Marijuana and the brain

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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]. Studies pertaining to the beliefs held by drug users and the public at large concerning the harmfulness of drugs of abuse have revealed disturbing misconceptions. This includes the finding that ratings of perceived harmfulness seem to decrease not only for the drug being abused, but also for other drugs as drug usage increases [2]. This finding is particularly alarming, and it aids in illuminating the complexities involved in rehabilitation and in treatments for drug addiction. 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). Nevertheless, treatment options have been made available for the rehabilitation of individuals experiencing marijuana addiction and some have shown to be successful. The effects of marijuana usage are widespread, and can be examined from a variety of different perspectives. It’s adverse effects impact users on a cognitive, social as well as neuroanatomical level. In the cognitive domain, chronic marijuana use has been linked to impairments in memory, attention, learning ability as well as in motor coordination. Many adolescents become exposed to marijuana in social settings, and as such the social context of marijuana use plays a significant role in its use by interacting with neuroanatomical factors. Chronic use of this substance may lead to physical changes in the brain, which may affect the behaviour of the individual and their interactions with the environment.

Cognitive Correlates of Marijuana

File:Bodily effects of cannabis.png
Areas in the body affected by marijuana use.

Brain Function and Adolescent Marijuana Use

Previous studies have attempted to examine the effects of marijuana usage on the brain using functional imaging methods. Functional imaging is a relatively new technique that measures the oxygen consumption of cells in the brain and transfers this into an image; cells that are more active use more oxygen. Functional magnetic resonance imaging (fMRI) has been used in a number of studies to observe patterns of brain activity in relation to cannabis use. These methods have shown evidence that heavy marijuana users have a reorganization of neural networks in relation to spatial working memory demands [3]. These differences seem to point towards a compensation mechanism, in which marijuana users attempt to utilize different mechanisms in problem solving and in tasks that require executive functions such as memory and attention [4]. Adolescent marijuana users showed increased activation in the right parietal lobe and decreased activation in the right dorsolateral prefrontal cortex.[3] These areas are important for executive functioning and are used in attention and spatial rehearsal. There has also been evidence for increased activation in parietal, superior, temporal, hippocampal, and posterior cingulate regions during working memory tasks [3]. Alterations in brain function during tasks requiring executive control, including inhibition and decision-making [5] have been shown in marijuana users. This suggests that adolescents are especially susceptible to the long-term adverse effects of marijuana usage; a finding that is especially troubling considering that marijuana is most widely used by adolescents. Furthermore, fMRI studies have shown an increase in spatial working memory in brain response in marijuana users compared to non-users [1]. Marijuana users show differences in areas such as the prefrontal cortex, anterior cingulate and the basal ganglia which suggest a different approach to tasks through altered neural pathways [1]. Adolescent marijuana users demonstrated increased right hippocampal activity and poorer attention and verbal working memory performance [1]. In a study by Harvey et al. in 2007, it was found that adolescent regular marijuana users performed worse on tests of attention, nonverbal memory, and learning, and the longer time that cannabis was used predicted poorer performance on executive functioning and working memory tests [3].

Motivational Consequences of Marijuana Use

There is evidence illustrating consequences in marijuana users in terms of motivation levels [6]. A study conducted by Lane et. al in 2005 demonstrated that marijuana users exhibited significantly reduced motivation than non-users. In a study where participants were instructed to gain as much money as possible via two possible ways, marijuana users switched over to the method which required less work and effort sooner than non-marijuana users [6]. This study was set up so that the option which required more work and effort produced greater amounts of money than the non-work option. Switching from the work option to the non-work option was construed as a decrease in motivation level. The study’s authors also found that a greater proportion of marijuana users’ earnings came from the non-work option, whereas this discrepancy was not as pronounced for non-marijuana users. The result of this study brings an important characteristic of marijuana users to light—specifically, their decreased motivational drive. This can have serious implications for the way in which heavy or problematic users are treated.

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 [7]. 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 [8]. 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 [9]. 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 [8]. 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 [10]. Furthermore, when presenting these cues to marijuana users, they are more likely to report cravings for the drug [11].

