp. 160–168, 2002.
- A. Pencer and J. Addington, “Substance use and cognition in early psychosis,” Journal of Psychiatry and Neuroscience, vol. 28, no. 1, pp. 48–54, 2003.
- M. C. Jockers-Scherübl, T. Wolf, N. Radzei et al., “Cannabis induces different cognitive changes in schizophrenic patients and in healthy controls,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 31, no. 5, pp. 1054–1063, 2007.
- S. Kumra, E. Thaden, C. DeThomas, and H. Kranzler, “Correlates of substance abuse in adolescents with treatment-refractory schizophrenia and schizoaffective disorder,” Schizophrenia Research, vol. 73, no. 2-3, pp. 369–371, 2005.
- S. Sevy, K. E. Burdick, H. Visweswaraiah et al., “Iowa Gambling Task in schizophrenia: a review and new data in patients with schizophrenia and co-occurring cannabis use disorders,” Schizophrenia Research, vol. 92, no. 1–3, pp. 74–84, 2007.
- J. Stirling, C. White, S. Lewis et al., “Neurocognitive function and outcome in first-episode schizophrenia: a 10-year follow-up of an epidemiological cohort,” Schizophrenia Research, vol. 65, no. 2-3, pp. 75–86, 2003.
- J. Stirling, S. Lewis, R. Hopkins, and C. White, “Cannabis use prior to first onset psychosis predicts spared neurocognition at 10-year follow-up,” Schizophrenia Research, vol. 75, no. 1, pp. 135–137, 2005.
- C. M. Coulston, M. Perdices, and C. T. Tennant, “The Neuropsychology of cannabis and other substance use in schizophrenia: review of the literature and critical evaluation of methodological issues,” Australian and New Zealand Journal of Psychiatry, vol. 41, no. 11, pp. 869–884, 2007.
- American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, APA, Washington, DC, USA, 4th edition, 1994.
- H. G. Pope Jr., A. J. Gruber, J. I. Hudson, M. A. Huestis, and D. Yurgelun-Todd, “Neuropsychological performance in long-term cannabis users,” Archives of General Psychiatry, vol. 58, no. 10, pp. 909–915, 2001.
- C. M. Coulston, M. Perdices, and C. C. Tennant, “The neuropsychological correlates of cannabis use in schizophrenia: lifetime abuse/dependence, frequency of use, and recency of use,” Schizophrenia Research, vol. 96, no. 1–3, pp. 169–184, 2007.
- M. Keyes, “Assessing schizophrenia with the MMPI-2,” Dissertation Abstracts International. Section B, vol. 64, p. 5788, 2004.
- T. A. Ban, “Neuropsychopharmacology and the genetics of schizophrenia: a history of the diagnosis of schizophrenia,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 28, no. 5, pp. 753–762, 2004.
- E. B. Binder, B. Kinkead, M. J. Owens, and C. B. Nemeroff, “The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs,” Biological Psychiatry, vol. 50, no. 11, pp. 856–872, 2001.
- L. Farde, “Brain imaging of schizophrenia—the dopamine hypothesis,” Schizophrenia Research, vol. 28, no. 2-3, pp. 157–162, 1997.
- F. P. Bymaster, D. L. Nelson, N. W. DeLapp et al., “Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and α1-adrenergic receptors in vitro,” Schizophrenia Research, vol. 37, no. 1, pp. 107–122, 1999.
- J. Ma, N. Ye, N. Lange, and B. M. Cohen, “Dynorphinergic GABA neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus,” Neuroscience, vol. 121, no. 4, pp. 991–998, 2003.
- D. Tarsy, R. J. Baldessarini, and F. I. Tarazi, “Effects of newer antipsychotics on extrapyramidal function,” CNS Drugs, vol. 16, no. 1, pp. 23–45, 2002.
- J. L. Waddington, P. J. Scully, and E. O'Callaghan, “The new antipsychotics, and their potential for early intervention in schizophrenia,” Schizophrenia Research, vol. 28, no. 2-3, pp. 207–222, 1997.
