Marijuana and the brain
Marijuana is the most widely used illicit drug in the United States in the adolescent population, and almost half (44%) of senior high-school students have reported using marijuana in their lifetime . Of these, 5% report daily usage; which seems to decrease with age [1]. Despite cognitive, social as well as neurological evidence to the contrary, the existence of marijuana addiction and conversely marijuana dependency has been disputed and it is not as of yet included as an addictive disorder in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
Cognitive Correlates of Marijuana
Brain function and adolescent marijuana use
Magnetic resonance imaging (MRI) has been used in a number of studies to observe patterns of brain activity in relation to cannabis use. These methods have shown some evidence that heavy marijuana users have a subtle reorganization of neural networks in relation to spatial working memory demands, which may largely resolve following several months of abstinence[2]. Adolescent marijuana users show a variety of minor changes in brain activation, including increased activity in the right parietal lobe and right dorsolateral prefrontal cortex, areas important for executive functioning and attention.[2] There has also been evidence for increased activation in parietal, superior, temporal, hippocampal, and posterior cingulate regions during working memory tasks [2]. Adolescent regular marijuana users perform worse than control subjects on tests of attention, nonverbal memory, and learning, although the differences are not large in magnitude [2].
Implicit Cognition and Marijuana Use
The dopaminergic system is activated after using marijuana which creates a sense of pleasure within the user. Users learn from their physiological marijuana experience and many people do not experience the subjective effects of marijana until they have used it multiple times [3]. The learning experienced from using marijuana multiple times suggests that memory may play a part in the use of marijuana, and it's not surprising that drug reinforcement and addiction has been examined from expectancy and memory association perspectives. In these paradigms, expectancy is viewed as implicit nodes of information pertaining to marijuana that is connected to an extensive semantic network that joins the individual’s prior experiences (and therefore memories of these experiences) that are in some way related to the idea of marijuana. These expectancies act as associations that bind memories, and the more memories an individual has that are related to a specific idea, the more probable it is that this network will be activated. This network can be activated by a variety of stimuli that are captured by a variety of senses and subsequently encoded into memory, and is thus cross modal [4]. For instance, a particular smell may elicit a visual memory, or a particular sound heard by the individual may elicit a specific smell from memory. These memories also extend to affective evaluations as well as motor sequences associated with a particular experience. As a result, stimuli encountered in the environment may activate this network and thus influence the individual’s resulting behaviour. Using this paradigm as a framework for research, studies have found that marijuana users are more likely than non-users to activate this network when presented with cues related to marijuana usage (i.e. marijuana paraphernalia) in comparison to neutral cues. Furthermore, heavy users’ networks consist of positive expectancies such as relaxation, enhanced abilities on cognitive tasks, as well as stimulating social behaviour, whereas the opposite effect was found in non-users. This may help explain the reinforcing effects of drugs on individuals who as a result become addicted to the substance. As such, it becomes difficult when attempting to disentangle the chemical effects of marijuana from the associations between previous experiences, since both play a part in addiction. This becomes especially apparent in the phenomenon known as reverse tolerance, in which individual differences result in different experiences when initially exposed to marijuana. Some individuals fail to experience the intoxicating effects associated with marijuana usage during primary exposure, and these effects materialize only after multiple exposures [5]. Drug users attribute more positive connections to drug use than non-users, and as such they become biased in their evaluations of related as well as unrelated cues and are more likely to connect neutral cues to the drug network than non-users [4]. This cue reactivity suggests that drug users are more likely to be reminded of drugs, and are thus more likely to engage in the act of using drugs [6]. Furthermore, when presenting these cues to marijuana users, they are more likely to report cravings for the drug [7].
Motor Skills
Not only are the motor skills of adults and adolescents affected by marijuana, but children and newborns born to cannabis users also suffer from such motor problems. Newborns and infants born to cannabis users have increased tremors, exaggerated startle responses and poor habituation to novel stimuli and by the age of 10 children were reported to have increased hyperactivity, inattention, and impulsive symptoms [8].
