Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia
Research highlights
▶ Adolescent exposure to THC may disturb functioning of the endocannabinoid system. ▶ The endocannabinoid system controls glutamate and GABA homeostasis. ▶ Glutamate/GABA determine experience-dependent maturation of prefrontal circuitry. ▶ Disturbed adolescent prefrontal maturation may result in psychosis or schizophrenia.
Introduction
There is now accumulating and converging evidence from epidemiological studies and reanalyses of existing data suggesting that cannabis use is a risk factor for the development of psychosis or schizophrenia (Smit et al., 2004, Semple et al., 2005, Moore et al., 2007). The risk increases with the frequency of cannabis use, indicating a causal relationship (van Os et al., 2002, Zammit et al., 2002, Arseneault et al., 2004, Smit et al., 2004, Henquet et al., 2004, Di Forti et al., 2009). In particular, the use of cannabis during adolescence increases the risk of development of schizophrenia later in life (Arseneault et al., 2002, Zammit et al., 2002, Henquet et al., 2004, Stefanis et al., 2004, Rubino and Parolaro, 2008, Konings et al., 2008).
The increased risk of developing schizophrenia is specifically due to the use of cannabis, since it is independent of the use of other drugs, e.g. alcohol (Arseneault et al., 2002, van Os et al., 2002, Zammit et al., 2002, Henquet et al., 2004). In addition, the outcome of psychosis or schizophrenia may be specific, because an association between cannabis use and later depression was not found (Arseneault et al., 2002), although more recent studies indicate a link between the use of cannabis and mood disorders such as bipolar disorder and depression (Moore et al., 2007, van Laar et al., 2007). However, this evidence is less strong than for the association between cannabis and schizophrenia, and might be due to overlapping symptoms between psychiatric disorders (Tsuang et al., 2004, Tamminga and Davis, 2007, van Os and Kapur, 2009).
Cannabis use preceding psychosis, the presence of a dose–effect relationship, and persisting association after controlling for potential confounding factors all suggest strongly that cannabis use plays a causal role in the onset of schizophrenia. However, in the determination of causal links, epidemiological research has its limitations. These studies, by their nature, cannot definitively prove that cannabis use is directly related to the risk of developing schizophrenia. Although they provide evidence of a causal link, the underlying neurobiological processes leading to an increased risk of psychosis have not been elucidated (Fergusson, 2004). To quantify the extent to which statistical linkages between cannabis and schizophrenia reflect underlying causal processes, a better understanding of the possible neurobiological pathways is needed.
To explain the neurobiology of cannabis-induced schizophrenia, the neurobiological literature was selectively reviewed using a toxicological approach (Niesink et al., 1995). This approach is based on the available epidemiological data, and implies a toxic substance affecting the central nervous system during a critical period, resulting in irreversible structural changes. These changes subsequently cause psychopathological effects. It is assumed that Δ9-tetrahydrocannabinol (Δ9-THC, henceforth mentioned as THC), the main psychoactive substance in cannabis, is the neurotoxic substance and that adolescence is the critical period. The interference of THC with a maturational process in the brain of adolescents is supposed to induce structural and functional changes. The following aspects will be reviewed in subsequent sections:
- 1.
Is cannabis a neurotoxic substance?
- 2.
Which brain structures are still undergoing maturation during adolescence?
- 3.
Which of these structures are implicated in schizophrenia or psychosis?
- 4.
Which physiological mechanisms form the basis for these maturational changes?
- 5.
What is the role of the endogenous cannabinoid system in this process?
- 6.
In what way does THC interfere with this physiological process?
One of the major problems in the debate revolving cannabis and schizophrenia is the definition of the term ‘schizophrenia’. In epidemiological studies, schizophrenia is used to describe a broad range of psychotic conditions. However, the psychiatric outcome of interest in the present review may be better described as a continuum between incidentally occurring psychotic symptoms and full-blown disorders as observed in patients diagnosed with schizophrenia seen in mental health clinics. Throughout this paper, the terms schizophrenia and psychosis are used as generic names, referring to this continuum. More detailed information on the nature and pathophysiology of schizophrenia is provided in Section 5.