- D. C. Goff and J. T. Coyle, “The emerging role of glutamate in the pathophysiology and treatment of schizophrenia,” American Journal of Psychiatry, vol. 158, no. 9, pp. 1367–1377, 2001.
- A. Meyer-Lindenberg, R. S. Miletich, P. D. Kohn et al., “Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia,” Nature Neuroscience, vol. 5, no. 3, pp. 267–271, 2002.
- F. M. Benes, S. L. Vincent, A. Marie, and Y. Khan, “Up-regulation of GABA(A) receptor binding on neurons of the prefrontal cortex in schizophrenic subjects,” Neuroscience, vol. 75, no. 4, pp. 1021–1031, 1996.
- H. F. Clarke, J. W. Dalley, H. S. Crofts, T. W. Robbins, and A. C. Roberts, “Cognitive inflexibility after prefrontal serotonin depletion,” Science, vol. 304, no. 5672, pp. 878–880, 2004.
- J. T. Coyle, “The GABA-glutamate connection in schizophrenia: which is the proximate cause?” Biochemical Pharmacology, vol. 68, no. 8, pp. 1507–1514, 2004.
- J. W. Dalley, D. E. Theobald, E. A. C. Pereira, P. M. M. C. Li, and T. W. Robbins, “Specific abnormalities in serotonin release in the prefrontal cortex of isolation-reared rats measured during behavioural performance of a task assessing visuospatial attention and impulsivity,” Psychopharmacology, vol. 164, no. 3, pp. 329–340, 2002.
- J. I. Friedman, H. Temporini, and K. L. Davis, “Pharmacologic strategies for augmenting cognitive performance in schizophrenia,” Biological Psychiatry, vol. 45, no. 1, pp. 1–16, 1999.
- J. Ichikawa, J. Dai, I. A. O'Laughlin, W. L. Fowler, and H. Y. Meltzer, “Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum,” Neuropsychopharmacology, vol. 26, no. 3, pp. 325–339, 2002.
- M. Sarter and J. P. Bruno, “Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders,” Trends in Neurosciences, vol. 22, no. 2, pp. 67–74, 1999.
- K. Zavitsanou, P. B. Wards, and X.-F. Huang, “Selective alterations in inotropic glutamate receptors in the anterior cingulated cortex in schizophrenia,” Neuropsychopharmacology, vol. 27, pp. 826–833, 2002.
- P. Hertel, G. G. Nomikos, B. Schilström, L. Arborelius, and T. H. Svensson, “Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortex: role of α2-adrenoceptor antagonism,” Neuropsychopharmacology, vol. 17, no. 1, pp. 44–55, 1997.
- J. Ichikawa, T. Kuroki, J. Dai, and H. Y. Meltzer, “Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens,” European Journal of Pharmacology, vol. 351, no. 2, pp. 163–171, 1998.
- K. E. Jardemark, I. Ninan, X. Liang, and R. Y. Wang, “Protein kinase C is involved in clozapine's facilitation of N-methyl-D-aspartate- and electrically evoked responses in pyramidal cells of the medial prefrontal cortex,” Neuroscience, vol. 118, no. 2, pp. 501–512, 2003.
- L. P. Lacroix, M. E. Hows, A. J. Shah, J. J. Hagan, and C. A. Heidbreder, “Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex,” Neuropsychopharmacology, vol. 28, no. 5, pp. 839–849, 2003.
- S. Potvin, E. Stip, and J.-Y. Roy, “Clozapine, quetiapine and olanzapine among addicted schizophrenic patients: towards testable hypotheses,” International Clinical Psychopharmacology, vol. 18, no. 3, pp. 121–132, 2003.
- W. Zhang, K. W. Perry, D. T. Wong et al., “Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex,” Neuropsychopharmacology, vol. 23, no. 3, pp. 250–262, 2000.
- E. Costa, J. M. Davis, E. Dong et al., “A GABAergic cortical deficit dominates schizophrenia pathophysiology,” Critical Reviews in Neurobiology, vol. 16, no. 1-2, pp. 1–23, 2004.
