Cannabis Use

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1		Laura Prieto-Arenas	+ 3201 word(s)	3201	2022-03-24 07:43:15	\|
2	formating	Jason Zhu	+ 3 word(s)	3204	2022-03-28 04:00:56	\|

This entry is adapted from the peer-reviewed paper 10.3390/brainsci12030388

Cannabis is a natural drug that humans have been consuming for over 4000 years for medicinal, industrial and ritual purposes. More than 400 chemical compounds can be found in the cannabis plant, of which at least 144 are cannabinoids. Among the cannabinoid compounds, the most important one is tetrahydrocannabinol or delta-9-tetrahydrocannabinol (THC or Δ9-THC), the main psychoactive component of cannabis. Recently, the increase in its use, both medicinal and recreational, its progressive legalization and the change in the cannabis market have caused a greater interest in the research of this drug.

Cannabis Risk Endocannabinoid

1. Epidemiology and Risk Factors for Cannabis Use

The most consumed illegal psychoactive substance in recent years is cannabis, with an upward trend observed mainly among the young population ^[1]^[2]. It is estimated that 27.2% of the European population aged between 15 and 64 years have consumed it at some time in their lives ^[3], and this number is as high as 37.5% in countries such as Spain ^[4]. It is the most consumed drug worldwide, with an increase in the global number of past-year cannabis users of 18% between the years 2010 and 2019 ^[5]. It is a drug preferentially used by young people. Approximately 17.3% of European students between the ages of 15 and 16 have used it in the last year. Surveys of the general population reported that about 1.8% of people aged 15–64 in the European Union are daily or almost daily cannabis users, having used the drug for 20 days or more in the last month, most of whom (61%) are under 35 years of age ^[5]. In Spain, the population aged 15–64 that admits to having consumed cannabis daily during the last month reached 2.9%, and 1.9% have a risky use, rating four or more on the Cannabis Abuse Screening Test ^[4].

Clearly, the perception of risk associated with cannabis use has declined among the young population ^[4]^[6]^[7]. A perception of lower risk is related to higher drug use, although it is still being discussed as to what extent this reduced perception of harmfulness is responsible for the long-term increase in cannabis use ^[2]. The legalization of cannabis for recreational use is considered to be a main cause of this decreased risk perception. However, the findings of studies that examined the relationship between policy changes and the prevalence of adolescent cannabis use are conflicting. Some studies have found that the legalization of cannabis has increased the prevalence of cannabis use disorder among young people, but others have failed to find any relationship or even suggest a paradoxical decline in use after legalization ^[8].

On the other hand, it is evident that cannabis is the drug with the highest perceived availability ^[1], with 59.4% of the Spanish population believing that it would be easy for them to obtain it within 24 h ^[4]. This possibly also contributes to the fact that, along with alcohol, it is among the first drugs of abuse to be consumed among adolescents. Although the average age of initiation of cannabis use has remained stable since the year 2000, it is below 17 years of age ^[4]^[5]. It is well known that adolescence is a critical period of brain development characterized by significant structural change in the brain, specifically in the cerebral cortex ^[9]. Therefore, this period is also associated with a vulnerability to psychopathology. It has been well documented that a marked upsurge in psychiatric illness, including anxiety, depression and psychotic disorders, occurs during adolescence ^[10]^[11]. Recently, it has been demonstrated that the endocannabinoid system plays a role in the development of other systems, in particular dopamine circuits, during adolescence ^[12].

Currently, the cannabis market is changing, with a very high increase in tetrahydrocannabinol (THC) levels in products ^[1], which are prepared by extracting cannabinoids from the plant to make a product with THC concentrations that usually range from 52 to 69% THC, but which can be as high as 90–95% ^[13]. This high THC content in cannabis products now available in Europe has been linked to the increase in the overall number of first-time admissions to treatment for cannabis problems in recent years ^[5]. With respect to the number of admissions to treatment of all entrants, cannabis is at 28.1% in Spain and 36% in the European Union, which increases to 46.8% in treatment demands for first-time entrants ^[5]. It is also important to highlight that 95.2% of people under 18 who were treated for illicit drug use in Spain did so for problems associated with cannabis use ^[4].

In addition, the presence of cannabis has continued to increase in Spain in hospital emergencies related to non-medical drug use and in toxicological analyses of deaths due to acute reactions to psychoactive substances. In 2019, more than 50% of hospital medical emergencies related to drug use were due to cannabis; and this drug was detected in 25.5% of those who died of an acute drug reaction, the highest value recorded in the historical series ^[4]. As it is usually consumed in combination with other substances, such as hypnosedatives, opioids, cocaine or alcohol, it cannot be established how it contributed to the subject’s death. Thus, cannabis abuse, by itself, does not seem to produce overdose like other drugs, but it does carry a significant psychiatric burden ^[14]. Moreover, cannabis use-related harms are not limited to the mental health domain, but also significantly affect the field of social security (mainly motor vehicle collisions, violence and suicidal behavior), although it has not yet been established what can be considered to be risky use of cannabis ^[15].

