Use of cannabis by adolescents in key developmental periods increases vulnerability to psychiatric disease and overlaps with biological changes in the endocannabinoid system. The endocannabinoid system is involved in a LOT of biological functions, including memory, appetite, energy balance and metabolism, stress response, immune function, multiple sclerosis, female reproduction, autonomic nervous system, analgesia, thermo-regulation, and sleep

Adolescence is associated with an increased incidence of psychiatric illness, and exposure to cannabis during this developmental window strongly predicts subsequent development of mood disorders, addictive disorders, and schizophrenia (A). Components of the endocannabinoid system appear as early as embryonic life, but maximal CB₁R mRNA expression occurs during adolescence.

When people advocate for legalizing marijuana and tout its healing benefits, most seem to ignore that there are years and years of research linking marijuana use, especially in adolescents and teens, to increased risk for mental illness and psychotic episodes.

The other thing that advocates of marijuana legalization overlook, or are ignorant of, is the tremendous increase in THC levels relative to CBD (cannabidiol), a trend that makes for a greater high and a greater risk and negative side effects. The black market has bred marijuana to be higher in THC and lower in CBD.

Medical marijuana, on the other hand, at least in San Francisco, is being bred for a higher CBD level and a lower THC level. From Wikipedia:

Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.[3] It is a major constituent of the plant, second to tetrahydrocannabinol (THC), and represents up to 40% in its extracts.[4] Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC,[5] including to epilepsy,[6] multiple sclerosis spasms,[7] anxiety disorders, bipolar disorder,[5] schizophrenia,[8] nausea, convulsion and inflammation, as well as inhibiting cancer cell growth.[9] There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.[10][11][12] Cannabidiol has displayed sedative effects in animal tests.[13] Other research indicates that CBD increases alertness.[14] CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.[15]

Anyway, this article offers pretty solid evidence for the risks in allowing adolescents and teens to smoke marijuana, which would likely be prohibited if and when marijuana becomes widely legal. Still, kids are going to smoke weed just like kids are going to drink their parents' beer.

Cannabis use during adolescent development: Susceptibility to psychiatric illness

Benjamin Chadwick [1], Michael L. Miller [1], and Yasmin L. Hurd [1,2,3]

1. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3. James J. Peters VA Medical Center, Bronx, NY, USA

ABSTRACT

Cannabis use is increasingly pervasive among adolescents today, even more common than cigarette smoking. The evolving policy surrounding the legalization of cannabis reaffirms the need to understand the relationship between cannabis exposure early in life and psychiatric illnesses. cannabis contains psychoactive components, notably Δ9-tetrahydrocannabinol (THC), that interfere with the brain’s endogenous endocannabinoid system, which is critically involved in both pre- and post-natal neurodevelopment. Consequently, THC and related compounds could potentially usurp normal adolescent neurodevelopment, shifting the brain’s developmental trajectory toward a disease-vulnerable state, predisposing early cannabis users to motivational, affective, and psychotic disorders. Numerous human studies, including prospective longitudinal studies, demonstrate that early cannabis use is associated with major depressive disorder and drug addiction. A strong association between schizophrenia and cannabis use is also apparent, especially when considering genetic factors that interact with this environmental exposure. These human studies set a foundation for carefully controlled animal studies which demonstrate similar patterns following early cannabinoid exposure. Given the vulnerable nature of adolescent neurodevelopment and the persistent changes that follow early cannabis exposure, the experimental findings outlined should be carefully considered by policymakers. In order to fully address the growing issues of psychiatric illnesses and to ensure a healthy future, measures should be taken to reduce cannabis use among teens.

Full Citation: 
Chadwick B, Miller ML and Hurd YL. (2013, Oct 14). Cannabis use during adolescent development: susceptibility to psychiatric illness. Frontiers in Psychiatry: Addictive Disorders and Behavioral Dyscontrol, 4:129. doi: 10.3389/fpsyt.2013.00129

Introduction

Cannabis sativa is grown worldwide for its production of Δ9-tetrahydrocannabinol (THC), a psychoactive compound found in the recreational drugs marijuana and hashish. The pervasiveness of this drug worldwide, along with its relatively low lethality, has led many to believe that it is of little harm. Indeed, the use of cannabis currently exceeds that of tobacco smoking among adolescents in the United States (1) (Figure 1). Whether cannabis is harmless, and without significant physiological or mental health impact, is actively debated. Unfortunately, these discussions are often not guided by evidence-based data. Research focused on the relationship between cannabis and mental health is thus important especially considering that psychiatric illnesses are complex disorders with multiple factors contributing to vulnerability and eventual expression of the illness. Based on the accruing data to date outlined in this review, developmental cannabis exposure is an important contributing factor to psychiatric vulnerability (Figure 2A).

FIGURE 1

Figure 1. Cannabis consumption is widespread in adolescents. Prevalence of this drug’s intake exceeds other illicit drug’s in eighth through twelfth graders in the USA (A), and it recently surpassed cigarette use (B). Graphs based on data adapted from Johnston et al. (1)(A,B).
 
FIGURE 2

 

Figure 2. Developmental cannabis increases vulnerability to psychiatric disease and overlaps with ontogenic changes in the endocannabinoid system. Adolescence is associated with an increased incidence of psychiatric illness, and exposure to cannabis (arrow head) during this developmental window strongly predicts subsequent development of mood disorders, addictive disorders, and schizophrenia (A). Components of the endocannabinoid system appear as early as embryonic life, but maximal CNR1 mRNA expression occurs during adolescence (B). (Green line = cannabis-exposed and gray line = unexposed individuals.)

