Part 1-Addiction, substance abuse, and substance use disorder (SUD)
i. Terminology:
Substance use disorder is defined as a medical condition that affects the brain, characterized by the continuous consumption despite being aware of its negative impacts to a person, their family, friends and other people around (1). Eventually, a person will develop tolerance if they continue to use the drug for a long period of time. Tolerance describes the process in which the person is used to the effect obtained from the current dose and a higher amount is needed to provide the same effect (1). If the using dose is more than the amount their body can handle, the person is at risk of overdosing. Physical dependence can also occur in which the body gets used to a regular dosage, and if the supply is lowered or stopped, the person will experience withdrawal. Withdrawal are unpleasant reactions that occur when a person no longer uses the drug regularly (1). The severity and length of withdrawal depends on the type of drug, the dosage, and the duration of drug use. As withdrawal symptoms are often uncomfortable, it can be difficult for a person to stop using the drug.
ii. Neurobiology:
Neurobiologically, the brain is involved in the drug addiction process. Particularly, substance use triggers the “reward circuitry” of the basal ganglia, leading to the rewarding effects (2). As a person continues to use drugs for a prolonged period of time, the repeated activation of the “habit circuitry” leading to compulsive substance seeking (2). Moreover, through genome-wide association studies (GWAS), low expression level of gene CHRNA2 in the cerebellum was found to be linked with cannabis use disorder (3).
iii. Factors that influence addiction, abuse and SUD:
The concept of “nature” vs “nurture” thus comes to place. Social environment is also involved in drug abuse behavior. In animal studies, it showed that the presence of cage mates is associated with increased ethanol intake (4). This supported the results of study of peer pressure in human. Peer pressure includes peer involvement, peer conformity, and it was found have a relationship with emerging adult substance use, in both positive and negative ways (5). Furthermore, epigenetic changes in DNA methylation & chromatin remodeling were found to cause for illicit drug use (6). For instance, in rodent experimental study, cocaine activated c-fos and ΔFosB expression. Long-term increased level of ΔFosB leading to gradual accumulative effect, amplifying the reward response (6).
iv. Epidemiology:
According to the report from 2019 Canadian Alcohol and Drugs Survey (CADS), the prevalence of cocaine use in the general population increased from 2013 (0.9%) and 2015 (1.2%) (6). Collecting data showed that the prevalence of cocaine use was increasing three-fold from 2013 to 2019 (3.3% and 9.0% respectively) among people aged 20-24 (7). Unsurprisingly, adults aged 65 and older displayed the lowest rate of cocaine use compared to other groups. Additionally, males were found to have a higher prevalence of cocaine use than females (2.4% and 1.5% respectively).
Part 2: Drug profile
i. Drug description:
Ketamine is a noncompetitive antagonist of NMDA receptor (8). Ketamine is categorized under dissociative drugs which causing distortion of sight and sound perception and inducing the feelings of detachment from oneself and environment (9). This drug is commonly administered through intravenous, intramuscular, snorting, and smoking (10). Ketamine has a historical use as an anesthesia in the operating room for about 50 years. Additionally, ketamine can be used as a pain reliever. It blocks the afferent signals from the spino-reticular pathways and also suppresses the medial reticular formation which is responsible for relaying of emotional aspect of pain perception (11).
ii. Pharmacokinetics
Ketamine is highly lipophilic, so it is rapidly metabolized and distributed to peripheral tissues. The drug undergoes hepatic metabolism, namely N-demethylation and ring hydroxylation (12). Norketamine is known as the main metabolite, and its potency is one-third to one-fifth compared to ketamine. Norketamine and hydroxylated derivatives are excreted through urine and feces. In consideration of interacting with another drug, rifampicin enhances enzyme metabolism which increases clearance of both ketamine and norketamine (13). On the other hand, clarithromycin, an enzyme inhibitor, causing an opposite effect which decreasing metabolism and clearance of ketamine and its main metabolite. Furthermore, ketamine N-demethylation is inhibited by benzodiazepines (14) . Pharmacokinetic studies have showed that children have faster intramuscular absorption, slightly lower distribution volume, and shorter elimination half-life (14).