Impact on adolescent users
Marijuana use during adolescence is fairly common and the implications of its use are many. During adolescence the brain is developing and exposure to marijuana during this critical period could result in an interruption of maturational processes, however as of yet there is no evidence to prove this. Adolescents who use marijuana heavily tend to show disadvantaged attention, learning, and processing speed; subtle abnormalities in brain structure; increased activation during cognitive tasks despite intact performance.[2]
Neurological Impact of Marijuana in Adolescence
Adolescents are the most frequent users of marijuana in the United States, and they may be particularly vulnerable to the adverse effects associated with this illicit substance since the brain undergoes rapid neurodevelopment during this stage of life. Studies have examined these aversive effects in adolescent rats and found them to be impaired in tasks involving spatial working memory. Since the hippocampus is the neurological correlate of spatial memory, neuroplasticity in the form of less synaptic contacts is exhibited in this region in response to THC treatment [9]. Synaptic contacts connect neurons (nerve cells in the brain) by enabling them to communicate with each other, and if these contacts are disturbed, the area will not be able to function properly. Furthermore, it seems as though depressive mood states in females are initiated by chronic THC administration to adolescent rats, thus indicating morphological changes in the emotional circuit in the brain. Lasting deficits in recognition memory were also found in adult rats that had been chronically treated with THC in adolescence, and short-term learning impairments were also found. Adult rats who are administered THC in adulthood do not show any of these long-term effects, thus providing evidence that adolescents are especially vulnerable to these adverse effects produced by THC. These changes have been objectively measured by counting the amount of presynaptic (before the synapse) and postsynaptic proteins (after the synapse) VAMP2 and PSD95, respectively, in the hippocampus. Complex brain functions (such as learning and memory) require new synaptic contacts to be made, and decreases in VAMP2 and PSD95 can be found in adolescent rats treated with THC, thus indicating less synaptic contacts during these processes [9].
Marijuana and mental illiness
Research has also found that cannabis use, particularly heavy cannabis use, can produce confusion, amnesia, delusions, hallucinations, anxiety, or agitation [10] These consequences are more likely to occur more rapidly following a period of abstinence from marijuana.[10]
Cannabis use has been linked with psychosis. A study involving a large sample of Swedish conscripts found a relationship between the amount of cannabis consumed by participants and schizophrenia. Specifically, frequency of consumption by the age of 18 predicted the risk of obtaining a diagnosis of schizophrenia within the next 15 years.[10] It was found that cannabis use only exacerbated underlying schizophrenic symptoms and disorders within vulnerable users; cannabis use did not cause schizophrenia within an individual who did not have any underlying or genetic predisposition to the disorder.[10]
Effects on neurophysiology
Role of the Endocannabinoid System
Recent neurobiological studies have investigated the role of the endocannabinoid system in drug addiction in the brain and have examined its role in motivation and reward. It was found that this system is connected to the ventral tegmental area (VTA, which contains dopaminergic cell bodies) via the release of endocannabinoids in response to drug intake. It is through this mechanism that the rewarding effects of not only cannabinoids (found in marijuana), but nicotine (found in cigarettes), alcohol and opioids are mediated. This provides evidence for a common underlying mechanism in drug addiction that is activated by a variety of substances of abuse. Furthermore, the endocannibinoid system is involved in relapse, in which behaviour to actively seek drugs is re-instated following extinction. This behaviour is influenced by the social context of the environment; which initiates the motivation to seek drugs. The effects of the endocannabinoid system is regulated by the CB1 cannabinoid receptor found in the central nervous system.[11] These receptors are for the most part pre-synaptic in location, and exert their effects by inhibiting the release of neurotransmitters[12]. There are certain antagonists of this receptor, such as rimonabant, that are able to block the activation of the cannabinoid receptor. These antagonists could serve as a contemporary means for treating drug addiction since they prevent drugs from accessing the brain, which in turn would extinguish the rewarding effects associated with these substances [11].