Cannabis and Developmental Pattern of Use

Psychiatric illnesses are developmental in nature – the 12-month prevalence of any psychiatric illness is ∼40% in adolescents (2), but ∼25% in adults (3) – making it significantly germane to the strong developmental pattern of cannabis use. A plethora of studies and national surveys monitored the patterns of cannabis use in multiple ethnic and geographic populations worldwide. In the United States, cannabis use is highly prevalent during adolescence (Figure 1), the developmental period when most people initiate use. There are over 6000 first-time cannabis users per day in the US, over 60% of which are under the age of 18 (4). Approximately 34–45% of ninth through twelfth graders reported cannabis use at least once in their lifetime and the pattern of subsequent use appears more or less intermittent with 23% of 12 graders reporting use in the past month (1, 5, 6). Data from wave I–III of the National Longitudinal Study for Adolescent Health recapitulate this pattern of wide spread yet occasional use in adolescents. While the majority of teens have infrequent use, still a significant percentage, 6.6%, report daily use. Determining the long-term impact of occasional and heavy cannabis use during active periods of brain development, such as adolescence, is of critical importance. To provide such insights, data garnered from epidemiological and experimental studies is reviewed in this article. The emerging evidence strongly suggests that cannabis exposure during adolescence increases an adult’s individual vulnerability to drug addiction and schizophrenia and may also produce long-lasting effects on anxiety and mood disorders.

Endocannabinoid System

The psychoactive effects of cannabis, principally mediated by THC, occur via its interaction with the endocannabinoid system, which regulates numerous biological processes involved in development and neuroplasticity. The endocannabinoid system consists of lipid-derived ligands, receptors, and enzymes that orchestrate intercellular communication and intracellular metabolism. The most characterized endocannabinoid ligands – or endocannabinoids (eCBs) – include 2-AG and anandamide, which are presumably synthesized via phospholipase-mediated pathways. At least two G-protein coupled receptors, referred to as cannabinoid receptor-1 (CB₁R) and -2 (CB₂R), interact with these ligands. Additionally, recent evidence suggests that eCBs bind to ligand-gated channels, particularly TRPV1. In regard to the ligands, eCBs are synthesized from membranous precursors and immediately diffuse to nearby cannabinoid receptors, classically expressed on pre-synaptic terminals. Following these events, co-expressed enzymes, such as monoacylglycerol lipase (MGLL), α-β-hydrolase domain 6 (ABHD6), and fatty acid amide hydrolase (FAAH), degrade the ligand to terminate its signal (7, 8). Tightly regulated biosynthetic and degradative pathways ensure proper signaling throughout development, and the correct function of these processes depends on the temporal and spatial patterning of this system. Exogenously consumed cannabis produces supraphysiological effects at eCB-targeted receptors and thus usurp the normal endocannabinoid system (9).

The endocannabinoid system is critical for neurodevelopment and as such is present in early development, and maintains expression throughout life (Figure 2B), exhibiting a broad spatial distribution to regulate synaptic plasticity (10, 11). The CB₁R is found in numerous central nervous system structures as early as the eleventh embryonic day, and throughout the embryonic period this receptor is expressed in subcortical and cortical regions (12). In cortical projection neurons, CB₁R and local eCBs facilitate the fasciculation of descending efferents and thalamic afferents, orchestrating the tight coupling of these two tracts (13). During adolescence, the endocannabinoid system still facilitates neurodevelopment through its intricate involvement in neuroplasticity and synaptic function. Receptor levels of CB₁R in the prefrontal cortex and striatum fluctuate during adolescence depending on the specific brain region. For instance, there is a rapid, sustained increase in cannabinoid receptor binding during adolescence, particularly in the striatum, that is substantially reduced (by half) in early adulthood (14). In addition, the expression of the CB₁R gene (Cnr1) is highest during adolescence and gradually decreases by adulthood with the greatest decreases observed in limbic-related cortical regions such as the cingulate, prelimbic, and infralimbic cortices (15). Concomitant to developmental changes in the CB₁R, levels of anandamide and 2-AG, as well as FAAH enzymatic activity, fluctuate throughout adolescence in a region- and time-specific manner (16, 17). The distinct changes in CB₁R and other components of the eCB system during adolescence, some of which occur during a narrow time window, suggest that certain phases during this dynamic ontogenic period may incur different sensitivity to cannabis exposure. These observations highlight the fact that despite significant studies of CB₁R in the adult brain, there are still gaps of knowledge as to the role of CB₁R and the endocannabinoid system in the extensive pruning and development that is evident throughout adolescence.
 

Addiction Vulnerability

A gateway drug hypothesis had long been proposed implying that adolescent cannabis use predisposes individuals to use other illicit drugs as adults, thereby increasing their vulnerability to substance use disorders (18) (Figure 2A). Although, the term “gateway” has sometimes been misinterpreted to imply that all individuals who use cannabis will directly abuse other drugs, this original hypothesis by Kandel (18) conducted on cohorts of high school students suggested that cannabis use is a critical illicit drug, intermediate in the transition from legal substance use (i.e., cigarettes and alcohol) to illicit drug use (i.e., heroin, amphetamines, and LSD). Over a quarter of individuals who progressed to illicit drug use had previous experience with marijuana while only 2–3% of legal drug users without marijuana experience progressed to illicit drug use. Subsequent longitudinal studies that tracked younger adolescents found that early cannabis use positively predicted cocaine and alcohol use across a 1-year period (19). Additional evidence that early-life cannabis consumption increases cocaine use later in life is supported by studies representing broad demographic populations (20), suggesting that these findings are likely generalizable.