iii. Pharmacodynamics
Ketamine stimulates sympathetic responses such as increased heart rate, blood pressure and cardiac output. However, the drug acts on receptors and inflammatory cascades, ultimately resulting in airway relaxation (15). Particularly, ketamine prevents calcium from flowing into smooth muscles by inhibiting L-type calcium channels (16). The drug is associated with loss of orthostatic reflexes, but consciousness remains intact. However, with high dose, consciousness can also be impaired (17). Uniquely, when the patient appears awake, the dissociative state created by the drug causes the patient to feel detached from the surroundings with their eyes remaining open (18). It was found that the drug causes the dissociation between thalamo-neocortical and limbic systems, so sensory inputs can reach cortical receiving regions but unable to do so in some association areas (19).
iv. Pathophysiology and outcomes of long-term use:
Consequences of long-term use of ketamine had been demonstrated using rodent model. Adults rats showed working memory deficits (20). Decreased object exploration was observed in adults rats that are administered with moderate dose twice daily for seven days (21). Memory disruption caused by prolonged use of ketamine was determined to be dependent on the length of treatment and the length of time since treatment ended (22). In another study, prolonged inhibition of NMDAR function causes decreased brain-derived neurotrophic factor (BDNF) levels, increased cell death, diminished synaptogenesis and formation of neuronal network (23). As a result, chronic exposure to ketamine leads to long-lasting impairments in synaptic plasticity and cognition. Additionally, repeated usage stimulates upregulation of NMDAR, leading to accumulation of calcium into neuronal cells after ketamine is removed. Subsequently, this increases ROS (reactive oxygen species) generation, causing neuronal apoptosis (24). Moreover, ketamine abuse was associated with epigastric pain, recurrent vomiting, anemia, gastrointestinal bleeding (25). Abdominal pain and urinary tract symptoms were also reported among heavy ketamine users (26). The positive reinforcing effect of this drug (including euphoria) leads to continuous drug taking behavior, while the negative reinforcing effect prevents unpleasant drug withdrawal symptoms (27). Together with its anesthetic effect, ketamine has been taken advantages by many people which makes it become one of the most abusive and misused drugs in many countries.
v. Epidemiology:
The lifetime prevalence of ketamine misuse ranged from 0.1% to 4% in Australia, Canada, the United Kingdom, and the United States (28). The data provided by the Drug Abuse Warning Network reported that people aged 12- 25 contributed to 74% of ketamine emergency in the United States in 2000 (29). The recreational use of ketamine was found to be most common in East and South-East Asia (30). A study was conducted among festival goers in New York City, and its results showed the prevalence of ketamine use was increased from 5.9% to 15.3% from 2016-2019 (31). Ketamine is commonly used among teenagers in nightclub setting, therefore, this drug is also known as “club drug”. It was misused by perpetrators to facilitate sexual assault (32). When slipped in the drink, the drug becomes odorless, colorless, and tasteless. Beside from its dissociative feeling effects, ketamine can also cause amnesia, making the victim unable to recall the events (32).
vi. Novel findings:
Interestingly, ketamine was found to be a promising therapeutic treatment for PTSD (33). A preclinical study conducted in “fear-generalized mice” and its result showed that a single sub-anesthetic IP dose of ketamine, administered 22h after fear conditioning, caused a reduction in fear generalization (34). In another study, a fear conditioning (foot shocks paired with a tone) was applied to rats, and ketamine was administered to them IP 24h after going through the fear event. Enhanced fear extinction training was observed among the ketamine-treated rats (35). Furthermore, result from the following week showed that the return of fear when exposed to the original fear conditioning was less likely to occur in these rats. Followed by the promising results of preclinical studies, clinical trials of treatment of chronic PTSD by single IV ketamine infusion is currently being carried out.
References:
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