2. The Endocannabinoid System

Cannabis is the generic name used to refer to psychoactive substances obtained from the Cannabis sativa female plant, known as cannabinoids ^[16]. Overall, a cannabinoid is an organic compound belonging to the group of terpenophenolics, which can activate the cannabinoid receptors of humans. It can be distinguished three general types of cannabinoids: endogenous cannabinoids or endocannabinoids, produced by the human body and which constitute the endocannabinoid system; herbal cannabinoids or phytocannabinoids, naturally synthesized from the cannabis plant; and synthetic cannabinoids, which are similar compounds generated in the laboratory ^[17]. In general, cannabinoids exert their psychoactive action by binding to brain cannabinoid receptors.

Among the phytocannabinoids, THC, or Δ9-THC, is the cannabinoid with the best known effect and the main psychoactive component of the cannabis plant. Other cannabinoids present in the Cannabis sativa plant with a lower psychoactive potency are cannabidiol (CBD) and delta-8-tetrahydrocannabinol. In particular, CBD is a cannabinoid that is not currently considered to be psychoactive or, at least, not addictive ^[14]^[16]^[18]. In fact, while THC acutely impairs learning and can produce psychosis-like effects and increase anxiety, CBD can enhance learning and seems to have antipsychotic and anti-anxiety properties in humans ^[18]. Thus, these two compounds appear to have a variety of opposing effects on the brain and human behavior ^[19], which is probably as result of their different actions on the endocannabinoid system. While THC acts as an agonist in the cannabinoid receptors, CBD seems to have a more antagonist effect, although its mechanisms of action are still not completely understood ^[18]. Consequently, taken together, CBD can improve the negative effects of THC. However, the market for cannabis has evolved over the past two decades and the THC content in street cannabis has increased dramatically, while its CBD content has remained stable ^[20] or has decreased to negligible levels ^[19].

The chemical structure of THC was discovered in 1964, but it was not until 1988 that the first specific brain receptor where cannabinoids act was identified: the so-called CB1 cannabinoid receptor ^[21]. Similar to what happened with endogenous opiates, while investigating the mechanism of cannabis action, it was discovered that the brain produces chemical substances with a structure similar to that of THC. Therefore, this neurotransmitter system was named endocannabinoid.

The endocannabinoid system is composed of ligands or neurotransmitters, endocannabinoids (anandamide and 2-arachidonoylglycerol), specific receptors (CB1 and CB2) and another biological signal, such as transporters in charge of neurotransmitter receptors and enzymes in charge of neurotransmitter degradation ^[21].

Endogenous cannabinoids are small lipid molecules that are not restricted to the central nervous system, as they have been detected throughout the body. Moreover, endocannabinoid production in the central nervous system does not only happen in neurons, but also in glial cells ^[22]. The best known endocannabinoid or endogenous cannabinoid is anandamide, which was identified in 1992. It acts mainly at the brain level on presynaptic receptors regulating the release of other neurotransmitters, such as GABA, glutamate or acetylcholine, in different brain areas, such as the hippocampus, the cerebellum or the thalamus. Anandamide has many actions, such as stimulating hunger or decreasing motor activity, body temperature and pain sensitivity. It also acts outside the central nervous system in organs such as the spleen, where it regulates the immune system. THC simulates the action of anandamide, but with greater intensity and duration ^[22].

2-Arachidonyl glycerol, or 2-AG, is another endocannabinoid that was identified only three years later, in 1995. It also acts by regulating neurotransmitter release in GABAergic and glutamatergic neurons, being much more abundant than anandamide in the central nervous system, for which it is considered to be the main neurotransmitter of the endocannabinoid system. There are other endocannabinoids, such as virodhamine, arachidonyl-glyceryl-ether, N-arachidonoyl-dopamine and oleamide, among others ^[22].