Prospective longitudinal studies have also offered compelling evidence in support of the gateway drug hypothesis. A landmark 25 year-long study conducted on a birth cohort from New Zealand assessed associations between age of onset, and frequency of cannabis use, with the use and/or dependence of other substances (21). Even after controlling for a number of confounding variables, such as socio-economic background, other illicit substance use, family functioning, child abuse, and personality traits, early cannabis use was still significantly associated with subsequent drug abuse and dependence. Additionally this effect was age-related such that the association between cannabis use and the development of drug abuse and dependence declined with increasing age of initiation. An important strength of this study was that data collection extended beyond self-reports, and included parental interviews, medical records, psychometric assessment, and teacher reports. Twin-studies, which control for potential confounds such as genetics and shared environmental influences, have also confirmed that early adolescent onset of cannabis use increases the likelihood of developing drug dependence later in life (22).

One concern with human epidemiological studies is the inability to distinguish between casual and purely associative relationships. This is highlighted by a common-factor modeling study which suggests that correlations between cannabis and illicit drugs were principally attributed to other factors, namely an individual’s opportunity for and propensity to use drugs (23). Therefore, it has been argued that the transition from cannabis use to other drugs is not causal but is simply an expected sequence engaged by individuals that would normally go on to use other illicit drugs. Moreover, many teens who routinely smoke cannabis also use other drugs (e.g., alcohol and tobacco). While sequential transitions and the co-abuse of other drugs during such times could potentially contribute to enhance psychiatric risk, it is impossible to ignore the growing body of evidence that suggest a significant contribution of early adolescence cannabis specifically to the propensity to develop substance abuse disorders later in life even when controlling for other substances (21, 22) (Figure 3).

FIGURE 3

Figure 3. Cannabis use is associated with progression to use other illicit substances in humans. Twin-studies illustrate that cannabis users have an increased risk of developing substance abuse disorder compared to their discordant twin. Graph based on data adapted from Lynskey et al. (22) (A). Cross-sectional studies reveal that earlier and more frequent cannabis use further increases this risk. Graph based on data adapted from Fergusson et al. (21) (B).

Animal studies allow the possibility to directly test the causal relationship between adolescent cannabinoid exposure and subsequent risk for drug addiction, independent of subject-specific factors that confound human investigations. Although a weakness of animal studies is that they do not mimic the complex nature of psychiatric disorder, specific phenotypes relevant to such disorders can be examined. In contrast to most psychiatric disorders, modeling addiction in animals is very predictive of the human condition through the use of self-administration paradigms wherein animals control their own drug intake. Under such conditions, adolescent exposure to THC reliably increases heroin self-administration (24, 25). In a similar investigation, performed in slightly older rats (approximately late adolescence), THC pre-exposure increased heroin self-administration when the contingency for heroin was fixed, but not when the work necessary to acquire heroin was progressively increased (26). Such findings imply that adolescent THC exposure increases the hedonic, but not motivational, aspects of heroin-seeking. Limited animal investigations have examined the sensitivity of early THC exposure to other “heavy” drugs of abuse such as cocaine, but the existing studies to date do highlight the generally enhancing effects of adolescent cannabinoid exposure on future drug-seeking behaviors, and experimentally support the gateway drug hypothesis.

Animal studies also provide specific insights about discrete neurobiological disturbances associated with developmental cannabinoid exposure. For example, adolescent THC increases inhibitory G-protein coupled signaling in the rodent midbrain, which by modulating dopaminergic projections, enhances mesolimbic dopamine, all adaptations strongly associated with enhanced reward (24). In addition, adolescent THC exposure increased mu opioid receptor function in the nucleus accumbens, a brain region central to reward and motivated behaviors, and these receptor impairments directly correlated to heroin intake (24). Moreover, increased gene expression of proenkephalin, an opioid neuropeptide that directly modulates heroin self-administration behavior, is also induced in the nucleus accumbens of adult rats with adolescent THC exposure (25). Enhanced cocaine self-administration has also been observed in female rats as a consequence of early-life exposure to the cannabinoid agonist CP-55,940 which was associated with altered striatal dopamine transporter binding in adulthood (27), and this transporter’s disturbance is highly implicated in addiction-related behaviors. Together these and other accumulating evidence in the literature emphasize that adolescent cannabinoids persistently change mesolimbic brain regions of the adult that sufficiently predict future self-administration behavior, a phenotype relevant to drug addiction vulnerability.
 