Motor Skills

Not only are the motor skills of adults and adolescents affected by the effects of 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 [12].

Within adolescents and adults results from investigations using positron emission tomography (PET) and fMRI techniques have reported metabolic alterations within frontal regions of marijuana smokers [5]. The central cannabinoid (CB1) receptors in the basal ganglia, the cerebral cortex and the cerebellum indicate their implication in the regulation of motor activity [13]. These areas are involved in skills and judgement tasks and the effects of marijuana on these areas result in decreased capacity to accurately judge distances, slower reflexes and distorted perceptions [13].

Marijuana and Driving

The vast majority of individuals are well aware of the tragic and devastating effects of drinking and driving; these effects have been well researched and well documented. The effects of marijuana and driving have not been as thoroughly investigated by research. Research that has been conducted on the effects of marijuana and driving has yielded different consequences for different types of users. For chronic or more severe marijuana users, driving was found to be one of the most serious consequences. Tasks which required sustained attention were found to have the most significant impairment, which explains the serious impairments found in driving [14]. In addition, as mentioned previously, psychomotor functioning is affected while under the influence of cannabis; this lends another explanation to impairments in driving ability.

For occasional or recreational users, substantial results have not been found to support the claim that driving is also impaired for these users. This is not to say that occasional users do not exhibit deficits in driving. They do exhibit impairments in driving stimulations; however, these are more modest impairments [14]. It has been noted; however, that marijuana users often use tobacco and alcohol simultaneously. This can have an effect on the results, as the results can reflect the impairment of a combination of these three drugs.

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. 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 [3].

File:Marijuanasmall.jpg
Adolescents comprise the largest proportion of marijuana users.

Adolescents, as a demographic, are prone to making many risky decisions. These decisions, unfortunately, often have adverse and/or immediate consequences on their health and well-being. According to the cognitive model of drug addiction proposed by Beck, Wright, Newman, and Liese (1993) [15], there are three core drug-related beliefs associated with drug dependence: 1) liberal beliefs, where drug use is considered acceptable and normal; 2) anticipatory beliefs, where positive consequences of drug use are expected; and 3) relief-oriented goals, where the drug is used to relieve stress or to provide an escape.

A study conducted by Chabrol, Massot, and Mullet (2004) investigated which of the above three beliefs predicted cannabis use among adolescents. Surveys which assessed participants’ drug use beliefs were distributed to a sample of high school students. Results showed that liberal beliefs were found to be associated with cannabis use, while relief-oriented goals predicted cannabis dependence among heavy users [16]. The study’s authors have stated the clear implications of these findings, indicating that treatment for heavy marijuana users should target these two specific beliefs.

Longitudinal studies

A longitudinal study was conducted, which followed a sample of marijuana dependent adolescents into adulthood. Heavy marijuana use continues to have a lasting effect for approximately 25 years, thereby continuing into middle adulthood [17] Results demonstrated gender differences in socioeconomic status and employment in adulthood. Females who were heavy users in adolescence were at a greater risk of experiencing poverty, having a lower income at 42 years old, and having a period of unemployment between ages 32 and 42 years [17] None of these findings were found for males.

Heavy adolescent marijuana users were also at a greater risk for drug use and abuse during middle adulthood. Again, gender differences were found; however, it is important to note that this increased risk of drug use during middle adulthood was found for both genders. Females were more likely to continue using marijuana into middle adulthood, while males were more likely to shift to cocaine and heroin during middle adulthood. Only males were found to have an increased risk of drug abuse during middle adulthood [17] Other research has found that there is an association between marijuana use in adolescence and early dropping out of high school, as well as instability in employment [14] The implications of these findings are diminished, however, once the study authors controlled for the fact that marijuana users tend to experience poor high school performance prior to experimenting with cannabis [14]

It has been found that adolescent marijuana users are at a higher risk of certain health and psychosocial consequences: sexually transmitted infections, pregnancy, early school dropout, delinquency, coming into contact with the legal system and lowered educational and employment goals [18]. A related study found similar results, where the level of education obtained by a heavy user was lowered compared to nonusers or light users [17]

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 [19]. 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 [19].