Two types of cannabinoid receptors have been documented, CB1 and CB2, which are metabotropic G protein-coupled receptors. However, new families of receptors to which endocannabinoids can bind are being described ^[21]^[22]. The CB1 receptor is the most abundant and widely distributed receptor in the central nervous system, both in neurons and glia. However, although the CB2 receptor was initially thought to be found exclusively at the peripheral level, mainly in the immune system, it is now known to be widely expressed in microglia, astrocytes, oligodendrocytes and other brain cells, including neurons. Thus, both cannabinoid receptors of a very complex structure are present in many structures of the nervous system, both central and peripheral, and are linked to many other neurotransmitter systems. In addition, there is evidence of mitochondrial CB1 receptors being involved in the regulation of metabolic processes and memory ^[22]. Currently, the presence of hemoglobin-derived peptide cannabinoids has been identified in the brain and other organs of the body, suggesting that they are the novel ligands of endogenous CB receptors. These peptide endocannabinoids not only coexist with lipid endocannabinoids, but interact with them. Their peptide nature, i.e., as hydrophilic molecules, provides new biological properties to the cannabinoid signal ^[21]^[22].

In summary, as far as is known to date, the main physiological function of endocannabinoids at the brain level consists of the regulation of neurotransmitter release, although they are also primarily involved in synaptic plasticity processes. Both anandamide and 2-AG are produced and released by postsynaptic neurons at the synapse, acting as retrograde messengers on presynaptic receptors. However, anandamide can also be synthesized at the presynaptic level, mediating a postsynaptic form of synaptic plasticity through AMPA receptors in structures such as the nucleus accumbens and hippocampus ^[22].

It is now known that the endocannabinoid system has many actions, modulating many systems in addition to the nervous system, such as the cardiovascular, immune and endocrine systems. Thus, it is involved in important physiological and psychological processes, including learning and memory, motivation, emotional control, decision making, the regulation of voluntary and learned movements, motor control and spatial coordination, reinforcement, anxiety and stress, the control of the sleep/wake cycle, fear, nociception, eating behavior, as well as neural development, energy metabolism and synaptic plasticity processes ^[23]^[21]^[22].

3. The Effects of Cannabis Use

Acute cannabinoid use induces changes in brain neurochemistry, such as an increased dopamine release, reduced glutamatergic transmission, the release of endogenous opioids and the inhibition of acetylcholine secretion ^[16]. These brain biochemical changes are responsible for the acute effects of cannabis, which can be divided into physiological, psychological or behavioral and cognitive effects ^[19]^[24].

Among the many physiological effects it produces, it can be highlighted an increased appetite, anti-emesis, dry mouth, analgesia, drowsiness, sedation, dizziness, decreased intraocular pressure, eye reddening and hypothermia. It also produces neuroendocrine effects, among which the activation of the hypothalamic–pituitary–adrenal axis or a decrease in growth hormones, gonadotropin and prolactin can be highlighted. Moreover, it causes effects at the cardiovascular level, such as increased heart rate, cardiac output and blood pressure. In addition, when smoked, which is the main route of consumption, it causes the inflammation of the respiratory tract similar to the effect of tobacco ^[16]. Thus, despite its many actions, cannabis use has not been associated with a direct risk of death by overdose ^[23]^[14]; however, this fact does not imply that it does not have negative consequences.

Relaxation, well-being or euphoria are the main psychological effects of cannabis sought in its recreational consumption, although it can also cause stress and anxiety reactions, especially at high doses. Regarding behavioral effects, perceptive alterations and the deterioration of psychomotor performance were found, such as ataxia, catalepsy and immobility ^[23]^[16]^[24].

Finally, at the cognitive level, cannabis produces a clear attentional deterioration, difficulties in concentration and inhibitory processes, alterations in judgment and working memory, as well as short-term memory, mainly of the verbal type ^[16]^[19]^[24].

In general, researchers can separate the acute effects of cannabinoids into positive and negative. Within the positive ones, researchers highlight euphoria, relaxation and sensory intensification. Adverse or negative effects include anxiety, paranoia, impaired psychomotor performance and cognitive dysfunction ^[19]^[24]. The increase in THC concentrations in the cannabis consumed is causing an increase in the number of emergencies derived from its acute use, mainly due to panic attacks ^[23].

It is well known that the repeated use of a psychoactive substance causes adaptive changes in the central nervous system, which means that the effects of the drug after chronic use may be different from acute use. Thus, regular cannabis users present brain alterations, mainly in the regions with the greatest presence of CB1 receptors, such as the prefrontal and limbic areas. For this reason, the continuous consumption of cannabinoids sometimes produces effects that are the opposite of those caused by acute consumption ^[16]. These changes can be more or less long-lasting, depending on the moment in the life cycle in which the consumption occurs. Thus, exposure to a drug during a critical period of brain development, such as gestation, childhood or adolescence, will have more serious and lasting consequences on neurochemistry and brain anatomy ^[25]^[26].