- A. J. Bourdelais and A. Y. Deutch, “The effects of haloperidol and clozapine on extracellular GABA levels in the prefrontal cortex of the rat: an in vivo microdialysis study,” Cerebral Cortex, vol. 4, no. 1, pp. 69–77, 1994.
- X. Wang, P. Zhong, and Z. Yan, “Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex,” Journal of Neuroscience, vol. 22, no. 21, pp. 9185–9193, 2002.
- Z. Yan, “Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications,” Molecular Neurobiology, vol. 26, no. 2-3, pp. 203–216, 2002.
- C. H. Ashton, “Pharmacology and effects of cannabis: a brief review,” British Journal of Psychiatry, vol. 178, pp. 101–106, 2001.
- I. Grant, R. Gonzalez, C. L. Carey, L. Natarajan, and T. Wolfson, “Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study,” Journal of the International Neuropsychological Society, vol. 9, no. 5, pp. 679–689, 2003.
- M. Kathmann, U. Bauer, E. Schlicker, and M. Göthert, “Cannabinoid CB1 receptor-mediated inhibition of NMDA- and kainate- stimulated noradrenaline and dopamine release in the brain,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 359, no. 6, pp. 466–470, 1999.
- C. S. Breivogel and S. R. Childers, “The functional neuroanatomy of brain cannabinoid receptors,” Neurobiology of Disease, vol. 5, no. 6, pp. 417–431, 1998.
- A. N. Gifford, A. Makriyannis, N. D. Volkow, and S. J. Gatley, “In vivo imaging of the brain cannabinoid receptor,” Chemistry and Physics of Lipids, vol. 121, no. 1-2, pp. 65–72, 2002.
- A. B. Ilan, M. E. Smith, and A. Gevins, “Effects of marijuana on neurophysiological signals of working and episodic memory,” Psychopharmacology, vol. 176, no. 2, pp. 214–222, 2004.
- Y. B. Shah, M. J. W. Prior, A. L. Dixon, P. G. Morris, and C. A. Marsden, “Detection of cannabinoid agonist evoked increase in BOLD contrast in rats using functional magnetic resonance imaging,” Neuropharmacology, vol. 46, no. 3, pp. 379–387, 2004.
- P. W. Vik, T. Cellucci, A. Jarchow, and J. Hedt, “Cognitive impairment in substance abuse,” Psychiatric Clinics of North America, vol. 27, no. 1, pp. 97–109, 2004.
- M. Diana, M. Melis, A. L. Muntoni, and G. L. Gessa, “Mesolimbic dopaminergic decline after cannabinoid withdrawal,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 17, pp. 10269–10273, 1998.
- E. D. French, K. Dillon, and X. Wu, “Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra,” NeuroReport, vol. 8, no. 3, pp. 649–652, 1997.
- G. Gessa, M. Melis, A. Muntoni, and M. Diana, “Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors,” European Journal of Pharmacology, vol. 341, no. 1, pp. 39–44, 1998.
- N. Hiroi, “Dependence, tolerance, and alteration in gene expression,” in Marihuana and Medicine, G. G. Nahas, K. M. Sutin, and D. Harvey, Eds., pp. 207–211, Humana Press, Totowa, NJ, USA, 1999.
- V. Patel, M. Borysenko, and M. S. A. Kumar, “Effect of Δ9-THC on brain and plasma catecholamine levels as measured by HPLC,” Brain Research Bulletin, vol. 14, no. 1, pp. 85–90, 1985.
- S. M. Stahl, “Getting stoned without inhaling: anandamide is the brain's natural marijuana,” Journal of Clinical Psychiatry, vol. 59, no. 11, pp. 566–567, 1998.
- E. Valjent, C. Pagès, M. Rogard, M.-J. Besson, R. Maldonado, and J. Caboche, “δ9-tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depends on dopaminergic transmission,” European Journal of Neuroscience, vol. 14, no. 2, pp. 342–352, 2001.