Social Aspects of Marijuana Use

Trends in Marijuana Use

As stated previously, marijuana is the most widely used illicit drug of developed societies. Specifically, the majority of European young adults have experimented with marijuana, and a large number of American and Australian young adults have also experimented with this drug. Despite its prevalent use as a prohibited drug, statistics indicate that the vast majority of individuals use the drug experimentally and/or occasionally throughout young adulthood.

Following young adulthood, marijuana use usually ceases altogether. Additionally, it should be noted that very few young adults engage in daily marijuana usage. It is estimated that only 10% of those who use marijuana become daily users, and approximately 20% to 30% of the same users become weekly users [14] Despite these figures, it is important to keep in mind that marijuana is still considered to be the most widely used prohibited drug. It is very likely that these figures have increased over recent years [20]

There are also certain characteristics that have been found to be associated with chronic or daily cannabis users. These types of users are more likely to be male, to be less educated, to use alcohol and tobacco regularly, and to use a variety of other drugs such as amphetamines, hallucinogens, psychostimulants, sedatives, and opioids [14]

The Social Contexts of Marijuana Use

The social context in which marijuana is consumed by college students was investigated in a study conducted by Beck et. al. (2009)[15]. Four possible social contexts were examined: 1) social facilitation, where marijuana is consumed for enhance confidence and feelings of well-being in social interactions; 2) peer acceptance, where marijuana is consumed for acceptance and feelings of belonging; 3) emotional pain, where marijuana is used as coping strategy; and 4) sex seeking, where marijuana is used to initiate sexual contact with another. All investigated social contexts were found to be relevant to the college population, and there were no gender differences. The main reason marijuana is consumed by college-aged students is for social facilitation purposes. It was also found that depressed students were more likely to use marijuana in a sex seeking and peer acceptance context [15] . Chronic or people diagnosed with CUD were more likely to use cannabis for social facilitation and emotional pain than non-users. Interestingly, using marijuana in the context of emotional pain was associated with CUD and depression.The risk of developing a chronic marijuana habit increases greatly in individuals who use cannabis for social facilitation purposes [15].

Risk and Protective Factors for Marijuana Use

Marijuana is the most widely used illegal drug worldwide, with adolescents comprising the largest proportion of users [21] Additionally, many individuals—especially marijuana users—have the misconception that marijuana is a harmless drug with little or no negative consequences [20] It has been shown that symptoms of withdrawal occur in heavy cannabis users, indicating the high probability of an existing addiction and, subsequently, difficulty to quit. Furthermore, cannabis use disorders (CUD) exist, and are diagnosed according to DSM-IV criteria for abuse and dependence [15]. A review of studies indicated that marijuana is commonly used as a stress-coping strategy. Specifically, negative life events, trauma, and maladaptive or inadequate coping skills contribute to increased cannabis use [20] Adolescents with a tendency to use physical aggression as a conflict resolution style were at a greater risk for marijuana use. Prenatal maternal use of marijuana have also been found to predict cannabis use in later adolescent years, which includes age of first use and frequency of use [21]

Family dysfunction and poor familial relations has also been attributed to an increased use and reliance on marijuana [20] Specifically, adolescents who had experimented with, or became heavy users, by the age of 16, were more likely to come from socially disadvantaged backgrounds, to have experienced family problems as a child, and to have become friends with delinquent peers [20] Victims of trauma involving sexual abuse, sexual coercion, and/or sexual violence have been found to use cannabis more frequently as a coping strategy. Victims of sexual abuse, sexual coercion, and/or sexual violence relied on cannabis as an escape more than victims of physical abuse or violence [20] Studies also show that the use of marijuana as a coping strategy may be more dominant in heavy users, as alternative coping strategies may be unavailable or underdeveloped in these individuals [20]

There are a number of psychological risk factors associated with the initiation of adolescent marijuana use, which includes difficulties in school, low self-esteem, anxiety and depressive symptoms or disorders, conduct disorders, hyperactivity, borderline personality disorder or characteristics and personality traits such as sensation seeking, impulsivity, aggression, and rebellion [22]. Sociological risk factors associated with the initiation of adolescent marijuana use includes substance abuse by parents and friends, their attitudes towards substance use, and the number of friends who use marijuana [22].