It is the neurological changes that are effected by the properties of drugs of abuse that mediate the behaviour of the individual, and as such the prevention of these cellular changes will manifest as a cessation of habitual drug taking behaviour. This is accomplished by eliminating the rewarding properties of drugs and thus the motivation to seek drugs. The environmental conditions associated with initial drug taking, abstinence and relapse all cause neurological adaptations in the brain that the organism attempts to physically adapt to [11]. This is what underlies the phenomena of tolerance and withdrawal, and it provides a complex view of interacting biological and environmental forces in drug addiction. These neural circuits are modulated by chemicals in the brain (called neurotransmitters) as well as by the chemicals provided by drugs, and change morphologically in response to the concentration of the chemicals from the drugs [11]. When the organism suddenly terminates drug intake, these circuits become dysregulated, causing adverse side-effects which then serve to motivate the individual to re-initiate drug taking.
The phenomenon of morphological changes in neural circuits is referred to as plasticity, and this has been found in a brain structure called the nucleus accumbens. The nucleus accumbens is involved in behaviour initiated by the lure of reward, and as such contributes to drug addiction. Not only does the nucleus accumbens contain CB1 receptors, but they can be found in many other brain structures as well, some of which include the VTA (as mentioned earlier), the basolateral amygdala, the cerebellum, the basal ganglia as well as the hippocampus [12]. Furthermore, deactivation has been found in the prefrontal cortex in response to THC administration in rats. The amygdala shares connections with the prefrontal cortex, and together they act to mediate anxiety. Thus, THC has been found to influence anxiety-like behaviour in rats by reducing the automatic fear-response that accompanies uncertain situations, and instead induces risky behaviour [13]. It is assumed that these findings can be generalized to humans, so it is clear to see the possible implications that this may pose socially. The hippocampus is critically involved in memory processes and the cerebellum and basal ganglia play a role in movement; which suggests an involvement of cannabinoids in short-term memory interference and inhibition of movement [12].
Cannabinoids and Pain
Studies on mice have shown that chronic administration of delta9-tetrahydrocannibinol (THC); which is the psychoactive ingredient in cannabis, produces tolerance in the form of neurological adaptation. Some of the symptoms asscociated with cannabinoid administration are decreased sensitivity to pain [12]. Due to their analgesic properties, cannabinoids have been used clinically for patients suffering from chronic pain. However, since tolerance is known to develop after chronic use, these antinociceptive effects become reduced and increasing doses are required to maintain these effects. Specifically, tolerance is exhibited by the interaction of the CB1 receptor with a G-protein-associated sorting protein (GASP1), which is a protein that sorts CB1 receptors into compartments called lysosomes that act to digest the receptor. This digestion process breaks the receptor apart through the action of enzymes, thus deactivating and destroying it. When this interaction is disrupted, tolerance developed in response to cannabinoid administration is also disrupted, and thus the analgesic effects produced by cannabinoids continue to be experienced [14]. Individual differences have been found with respect to cannabanoid tolerance. This can be explained on a cellular level, where different people display varying concentrations of CB1 receptors in different locations in the brain. Repeated administration of high doses of cannabinoids or chronic administration of smaller doses of cannabinoids leads to tolerance in the form of the downregulation and desensitization of receptors; which has recentlyTemplate:When been found in the brains of human cannabis users. This adaptive mechanism varies by brain region, where some regions exhibit greater tolerance in comparison to other regions [11][12].
Tetrahydrocannabinol and Anxiety
Recent studies using animal models have shown that tetrahydrocannabinol may play a role in inducing anxiety-like behaviour in rats. This had been demonstrated using the elevated plus maze (EPM), which is a method used to determine the relative anxiety experienced by rats by observing how much time they spent in an enclosed arm of the maze versus an open arm of the maze. However, the specific role of cannabinoids in anxiety is controversial. Previous studies have found mixed results, where certain doses of cannabinoids produce anxiolytic-like response whereas others seem to produce anxiogenic-like responses, thus suggesting a dose-dependent behavioural response [13]. Interestingly, these effects were also mediated by contextual factors in the environment, thus reinforcing the notion that internal and external variables interact to produce the organism’s experience. These studies have also used cFos expression to map anatomical regions and identify cells belonging to specific neurological circuits as they are activated to specific chemical as well as environmental stimuli. This helps researchers to identify the regions in the brain that are involved in certain responses to drugs of abuse. Evidence supporting this comes from the use of CB1 receptor antagonists, which when administered block and reverse the anxiolytic effects of THC [13].