Negative Affect and Anxiety

Another major question regarding the impact of adolescent cannabis relates to its role in negative affective disorders, such as major depressive disorder (MDD), which are increasingly burdensome worldwide. While equivocal, several longitudinal studies demonstrate an association between MDD and early-life exposure to cannabis. A large multi-cohort longitudinal investigation that examined the effects of adolescent cannabis use on depression and anxiety showed that frequent adolescent cannabis use increased depression and anxiety in early adulthood (28). Furthermore measures of depression and anxiety during adolescence did not predict cannabis use in young adults suggesting that this relationship was not simply due to premorbid differences. Similarly, while individuals who used cannabis during early teens did not differ in depression, suicidal ideation, or suicide attempts during adolescence, by early adulthood these individuals had significantly higher incidence of suicidal ideation and suicide attempts (29). A consistent observation was reported in another large longitudinal investigation, which found that adults with early cannabis use had increased suicidal behaviors (30). Altogether these findings emphasize the important contribution of early cannabis exposure to MDD and suicidal ideation. Importantly, accumulating evidence also implies that both adolescent exposure and the continued use during adulthood are required for these associations (31, 32) suggesting that disease may be mitigated with cannabis cessation.

It is important to note that although most studies to date imply an association of early cannabis with negative affective disorders, the longitudinal cohort investigation by Harder et al. (33) did not find any difference in depression or anxiety either during early adolescence or at the last follow-up in adulthood. This inconsistency may be due to the study’s lenient definition of a “cannabis user,” which included any participant who ever smoked cannabis prior to age 17 (∼50% population). Although additional studies are needed to understand the long-term causative effects of adolescent cannabis on negative affect, a preponderance of the evidence accrued thus far strongly suggests a correlation between these two factors.

Future longitudinal studies are clearly still needed to examine the contribution of the developmental period of onset and cessation of cannabis to the risk of negative affect. In addition, in vivo neuroimaging in humans can also offer much needed neurobiological insights. Evidence already exists demonstrating volumetric impairments in the amygdala, a brain region central to affective and addictive disorders, in cannabis users during early (34), and late (35) adolescence. Similarly, structural changes in the hippocampus, which is linked to depression (36), has been reported in individuals with cannabis use during late adolescence (35, 37).

The use of animal models has also helped to fill gaps of knowledge regarding the direct link between early-life cannabis use and negative affect and anxiety. Such experimental studies have demonstrated that early exposure to cannabinoids directly leads to dysregulation of emotional processes and induces depressive-like phenotypes later in life. For instance, escalating doses of THC to adolescent rats decreases sucrose preference, a measure of anhedonia (38). Other behavioral strategies such as the forced-swim test used to measure depression-related symptoms also reveal a pro-depressive phenotype directly associated with adolescent THC (39), although these effects generally appear stronger in females (38, 40). These findings suggest that adolescent cannabinoid exposure could affect the liability to mood disorders later in life, and the potential gender differences may relate in those well-documented in human depression.

Altered anxiety-like behavior as a consequence of adolescent cannabinoid exposure is also apparent in experimental animals though the relationship is not straightforward per se. Anxiogenesis or anxiolysis has been reported depending on the period of cannabinoid exposure and the specific task used to model anxiety. For example, chronic exposure to cannabinoid agonists – such as THC, CP-55,940, or WIN-55,212-2 – during mid- to late-adolescence, increases social anxiety as measured with a social recognition task (41–44). Other measurements of stress that do not rely on social interaction, such as the open-field and elevated plus-maze tests, indicate varying degrees of anxiolysis, not anxiogenesis (41, 45, 46). These anxiolytic effects were observed after mid- to late-adolescent exposure, whereas earlier, pre-pubertal exposures (PND 15–40) were anxiogenic (47). Consistent with the notion of critical periods, persistent alterations in anxiety almost exclusively occur after early-life exposure and not in animals exposed as adults (39).

Few animal experimental studies have specifically focused on examining neurobiological mechanisms associated with regulation of emotion in association with adolescent cannabinoid exposure. Of the studies, Page et al. (48) demonstrated that administration of the cannabinoid agonist WIN-55,212-2 to adolescents, as compared to adult rats, more profoundly and persistently disrupted cells in the locus coeruleus, a midbrain region that contains noradrenergic neurons and is implicated with depression and anxiety. Similarly, adolescent animals treated with WIN-55,212-2 exhibit altered midbrain neuronal firing characteristics that were not observed in adult-exposed rats (39). Specifically, the cannabinoid treatment resulted in hyperactivity of the noradrenergic neurons concomitant with hypoactivity of serotonergic cells (39). Such neuroadaptations would be predictive of enhanced anxiety and depression-like behavior as a consequence of early cannabinoid exposure.
 

Schizophrenia and Schizoaffective Disorders

Although a small fraction of teens that use cannabis develop schizoaffective disorders, a number of epidemiological studies repeatedly demonstrate elevated risk to develop these psychiatric disorders in association with early-life cannabis use. Longitudinal studies assessing the relationship between early-life cannabis exposure and schizotypal personality disorder demonstrated that early adolescent use increases adulthood symptomatology (49). Moreover, the presence and severity of schizophrenic endophenotypes, such as psychotic symptoms and prepulse inhibition, were predicted by adolescent cannabis use (50, 51).

The first longitudinal studies demonstrating an association between cannabis use before adulthood and schizophrenia were conducted in Swedish conscripts (52, 53) Although no information was known about the individuals before conscription, subjects reporting previous cannabis use at the time of conscription were significantly more likely to be diagnosed with schizophrenia later in life. These findings were replicated in multiple studies emphasizing the reproducible relationship between adolescent cannabis use and increased schizophrenia symptoms in adulthood (54, 55).