One study has focused on the protective factors against adolescent marijuana use. Since adolescence is often characterized by an increase in time spent with peers, and less time spent with parents, the study chose to investigate two factors: parent-related factors and school-related factors [23]. While parental factors, such as having dinner with parents, did not demonstrate the expected protective effect on adolescent substance use, it was found that school-related factors provided a greater protective effect on adolescent marijuana use. Specifically, talking to teachers about problems and being happy in school were found to be protective factors against adolescent marijuana use [23].

Interestingly, a study was conducted which investigated the protective factors against marijuana use for adolescents of immigrant parents. Three protective factors were identified for these adolescents: individualism, assimilation, and integration. Individualism refers to when an adolescent has developed a stable sense of identity and preference for an individual, rather than being defined as a member of either group. This strong, stable personality will help adolescents resist offers from fellow peers to initiate marijuana use. Assimilation refers to when adolescents have adapted to their new environment, and has adapted well to the host culture. This normally is characterized by academic success in school. Integration refers to an incorporation of both cultures, thereby creating a strong, independent adolescent [22].

Psychiatric and Social Disorders

There have been several psychiatric and social disorders associated, or linked to, the heavy use of marijuana. Many studies found an increased risk for psychosis among marijuana users [21] Cannabis use has also been linked to an increased risk of schizophreniform spectrum disorders, particularly for heavy or chronic users, and for users started using marijuana at a young age. Marijuana use has also been found to aggravate underlying or pre-existing psychotic disorders [21] Interestingly, there is growing research investigating the relationship between marijuana use and bipolar disorder and depression [21]

A study conducted in Egypt in 1972 demonstrated the negative and severe consequences of marijuana use. These included high levels of anxiety, impaired memory, inability to concentrate, impaired learning ability, and psychomotor impairment, which included a reduction in the quality and quantity of work produced by such users [21] The findings of this study have been supported by the discovery of “clusters” of marijuana use throughout the world. Specifically, several communities in northern Africa and New Zealand have demonstrated high cannabis use. These communities are characterized by intellectual impairment, psychomotor slowing, poor work capacity, and severe social deprivation [21] As a result, while the initial Egyptian study was conducted decades ago, it is clear that its findings are still relevant and evident in today’s cannabis users.

Research has also found that cannabis use, particularly heavy cannabis use, produces one or more of the following consequences: confusion, amnesia, delusions, hallucinations, anxiety, and agitation [14] These consequences are more likely to occur more rapidly following a period of abstinence from marijuana [14] The fact that these consequences occur more quickly following a period of abstinence may imply that marijuana does have an addictive nature. As a result, this challenges the commonly held belief that marijuana is more harmless than harmful, and that it is not an addictive substance.

Interestingly, cannabis use has been linked with a devastating psychological disorder. 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 [14] 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 [14] Some social consequences have been implicated in marijuana use. Many heavy users have indicated family dysfunction and relationship problems, financial difficulties, reduced energy and self-esteem, unhappiness with productivity levels, and low life satisfaction [18].

Treatment

Treatment for marijuana users has always been an area of debate. While some research has found certain characteristics that must be kept in mind when developing and designing intervention programs for chronic users, there is much more than needs to be researched further. Adults seeking treatment for marijuana have been chronic users for a long period of time—most adults have been daily users for approximately 10 years. These same users have attempted to stop using marijuana at least 6 times [18]. A major reason behind this is the fact that the majority of these individuals have a pessimistic outlook on their ability to quit, and many experience a withdrawal syndrome upon quitting [18].

A substantial amount of research has been conducted into the various treatment methods for marijuana dependence. These include behavioural treatments, such as motivational enhancement therapy (MET), cognitive-behavioural therapy (CBT), and contingency management (CM), as well as family-based treatment methods. MET and CBT treatment methods are also known as coping skills training. Outpatient treatment for adolescent abusers has begun to grow as an option in treating chronic, adolescent users with success. The mentioned behavioural and family-based treatment methods have also experienced success in treating adult abusers [18].