References
- ↑ Padula, C., Schweinsburg, A. & Tapert, F. (2007). Spatial working memory performance and fMRI activation interactions in abstinent adolescent marijuana users. Psychology of Addictive Behaviors, 21(4), 478-487.
- ↑ 2.0 2.1 2.2 2.3 2.4 Jacobus J, Bava S, Cohen-Zion M, Mahmood O, Tapert SF (2009). "Functional Consequences of Marijuana Use in Adolescents". Pharmacol Biochem Behav. PMID 19348837.
- ↑ Linkovich-Kyle, T.L., & Dunn, M.E. (2001). Consumption-related differences in the organization and activation of marijuana expectancies in memory. Experimental and Clinical Psychopharmacology. 9, 3, 334-342.
- ↑ 4.0 4.1 Stacy, A. (1995). Memory association and ambiguous cues in models of alcohol and marijuana use. Experimental and Clinical Psychopharmacology. 3(2), 183–194.
- ↑ Dunn, M. & Linkovich-Kyle, T. (2001). Consumption-related differences in the organization and activation of marijuana expectancies in memory. Experimental and Clinical Psychopharmacology. 9(3), 334–342.
- ↑ Ames, S., Dent, C., Stacy, A. & Sussman, S. (1996). Implicit cognition in adolescent drug use. Psychology of Addictive Behaviors. 10(3), 190–203.
- ↑ Gray, K., LaRowe, S. & Upadhyaya, H. (2008). Cue reactivity in young marijuana smokers: a preliminary investigation. Psychology of Addictive Behaviors. 22(4), 582–586.
- ↑ Lutz, B. (2009). From Molecular neurodevelopment to psychiatry: new insights in mechanisms underlying cannabis-induced psychosis and schizophrenia. Psychiatry Clinical Neuroscience, 259, 369-370.
- ↑ 9.0 9.1 Braida, D., Bartesaghi, R., Capurro, V., Guidali, C., Sala, M., Parolaro, D., Pinter, M., Realini, N., Rubino, T. & Vigano, D. (2009). Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus, 19, 763-772.
- ↑ 10.0 10.1 10.2 10.3 Hall, W., & Solowij, N. (1998). "Adverse effects of cannabis". The Lancet volume=352: 1611-1616. PMID 9843121.
- ↑ 11.0 11.1 11.2 11.3 11.4 Berrendero, F., Maldonado, R. & Valverde, O. (2006). Involvement of the endocannabinoid system in drug addiction. Trends in Neurosciences, 29(4), 225-232.
- ↑ 12.0 12.1 12.2 12.3 12.4 Cassidy, M., Collier, L., Martin, B., McKinney, D., Selley, D., Sim-Selley, L. & Wiley, J. (2008). Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to Δ9-tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics, 324, 664-673.
- ↑ 13.0 13.1 13.2 Braida, D., Castiglioni, C., Guidali, C., Limonta, V., Parolaro, D., Realini, N., Rubino, T. & Sala, M. (2007). Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral Δ9-tetrahydrocannabinol in rats. Neuropsychopharmacology, 32, 2036-2045.
- ↑ Agarwal, N., Katona, I., Kuner, T., Kuner, R., Mackie, K., Martini, L., Mopnyer, H., Parolaro, D.,Rubino, T., Swiercz, J., Tappe-Theodor, A. & Whistler, J. (2007). A molecular basis of analgesic tolerance to cannabinoids. Journal of Neuroscience, 27(15), 4165-4177.