Although it is challenging to model schizophrenia in animals, phenotypes related to this disorder may be studied. Animals exposed to cannabinoids during adolescence demonstrate increased schizoaffective-like phenotypes, such as impaired sensorimotor gating, which, similar to humans, results in decreased prepulse inhibition (45). Consistent with the notion that developmental cannabinoids induce a schizophrenia-like phenotype, acute administration of the anti-psychotic haloperidol normalized prepulse inhibition in the cannabinoid-exposed rats (47).

Since not all cannabis users develop schizophrenia, early cannabis use likely interacts with other factors to facilitate the emergence of this disease (56). Accumulating data in recent years highlight that the association between early cannabis exposure and vulnerability to schizophrenia is related to individual genetics. Pioneering studies by Caspi et al. (57) demonstrated that the relationship between adolescent cannabis use and schizophreniform disorder, as well as the presence of various psychotic symptoms, was attributable to the presence of a functional polymorphism in the catechol-O-methyltransferase (COMT) gene. This enzyme degrades catecholamines, such as dopamine, and this functional variant (COMTvaline158) catabolizes this neurotransmitter more rapidly than the methionine allele (58). In cannabis users, schizophreniform disorder is predominantly observed in persons with at least one copy of the polymorphic COMT gene (59–61). Moreover, clinical laboratory experiments show that THC’s acute psychotomimetic effects are moderated by this COMT SNP with THC-induced psychotic-like experiences and cognitive impairments being more pronounced in individuals with the valine158 allele (62). Animal models also confirm a link between the genetic disturbance of COMT and developmental cannabis such that adolescent THC exposure in transgenic mice lacking endogenous COMT synergistically impacts behaviors relevant to schizophrenia (63). Overall, these human and animals studies highlight the significant association between early cannabis exposure and schizophrenia, supporting the so-called two-hit hypothesis which posits that both genetics and early environmental factors enhance individual risk to psychiatric illnesses.

Phytocannabinoids and Psychiatric Vulnerability

It is important to emphasize that while most studies focused on THC to understand the long-term impact of cannabis, the plant produces at least 70 cannabinoids (64). To date the most studied phytocannabinoid aside from THC is cannabidiol (CBD), the second major constituent of the cannabis plant. Interestingly, in contrast to THC, CBD appears to have more protective effects relevant to addiction, cognition, and negative affect. For example, CBD inhibits drug-seeking behavior associated with heroin-relapse in rats (65), reduces cigarette intake (66), and inhibits morphine reward (67). It also has anti-psychotic properties (68, 69) and reduces anxiety behavior in rodents (70) and humans (66). Most of these investigations, however, were carried out in adults. No published study to date has examined CBD in relation to adolescent development and subsequent behavioral consequences in later life. As such, it remains to be explored whether the potential positive effects of CBD on brain function seen in adults would also be evident with adolescent exposure. One intriguing consideration about CBD relevant to the developing brain is that cannabis plants today ingested by teens are grown for high THC, but low CBD content (71). This significant change in the THC:CBD ratio could reduce a normally apparent protective constituent of cannabis. The fact that so little is known about CBD and the developing brain highlights the need for research about this and other phytocannabinoids to more fully understand the impact of cannabis to psychiatric vulnerability.

Conclusion

The high prevalence of cannabis use among teens and the increasing number of states in the USA that legalize cannabis for both medicinal and recreational purposes are concerning given the surprisingly limited information known about the impact of cannabis on the developing brain and individual susceptibility. Though a causative relationship cannot be determined between marijuana’s glamorization and its increasing use in teenagers, important lessons can be learned from the major inroads made in reducing cigarette use in youths such as interventions through campaigns that made smoking less socially accepted. Based on the current evidence available from human and animal models, it is evident that cannabis use during adolescent development increases risk of psychiatric diseases such as drug addiction and schizoaffective disorders with genetic interactions. No convincing data exist to support one “common cause” that exclusively predicts which individuals using cannabis as teens will progress to addiction and psychiatric disorders later in life versus those who do not. Psychiatric diseases, such as those discussed in this review, are complex and multifactorial. Indeed, the complex transition from early cannabis use to subsequent psychiatric illness involves multiple factors such as genetics, environment, time period of initiation and duration of cannabis use, underlying psychiatric pathology that preceded drug use, and combined use of other psychoactive drugs. Whether the early onset of cannabis use relates to preexisting pathology that is then exacerbated by the drug is still debated. Additionally, it remains uncertain whether there exist specific critical windows of vulnerability during different phases of adolescent development relevant to the long-term trajectory of risk in adulthood. Longitudinal investigations, making use of neuroimaging and genetics, alongside concurrent studies in animal models are needed to fully elucidate molecular mechanisms that could provide novel treatment interventions for individuals with psychiatric disease and comorbid adolescent cannabis use.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References available at the Frontiers site

The Endocannabinoid System as a Possible Target for Treating Post-Traumatic Stress Disorder

Around 15-35% of those who experience serious trauma are likely to develop post-traumatic stress disorder (PTSD), and among those who have experienced abuse, neglect, or other adversity in childhood, the number tends toward the high end. Of those who develop PTSD , more than a third will fail to recover even after many years of therapy and medications (Darves-Bornoz et al., 2008). These people demonstrate considerable impairments in their overall quality of life, including physical health and psycho-social functioning (Schelling et al., 1998).

Obviously, the current treatment approaches (SSRI antidepressants, cognitive-behavioral therapy, and exposure therapy) are not working for a significant number of people.