- L. N. P. Voruganti, P. Slomka, P. Zabel, A. Mattar, and A. G. Awad, “Cannabis induced dopamine release: an in-vivo SPECT study,” Psychiatry Research: Neuroimaging, vol. 107, no. 3, pp. 173–177, 2001.
- X. Wu and E. D. French, “Effects of chronic Δ9-tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment,” Neuropharmacology, vol. 39, no. 3, pp. 391–398, 2000.
- L. Degenhardt, W. Hall, and M. Lynskey, “Testing hypotheses about the relationship between cannabis use and psychosis,” Drug and Alcohol Dependence, vol. 71, no. 1, pp. 37–48, 2003.
- W. Hall, “Reducing the harms caused by cannabis use: the policy debate in Australia,” Drug and Alcohol Dependence, vol. 62, no. 3, pp. 163–174, 2001.
- B. E. Akinshola, R. E. Taylor, A. B. Ogunseitan, and E. S. Onaivi, “Anandamide inhibition of recombinant AMPA receptor subunits in Xenopus oocytes is increased by forskolin and 8-bromo-cyclic AMP,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 360, no. 3, pp. 242–248, 1999.
- M. Nakazi, U. Bauer, T. Nickel, M. Kathmann, and E. Schlicker, “Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid CB1 receptors,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 361, no. 1, pp. 19–24, 2000.
- E. T. Tzavara, R. J. Davis, K. W. Perry et al., “The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions,” British Journal of Pharmacology, vol. 138, no. 4, pp. 544–553, 2003.
- G. Carta, F. Nava, and G. L. Gessa, “Inhibition of hippocampal acetylcholine release after acute and repeated delta-9-tetrahydrocannabinoid administration in rats,” Brain Research, vol. 809, pp. 1–4, 1998.
- E. F. Domino, “Cannabinoids and the cholinergic system,” Journal of Clinical Pharmacology, vol. 21, supplement 8-9, pp. 2495–2555, 1981.
- G. L. Gessa, M. S. Mascia, M. A. Casu, and G. Carta, “Inhibition of hippocampal acetylcholine release by cannabinoids: reversal by SR 141716A,” European Journal of Pharmacology, vol. 327, no. 1, pp. R1–R2, 1997.
- G. L. Gessa, M. A. Casu, G. Carta, and M. S. Mascia, “Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A,” European Journal of Pharmacology, vol. 355, no. 2-3, pp. 119–124, 1998.
- E. Schlicker, J. Timm, J. Zentner, and M. Göthert, “Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the human and guinea-pig hippocampus,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 356, no. 5, pp. 583–589, 1997.
- I. Göbel, A. U. Trendelenburg, S. L. Cox, A. Meyer, and K. Starke, “Electrically evoked release of [3H]noradrenaline from mouse cultured sympathetic neurons: release-modulating heteroreceptors,” Journal of Neurochemistry, vol. 75, no. 5, pp. 2087–2094, 2000.
- E. T. Tzavara, K. W. Perry, D. E. Rodriguez, F. P. Bymaster, and G. G. Nomikos, “The cannabinoid CB1 receptor antagonist SR141716A increases norepinephrine outflow in the rat anterior hypothalamus,” European Journal of Pharmacology, vol. 426, no. 3, pp. R3–R4, 2001.
- E. S. Vizi, I. Katona, and T. F. Freund, “Evidence for presynaptic cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the guinea pig lung,” European Journal of Pharmacology, vol. 431, no. 2, pp. 237–244, 2001.
- L. Ferraro, M. C. Tomasini, T. Cassano et al., “Cannabinoid receptor agonist WIN 55,212-2 inhibits rat cortical dialysate γ-aminobutyric acid levels,” Journal of Neuroscience Research, vol. 66, no. 2, pp. 298–302, 2001.
- N. Auclair, S. Otani, P. Soubrie, and F. Crepel, “Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons,” Journal of Neurophysiology, vol. 83, no. 6, pp. 3287–3293, 2000.