MET addresses the patient’s uncertainty in quitting marijuana and aims to increase motivation to quit. A variety of counseling techniques are used by the therapist, all of which are carried out in a non-confrontational manner. The counseling techniques used include reflection, summarization, reinforcing self-efficacy, listing the pros and cons of drug use, empathizing, and developing plans to retain commitment [18].

CBT teaches marijuana users skills that are important and helpful in cessation, including avoidance and management of situations or dilemmas that may interfere with successful desistance of marijuana use. Each session involves discussion and analysis of recent triggers of marijuana cravings and/or use, development of strategies to combat future triggers of marijuana cravings and/or use, drug refusal skills, and problem-solving skills [18].

The CM treatment approach to marijuana abuse has been adapted from a treatment approach known to be successful in treating cocaine dependence. This treatment method is abstinence-oriented, where individuals are encouraged to abstain from the drug by prosocial reinforcers. These prosocial reinforcers are obtained when individuals have collected enough vouchers, and are often retail items or services that encourage abstinence. Vouchers are given to individuals when they come in for drug testing, and their value increases if the drug test result is negative.

A number of studies have shown that a combination of MET and CBT as a treatment approach is more effective than either treatment approach used in isolation, as well as the use of CM in isolation. Moreover, a treatment approach integrating all three current treatment methods—MET, CBT, and CM—is most likely to produce positive results in marijuana users [18]. One study compared the outcomes of marijuana abusers after receiving either a 9-session MET-CBT treatment, a 2-session MET, or a delayed treatment control (DTC). Results from this study showed that both the MET-CBT treatment approach and the MET treatment approach yielded better abstinence results than DTC. The MET-CBT treatment approach, however, demonstrated that it was superior in abstinence length and frequency of marijuana use than MET alone.

Another study was conducted to determine the effects of CM when compared to MET-CBT treatment methods. This study compared the outcome of adult marijuana users in three different conditions: 1) a 4-session MET; 2) a 14-session MET-CBT; 3) a 14-session MET-CBT-CM. Individuals could earn up to $570 in vouchers if they consistently provided negative drug test results throughout the 11 weeks of treatment. Results indicated that individuals receiving the combined MET-CBT-CM treatment produced the greatest rate of abstinence [18]. An extended study was also conducted following completion of this study. In the extended study, the MET session was replaced by a CM session. The results of the extended study demonstrated two interesting findings. First, both MET-CBT-CM and CM treatment methods initially provided the greatest abstinence rate than MET-CBT [18]. The results of marijuana users treated via the MET-CBT-CM and CM approaches produced similar results; however, marijuana users treated with the combined MET-CBT-CM produced superior results post-treatment [18].

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.[24] These receptors are for the most part pre-synaptic in location, and exert their effects by inhibiting the release of neurotransmitters[25]. 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 [24].

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 [24]. 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 [24]. 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 [25]. 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 [26]. 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 [25].

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 [25]. 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 [27]. 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 recently 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 [24] [25].

Tetrahydrocannabinol and Anxiety

File:THC structure.png
Molecular structure of THC, the primary active ingredient found in marijuana.

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 [26]. 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 [26].