One of the innovations in recent years has been the use of beta-blockers (high blood pressure medication) to reduce anxiety, hypervigilance, flashbacks, and nightmares. The one I see most often is Prazosin, which seems to work, in part, by reducing adrenaline levels, thereby decreasing anxiety.

Prazosin is an alpha-adrenergic blocker originally used to treat hypertension. "The reason we think it works in the setting of nightmares is that prazosin crosses the blood–brain barrier, so it gets into the brain and kind of dampens the norepinephrine effects, which we think contribute to nightmares," Dr. King said.

In my experience, the side-effects of this medication are far less intrusive and long-lasting than those of the SSRI and SNRI medications. The benefits, even if it is only improved sleep can be considerable for those who are good responders.

In this new article from Frontiers in Behavioral Neuroscience, the authors propose that a potential target for treating the anxiety and hypervigilance symptoms, as well as many of the other symptoms (avoidance, arousal, and re-experiencing), is the endocannabinoid system. A quick Google Scholar search turned up a lot of research in this area, including these articles:

• Fraser, GA. (2009). The Use of a Synthetic Cannabinoid in the Management of Treatment-Resistant Nightmares in Posttraumatic Stress Disorder (PTSD). CNS Neuroscience & Therapeutics, 15; 84–88. doi: 10.1111/j.1755-5949.2008.00071.x

• Hill, MN and Gorzalka, BB. (2009). The Endocannabinoid System and the Treatment of Mood and Anxiety Disorders. CNS & Neurological Disorders - Drug Targets, 8, 451-458.  

• Viveros, MP, Marco, EM, Llorente, R, and Lopez-Gallardo, M. (2007). Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses. Neural Plasticity, Article ID 52908, 12 pages. doi: 10.1155/2007/52908

My issue with this Frontiers article is that the authors don't even mention possible treatments for PTSD that do not involve a pill. While I have many clients who need medication, at least in the short term, in order to get benefit from therapy, I have many who do not need medications, or who have enough affect regulation to manage the difficult symptoms when they come up.

No matter how many cool drugs are developed, we should always try to treat people without drugs first and foremost. Even with the medications that seem to have few side effects, such as the concepts proposed below, there are ALWAYS side effects.

The endocannabinoid system regulates memory, appetite, energy balance/metabolism, stress response, immune functions, pain perception, body temperature, and even neurogenesis. There is no way we can manipulate this system for one outcome and not impact its functions in other areas of the body.

Full Citation: 

Trezza V and Campolongo P. (2013, Aug 9). The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Frontiers in Behavioral Neuroscience, 7:100. doi: 10.3389/fnbeh.2013.00100

The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD)

Viviana Trezza [1] and Patrizia Campolongo [2]

1. Department of Sciences, Section of Biomedical Sciences and Technologies, University “Roma Tre,” Rome, Italy
2. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

Abstract

Post-traumatic stress disorder (PTSD) is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval, and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in endocannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that endocannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors.

* * * * *

Post-traumatic stress disorder (PTSD) is a psychiatric disorder of significant prevalence and morbidity (Layton and Krikorian, 2002). In the overall population, more than two thirds of persons may experience a serious traumatic event at some point in lifetime (Javidi and Yadollahie, 2012). Although not everyone develops PTSD after experiencing a traumatic event, the lifetime prevalence of PTSD is high, being estimated as 8.2% in Europe and in the United States, up to 9.2% in Canada (Kessler et al., 1995; Darves-Bornoz et al., 2008; Van Ameringen et al., 2008). More than a third of PTSD patients fail to recover even after many years of treatment (Darves-Bornoz et al., 2008), showing a significant impairments in many aspects of health-related quality of life, including psychosocial functioning (Schelling et al., 1998).

Feeling afraid is a natural response to threats and triggers many physiological changes to prepare the body to defend against the danger or to avoid it. In PTSD, this reaction is changed or damaged. Even if anxiety is a common symptom of PTSD patients, the pathogenesis of the disorder relies on paradoxical changes of memory processing (Cohen et al., 2006;Parsons and Ressler, 2013). From a physiological point of view, memories characterized by a strong emotional salience tend to be well consolidated, they are often retrieved in our brain and therefore tend not to be extinct; from an evolutionary perspective, this is of crucial importance for survival. However, in PTSD patients, all or part of this processes may become maladaptive. Three symptom categories characterize the disorder: (1) persistent re-experience of the traumatic event; (2) persistent symptoms of increased arousal; and (3) persistent avoidance of stimuli associated with the trauma, which may include amnesia for important aspects of the traumatic event (Brewin, 2001). These symptoms reflect excessive retrieval of traumatic memories that are again consolidated, thus cementing the traumatic memory trace, and retaining its vividness and power to evoke distress for decades or even a lifetime (de Quervain et al., 2009). It appears from this symptomatology that three phases of memory processing may become maladaptive and of crucial importance in the development and maintenance of PTSD: consolidation, retrieval, and extinction.