- A. F. Hoffman and C. R. Lupica, “Mechanisms of cannabinoid inhibition of GABA(A) synaptic transmission in the hippocampus,” Journal of Neuroscience, vol. 20, no. 7, pp. 2470–2479, 2000.
- J. M. Sullivan, “Mechanisms of cannabinoid-receptor-mediated inhibition of synaptic transmission in cultured hippocampal pyramidal neurons,” Journal of Neurophysiology, vol. 82, no. 3, pp. 1286–1294, 1999.
- M. Pistis, L. Ferraro, L. Pira et al., “Δ9-tetrahydrocannabinol decreases extracellular GABA and increases extracellular glutamate and dopamine levels in the rat prefrontal cortex: an in vivo microdialysis study,” Brain Research, vol. 948, no. 1-2, pp. 155–158, 2002.
- J. Trettel and E. S. Levine, “Cannabinoids depress inhibitory synaptic inputs received by layer 2/3 pyramidal neurons of the neocortex,” Journal of Neurophysiology, vol. 88, no. 1, pp. 534–539, 2002.
- N. Hájos, I. Katona, S. S. Naiem et al., “Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations,” European Journal of Neuroscience, vol. 12, no. 9, pp. 3239–3249, 2000.
- R. E. Hampson and S. A. Deadwyler, “Cannabinoids, hippocampal function and memory,” Life Sciences, vol. 65, no. 6-7, pp. 715–723, 1999.
- P. K. Chan, S. C. Chan, and W. H. Yung, “Presynaptic inhibition of GABAergic inputs into rat substantia nigra pars reticulate neurons by cannabinoid agonists,” Neuroreport, vol. 9, pp. 671–675, 1998.
- A. F. Hoffman and C. R. Lupica, “Direct actions of cannabinoids on synaptic transmission in the nucleus accumbens: a comparison with opioids,” Journal of Neurophysiology, vol. 85, no. 1, pp. 72–83, 2001.
- O. J. Manzoni and J. Bockaert, “Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens,” European Journal of Pharmacology, vol. 412, no. 2, pp. R3–R5, 2001.
- B. Szabo, S. Siemes, and I. Wallmichrath, “Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids,” European Journal of Neuroscience, vol. 15, no. 12, pp. 2057–2061, 2002.
- I. Wallmichrath and B. Szabo, “Cannabinoids inhibit striatonigral GABAergic neurotransmission in the mouse,” Neuroscience, vol. 113, no. 3, pp. 671–682, 2002.
- J. M. Crook, E. Tomaskovic-Crook, D. L. Copolov, and B. Dean, “Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment,” American Journal of Psychiatry, vol. 158, no. 6, pp. 918–925, 2001.
- J. D. Jentsch, E. Andrusiak, A. Tran, M. B. Bowers Jr., and R. H. Roth, “δ9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: blockade of dopaminergic effects with HA966,” Neuropsychopharmacology, vol. 16, no. 6, pp. 426–432, 1997.
- E. Acquas, A. Pisanu, P. Marrocu, S. R. Goldberg, and G. Di Chiara, “Δ9-tetrahydrocannabinol enhances cortical and hippocampal acetylcholine release in vivo: a microdialysis study,” European Journal of Pharmacology, vol. 419, no. 2-3, pp. 155–161, 2001.
- C. D. Verrico, J. D. Jentsch, L. Dazzi, and R. H. Roth, “Systemic, but not local, administration of cannabinoid CB1 receptor agonists modulate prefrontal cortical acetylcholine efflux in the rat,” Synapse, vol. 48, no. 4, pp. 178–183, 2003.
- L. Ferraro, M. C. Tomasini, G. L. Gessa, B. W. Bebe, S. Tanganelli, and T. Antonelli, “The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study,” Cerebral Cortex, vol. 11, no. 8, pp. 728–733, 2001.
- M. Steffens and T. J. Feuerstein, “Receptor-independent depression of DA and 5-HT uptake by cannabinoids in rat neocortex—involvement of /-ATPase,” Neurochemistry International, vol. 44, no. 7, pp. 529–538, 2004.
Copyright © 2011 Carissa M. Coulston et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.