The endocannabinoid system appears in the early stages of fetal development and is involved in the processes that develop and establish synapses, as well as neurogenesis and neuronal differentiation. These processes continue during adolescence, facilitating neurodevelopment thanks to its involvement in neuroplasticity and synaptic function ^[12]^[25]^[27]. In addition, it is related to the regulation of other neurotransmitter systems, such as the glutamatergic, dopaminergic or serotonergic systems, which are all also affected by chronic cannabis use ^[14]^[27]. This is why brain differences have been found due to prenatal exposure and chronic cannabis use compared to non-consumers ^[16]^[28]. Of note are the alterations observed in the activity of various brain areas, such as the prefrontal cortex, the mesolimbic system, the amygdala, the striatum and the hypothalamic–pituitary axis ^[14]^[25]^[28]. There is also a reduction in the hippocampus and the density of gray matter in different brain regions related to the limbic system ^[16], and structures involved in executive functions, emotional regulation and reinforcement systems ^[28]^[29]. Recently, a longitudinal study demonstrated that cannabis use during middle to late adolescence was related with cortical thinning in a dose-dependent manner, such that greater use from baseline to 5-year follow-up was associated with increased rates of cortical thinning in predominantly prefrontal regions during that same period ^[25].

Thus, at the cognitive level, high cannabis consumption is related to the impairment of nonverbal learning and episodic memory, not only in the short term but also in the long term ^[17]. Attentional and impulse control has also been impaired by cannabis abuse, although it seems to improve with abstinence ^[24]^[30]. The impairment of executive functions is related to a greater extent with a younger age of onset, a shorter time of abstinence, a higher dosage and a higher THC:CBD ratio ^[31].

Despite the multiple detrimental effects of continued cannabis use, some studies have demonstrated its usefulness in the treatment of palliative patients ^[16]. Some cannabinoids, such as cannabidiol in particular, have also been shown to be effective in the treatment of some childhood epilepsies ^[32], or even in the treatment of some types of schizophrenia ^[33]. However, a common mistake is to confuse the therapeutic use of certain cannabinoids, such as cannabidiol or medical cannabis, with recreational cannabis use. This confusion often occurs in public discourse and leads to a possible trivialization of the harm that cannabis use can produce in adolescent users, as well as to the reinforcement of the idea that recreational use is a harmless activity ^[34].

4. Cannabis Use Disorder

For many years, cannabis was not considered to be addictive. Addiction is defined as a chronic disease, with multiple relapses, characterized by active drug-seeking behavior and a compulsion to use the drug despite harmful consequences. It is considered to be a disease that presents long-lasting alterations of the brain, both in its structure and in its functioning ^[35]. Today, there is no longer any doubt that the continued use of cannabis can lead to the development of an addictive disorder ^[36]^[23]^[19]^[29]^[31]. Despite being a term still used by professionals, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) ^[37] does not consider the word addiction to be a diagnostic term, but encompasses it in the definition of “Substance Use Disorder”, which includes from mild to severe states of consumption. Specifically, cannabis use disorder (CUD) is defined by the DSM-5 as “a problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least two of the following (11 criteria), occurring within a 12-month period” ^[37] (p. 509).

The factor that has been most closely related to the development of a CUD in cannabis users is the person’s age at the onset of use. Late adolescence and early youth, when the brain has not yet reached full maturity, are the periods of brain development that have shown greater vulnerability in manifesting psychiatric pathology ^[14]^[12]. However, other factors, such as the frequency and severity of cannabis use, time of use and periods of abstinence, as well as the presence of comorbid disorders, use of other substances, gender and genetics, influence the severity of CUD.

Neuroimaging studies have shown that subjects with a CUD present a down-regulation of CB1 receptors after a short period of cannabis abuse. These changes are mainly observed in the neocortex and limbic cortex, structures that regulate cognition and emotions, as well as in the ventral striatum, which is involved in motivation and reinforcement ^[14]^[29]. Another neurotransmitter system that is highly involved in motivational processes and that is affected in habitual cannabis users is the dopaminergic system. As with any other drug that produces dependence, THC increases the release of dopamine in the ventral striatum after acute use. However, after continued use, there is a reduction in dopamine availability ^[14]^[29], similar to that observed in other drug use disorders, but not a decrease in dopaminergic D2/D3 receptors ^[14], which is also characteristic of addiction to other drugs ^[35]. Similarly, the glutamatergic system, regulated by CB1 receptors and highly involved in decision making, memory and pathologies such as schizophrenia, is compromised in individuals with a CUD ^[14]^[29]. Magnetic resonance imaging studies have revealed, in turn, structural alterations consistent with THC abuse in important brain areas, such as the prefrontal cortex, hippocampus and amygdala ^[14]^[25]^[29]. All of these brain changes observed in subjects with a CUD could explain the development of psychiatric symptomatology associated with cannabis use. In fact, repeated use has also been linked to the development of long-term psychiatric disorders ^[31].

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