PTSD is heterogeneous in its nature, and often associated with other psychiatric comorbidities; for these reasons, treating PTSD is rather difficult, and the disorder may persist over the patient's lifetime (Albucher and Liberzon, 2002). The therapeutic options to treat the anxiety symptoms of PTSD currently include serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOi), anticonvulsants, atypical antipsychotics and benzodiazepines (Albucher and Liberzon, 2002). Although SSRIs emerge as the preferred first line treatment to treat the anxiety symptoms of PTSD (Dow and Kline, 1997; Ipser et al., 2006), a large proportion of patients fails to respond to these medications (Ipser et al., 2006). Furthermore, no suitable treatment is currently available to treat the maladaptive cognitive features of PTSD and/or to prevent its development. This limitation is due to the scarce knowledge of PTSD neurobiology that hampers the identification of new pharmacological targets to treat this disorder. As Albucher and Liberzon (2002) pointed out, the diversity of the symptoms such as flashbacks, nightmares, hyperarousal, avoidance, numbing, anxiety, anger, impulsivity, or aggression suggests the involvement of multiple neurotransmitter systems (Goodman et al., 2012; Packard and Goodman, 2012).

An ideal pharmacological treatment for PTSD would be a drug able to block the pathological over consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. Although no such drug is currently available, recent clinical (Fraser, 2009; Hauer et al., 2013; Neumeister et al., 2013) and preclinical (Lutz, 2007; Akirav, 2011; Berardi et al., 2012; Ganon-Elazar and Akirav, 2012) studies point to the endocannabinoid system as a possible ideal therapeutic target to treat both the emotional and cognitive dysfunctions characterizing PTSD (Neumeister, 2013).

The central endocannabinoid system is a neuroactive lipid signaling system in the brain which shows functional activity since early stages of brain development; by controlling neurotransmitter release, it plays a relevant role in brain function during both pre- and post-natal life (Fernandez-Ruiz et al., 2000; Harkany et al., 2007; Trezza et al., 2008; Campolongo et al., 2009b, 2011). The endocannabinoid system consists of cannabinoid receptors (CB1 and CB2), their endogenous lipid ligands (endocannabinoids) and the enzymatic machinery for endocannabinoid synthesis and degradation (Piomelli, 2003; Di Marzo et al., 2005). Due to the wide expression of cannabinoid receptors throughout limbic regions of the brain, endocannabinoids control both emotional behavior and cognitive processes (Riedel and Davies, 2005; Campolongo et al., 2007, 2009a; Hill and Gorzalka, 2009; Atsak et al., 2012; Campolongo et al., 2012). Thus, while preclinical studies assessing the consequences of cannabinoid receptor blockade or activation on emotional responses have yielded sometimes controversial results, consensus exists that endocannabinoids have an essential role in maintaining emotional homeostasis (Haller et al., 2002,2004; Hill and Gorzalka, 2009; Moreira and Wotjak, 2010; Parolaro et al., 2010; Ruehle et al., 2012). Similarly, evidence exists that administration of cannabinoid drugs in animals influences memory consolidation, retrieval and extinction (Marsicano et al., 2002; Niyuhire et al., 2007; Marsicano and Lafenetre, 2009; Atsak et al., 2012; Campolongo et al., 2013). In particular, systemic administration of cannabinoid agonists impairs memory retrieval (Niyuhire et al., 2007) while facilitating memory extinction (Lutz, 2007). Direct evidence has been provided that endocannabinoids modulate emotional memory processing acting in the basolateral complex of the amygdala (BLA), in the hippocampus (de Oliveira Alvares et al., 2005, 2008; Campolongo et al., 2009a; Atsak et al., 2012) and in the prefrontal cortex (Egerton et al., 2006), key brain regions involved in memory consolidation, retrieval and extinction of emotionally arousing experiences (McGaugh, 2004; Quirk and Mueller, 2008;Roozendaal et al., 2008; Herry et al., 2010), and dysfunctional in PTSD patients (Bremner et al., 2008; Hughes and Shin, 2011).

Interestingly, emerging empirical work has indicated a link between traumatic event exposure and cannabis use. Data from the National Comorbidity Study demonstrated that adults suffering from PTSD were three times more likely to have cannabis dependence as compared with those without PTSD (Kessler et al., 1995). Studies involving military veterans have demonstrated an even higher rate of cannabis abuse among military veterans with PTSD (Stewart et al., 1998; Bonn-Miller et al., 2011). A positive association between PTSD and cannabis use among teenagers has also been reported (Cornelius et al., 2010). These results could be partially explained by recent data demonstrating that PTSD patients present important changes of plasma endocannabinoid levels and elevation in amygdala-hippocampal-cortico-striatal CB1 receptor availability (Hauer et al., 2013; Neumeister, 2013; Neumeister et al., 2013). The comorbidity between cannabis abuse and PTSD is always described in literature as a negative aspect, with the increase in substance abuse after a disaster as a cause for public long-term health consequences.

However, another side of the coin needs to be considered. It is possible that PTSD patients use cannabis as a self-medication. In support of this hypothesis, one study among Vietnam veterans indicated that cannabis use was helpful in managing PTSD symptoms, with particular respect to the hyperarousal state (Bremner et al., 1996). It has been shown that there is a correlation between post-traumatic stress symptom severity and motivation to use marijuana in order to cope with emotional distress (Bonn-Miller et al., 2007). Although the majority of the currently available clinical studies highlights the beneficial effects of cannabis use in PTSD patients, the positive association between cannabis use and relief from PTSD symptoms is not an universal finding. Thus, it has also been documented that, in certain conditions, cannabis abuse may facilitate PTSD development (Cougle et al., 2011). This may be due to the fact that direct activation of cannabinoid receptors by the active ingredient of cannabis, Delta-9-tetrahydrocannabinol, leads to a rapid down-regulation of the endocannabinoid signaling system (Hirvonen et al., 2012), resulting in tolerance. The complex scenario that emerges from the clinical setting makes it difficult to draw final conclusions about the relationship between cannabis use and PTSD.