References

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  1. ↑ 1.0 1.1 1.2 1.3 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. ↑ Fabricius, W., MacKinnon, D. & Nagoshi, C. (1993). Beliefs about the harmfulness of drug use in adults who use different drugs. Psychology of Addictive Behaviors, 27(1), 52-65.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Jacobus, J., Bava, S., Cohen-Zion, M., Mahmood, O., & Tapert, S.F. (2009). Functional consequences of marijuana use in adolescents. Pharmacology, Biochemistry and Behavior, 92, 559-565.
  4. ↑ Cherek, D., Dougherty, M. & Lane, S (2002). Possible amotivational effects following marijuana smoking under laboratory conditions. Experimental and Clinical Psychopharmacology, 10, 26-38.
  5. ↑ 5.0 5.1 Gruber, S,A., Rogowska, J., & Yurgelun-Todd, D,A. (2009). Altered affective response in marijuana smokers: an fmri study. Drug and Alcohol Dependence, 105, 139-153.
  6. ↑ 6.0 6.1 Lane, S.D., Cherek, D.R., Pietras, C.J., & Steinberg, J.L. (2005). Performance of heavy marijuana-smoking adolescents on a laboratory measure of motivation. Addictive Behaviors, 30(4), 815-828.
  7. ↑ 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.
  8. ↑ 8.0 8.1 Stacy, A. (1995). Memory association and ambiguous cues in models of alcohol and marijuana use. Experimental and Clinical Psychopharmacology. 3(2), 183–194.
  9. ↑ 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.
  10. ↑ Ames, S., Dent, C., Stacy, A. & Sussman, S. (1996). Implicit cognition in adolescent drug use. Psychology of Addictive Behaviors. 10(3), 190–203.
  11. ↑ Gray, K., LaRowe, S. & Upadhyaya, H. (2008). Cue reactivity in young marijuana smokers: a preliminary investigation. Psychology of Addictive Behaviors. 22(4), 582–586.
  12. ↑ Lutz, B. (2009). From Molecular neurodevelopment to psychiatry: new insights in mechanisms underlying cannabis-induced psychosis and schizophrenia. Psychiatry Clinical Neuroscience, 259, 369-370.
  13. ↑ 13.0 13.1 Roser, P., Gallinat, J., & Weinberg, G. (2009). Psychomotor performance in relation to acute oral administration of ∆9 – tetrahydrocannabinol and standardized cannabis extract in healthy human subjects. Psychiatry Clinical Neuroscience, 259, 284-292.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 14.9 Hall, W., & Solowij, N. (1998). Adverse effects of cannabis. The Lancet, 352(9140), 1611-1616
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Beck, K.H., Caldeira, K.M., Vincent, K.B., O’Grady, K.E., Wish, E.D., & Arria, A.M. (2009). The social context of cannabis use: Relationship to cannabis use disorders and depressive symptoms among college students. Addictive Behaviors, 34(9), 764-768.
  16. ↑ Chabrol, H., Massot, E., & Mullet, E. (2004). Factor structure of cannabis related beliefs in adolescents. Addictive Behaviors, 29(5), 929-933.
  17. ↑ 17.0 17.1 17.2 17.3 Stuart, E.A. & Green, K.M. (2008). Using full matching to estimate causal effects in nonexperimental studies: Examining the relationship between adolescent marijuana use and adult outcomes. Developmental Psychology, 44(2), 395-406.
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 Budney, A.J., Roffman, R., Stephens, R.S., & Walker, D. (2007). Marijuana dependence and its treatment. Addiction Science & Clinical Practice, 4(1), 1-13.
  19. ↑ 19.0 19.1 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.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 Hyman, S. & Sinha, R. (2009). Stress-related factors in cannabis use and misuse: Implications for prevention and treatment. Journal of Substance Abuse Treatment, 36(4), 400-413
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 Reece, A.S. (2009). Chronic toxicology of cannabis. Clinical Toxicology, 47(6), 517-524.
  22. ↑ 22.0 22.1 22.2 Chédebois, L., Régner, I., van Leeuwen, N., Chauchard, E., Séjourné, N., Rodgers, R., & Chabrol, H. (2009). Relative contributions of acculturation and psychopathological factors to cannabis use among adolescents from migrant parents. Addictive Behaviors, 34(12), 1023-1028.
  23. ↑ 23.0 23.1 Piko, B.F. & Kovács, E. (2010). Do parents and school matter? Protective factors for adolescent substance use. Addictive Behaviors, 35(1), 53-56.
  24. ↑ 24.0 24.1 24.2 24.3 24.4 Berrendero, F., Maldonado, R. & Valverde, O. (2006). Involvement of the endocannabinoid system in drug addiction. Trends in Neurosciences, 29(4), 225-232.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 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.
  26. ↑ 26.0 26.1 26.2 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.
  27. ↑ 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.
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