Another issue is the different psychotogenic effects that cannabis can induce. High-dose intoxication with cannabis can result in acute psychosis, usually transient (Chopra and Smith, 1974, Thomas, 1996). Cannabis use has been associated with higher relapse rates and poor treatment outcome of schizophrenia-like disorders (Linszen et al., 1994, Buhler et al., 2002, van Os et al., 2002). However, this review focuses on the third effect of cannabis: the ability to induce a permanent psychotic disorder, usually with a time lag between exposure to cannabis and the onset of the disease.
From the results of the literature search, it can be postulated that THC adversely affects normal physiological maturational processes during adolescence. Usually, the interaction of endogenous cannabinoids with the CB1 receptor is critically involved in brain maturation through its regulating role in the release of glutamate. Through its action on CB1 receptors, THC can interfere with this normal physiological process, resulting in disturbed glutamate release, subtle neurotoxic effects and subsequent structural defects. Since maturation of the prefrontal cortex (PFC) is one of the most important processes during adolescence, THC may predominantly affect the maturation of specific neurocircuitries within this brain region. Moreover, dysfunctioning of the PFC is a key feature of schizophrenia (Callicott et al., 2003, Minzenberg et al., 2009). The working hypothesis is therefore that THC interferes with normal maturation of the adolescent PFC, ultimately giving rise to psychotic symptoms or schizophrenia.
Section snippets
Is THC a neurotoxic substance?
THC is the main psychoactive substance in cannabis (Gaoni and Mechoulam, 1964). The neurotoxicity of cannabis, i.e. THC, has always been a subject of controversy. In vitro studies have demonstrated contradictory results. Some showed toxic effects of THC on cultured neurons, prevented by application of CB1 receptor antagonists (Chan et al., 1998, Campbell, 2001), whereas others demonstrated CB1-dependent neuroprotective effects of cannabinoids (Hampson et al., 1998, Shen and Thayer, 1998).
Adolescence and brain maturation
Brain development is an organized and highly dynamic multistep process, which is genetically determined, epigenetically directed and environmentally influenced (Tau and Peterson, 2010). In contrast to earlier beliefs, this process continues both through childhood and adolescence, the developmental period during which the body and brain emerge from an immature state to adulthood (Spear, 2000, Steinberg and Morris, 2001). Although no precise borders can be defined, adolescence broadly covers the
Experience, sensitive periods and mechanisms of cortical plasticity
Before various cortical areas have reached their mature structure, they pass through several developmental phases. Although differences exist between different cortical areas in the mechanisms underlying this process of cortical maturation, the individual maturational processes are basically the same. First, vast numbers of synapses and neurons are formed, followed by synaptic strengthening and elimination and pruning of redundant arbors. The forming of these more efficient microcircuitries
Schizophrenia and the prefrontal cortex
Psychosis can occur in numerous organic and functional disorders of which schizophrenia is only one. Schizophrenia itself is a scientific construct to indicate a group of imperfectly understood brain disorders characterized by alterations in higher functions related to perception, cognition, communication, planning and motivation. The clinical symptoms are usually classified as positive, negative and cognitive symptoms (Carpenter, Jr. and Buchanan, 1994). Positive symptoms include
The cannabinoid system and cortical maturation
To prevent excitotoxicity induced by an extreme influx of Ca2+ through postsynaptic ion channels, the synapse controls the amount of glutamate that is presynaptically released. An important mechanism to regulate glutamate homeostasis is the endogenous cannabinoid system (Schlicker and Kathmann, 2001, Wilson and Nicoll, 2002, Chevaleyre et al., 2006). It consists of cannabinoid receptors and endocannabinoid ligands that work on these receptors. At least two cannabinoid (CB) receptors have been
General discussion
Using a toxicological approach and based on recent biological and medical literature, it is postulated that the exposure of cannabis, more precisely THC, during adolescence results in disturbance of the experience-driven refinement of specific local neural circuits within the PFC. The dose, the exact time-window and duration of the exposure determine the severity and precise location of the cortical disturbance. The CB1 receptor is the primary target for this neurotoxic effect of THC. Under
Acknowledgements
We thank Dr. Jan M. van Ree for critical reading and commenting the manuscript and Dr. Susan Boobis for editing the first version of the paper.
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