Preclinical studies allow to control for the confounding variables that characterize the clinical observations, and therefore can provide essential information to elucidate the link between endocannabinoids and emotional memory processing, from physiological to pathological conditions. Thus, as highlighted above, it has been demonstrated that cannabinoid compounds strongly facilitate memory extinction in animals (Marsicano et al., 2002; Lutz, 2007), while impairing memory retrieval (Niyuhire et al., 2007; Atsak et al., 2012). It is thus tempting to speculate that cannabinoid compounds can attenuate the excessive retrieval of the traumatic event experienced by PTSD patients, while facilitating its extinction. Memory consolidation for emotionally salient events is also affected by cannabinoid drugs, although the results of the preclinical studies performed so far are controversial. Thus, it has been shown that post-training administration of cannabinoid receptor direct or indirect agonists facilitates memory consolidation in the inhibitory avoidance task (Campolongo et al., 2009a; Hauer et al., 2011).

These findings suggest that activation of cannabinoid receptors shortly after experiencing a stressful event could facilitate the development of maladaptive memories of this event. This, in turn, may provide preclinical rationale to the finding that the use of drugs indirectly enhancing endocannabinoid activity, such as propofol, or the use/abuse of cannabis, shortly after the experience of an aversive event, may facilitate PTSD development in humans and has to be avoided in the aftermath of an aversive experience (Cougle et al., 2011; Hemmings and Mackie, 2011;Usuki et al., 2012). However, cannabinoid agonists administered to rats shortly after exposure to a series of intense stressful events have been reported to prevent the impairment in avoidance extinction induced by the traumatic experience (Ganon-Elazar and Akirav, 2009, 2012, 2013). These findings leave open the possibility that cannabinoid drugs may be good candidates for secondary prevention of PTSD, that is, may be a good therapeutic option immediately after trauma exposure (Zohar et al., 2011).

It clearly appears from this scenario that, if from one side the data about the effects of cannabinoid drugs on memory retrieval and extinction are quite consistent and suggest that these compounds may facilitate PTSD recovery, on the other side the role of cannabinoids in memory consolidation is still debated. More research is therefore warranted to determine the extent to which differences in doses, routes of administration, timing of exposure and behavioral tasks used may be responsible for the opposite effects of cannabinoid agonists on memory consolidation reported so far. Conversely, encouraging clinical data exist on the use of cannabinoid compounds after the onset of the pathology (weeks or months after the experience of a traumatic event, when the memory consolidation of the traumatic event is completed) (Passie et al., 2012).

A recent clinical trial to evaluate the effects of nabilone, a cannabinoid receptor agonist, on treatment-resistant nightmares in PTSD patients demonstrated that the majority of patients (72%) receiving nabilone experienced either cessation of nightmares or a significant reduction in nightmare intensity (Fraser, 2009). Subjective improvement in sleep time, the quality of sleep, and the reduction of daytime flashbacks were also noted by some patients (Fraser, 2009). This is the first report of the use of nabilone for the management of treatment-resistant nightmares in PTSD. Although this evidence is encouraging, further studies on larger cohorts and with a more accurate identification of possible side effects of chronic use of direct cannabinoid agonists are warranted. The use of drugs that directly bind and activate brain cannabinoid receptors is indeed limited by their abuse potential (Tanda and Goldberg, 2003; Economidou et al., 2007;Ashton, 2012).

Two alternative pharmacological approaches exist to target cannabinoid receptors in the brain, without inducing abuse liability (Gobbi et al., 2005; Bortolato et al., 2006; Justinova et al., 2008). First, it has recently been reported that the non-psychotomimetic constituent of cannabis cannabidiol facilitates disruption of contextual fear memories (Stern et al., 2012) in rats while inducing anti-anxiogenic-like effects in rats and humans (Bitencourt et al., 2008; Bergamaschi et al., 2011). Alternatively, several preclinical studies have identified endocannabinoid deactivation inhibitors as a novel therapeutic approach for the treatment of neuropsychiatric disorders. In particular, indirect cannabinoid agonists have been proposed as anxiolitic and antidepressant agents (Kathuria et al., 2003; Bortolato et al., 2006; Piomelli et al., 2006; Vinod and Hungund, 2006) and have been reported to facilitate extinction of fear memory in rodents (Bitencourt et al., 2008; Pamplona et al., 2008). Thus, these compounds may prove effective to ameliorate the anxiety symptoms of PTSD and, at the same time, an increase in the endocannabinoid tone may be useful to treat the cognitive features (Varvel et al., 2007) of the pathology. These dual effects make these drugs gold candidates in the treatment and prevention of PTSD. Much attention, however, has to be dedicated to the time framing of pharmacological treatment, with an attempt to avoid the first early phases of memory consolidation.

It clearly appears that a deeper insight into the role of endocannabinoid neurotransmission in emotional memory processing, both in physiological and pathological conditions, will shed light in the neurobiological basis of PTSD; this, in turn, will open new frontiers for alternative and more efficacious therapeutic approaches for a complete resolution of the pathology.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References are available at the Frontiers site.