There are two basic substances in the cannabis plant called THC (Tetrahydrocannabinol) and CBD (Cannabidiol). THC is a psychoactive substance and is used as a drug. On the other hand, CBD is a non-psychoactive substance with medicinal properties. CBD is one of the most critical cannabinoids found in cannabis plants. Cannabinoids have an important role in the regulation of various physiological processes such as the immune system, appetite, pain, sensation of pleasure, mood, and memory. These are natural cannabinoids. There are also synthetic cannabinoids, which are cannabis-like chemicals produced in labs.
Synthetic cannabinoids, which are increasingly popular among drug users and also known as new generation psychoactive substances (designer drugs), are cannabis-like chemicals. They are available in pure form, solid, or oil form. Synthetic cannabinoids, which can also be called “synthetic marijuana” or “fake weed” among users, are known by names such as Spice, K2, Genie in Europe and the USA. Most of these compounds are extremely lipophilic and show good solubility in low polarity solvents such as methanol, ethanol, acetonitrile, ethyl acetate, acetone.
Synthetic cannabinoids are sprayed into the herbal mixture after dissolving in a solvent, after the solvent evaporates and the herbal mixture is dried again, they are packaged and marketed. These dried leaves, which are usually placed in small silver plastic bags and marketed as incense, are used by their users in cigarettes, pipes, or tea. Synthetic cannabinoids are offered for sale in packages containing “Bath salt”, “Plant fertilizer”, “Deodorizer”, “For research only”, “Not for human consumption”, “Incense”, “Pool cleaner” and similar phrases. It is mostly made in China, India, and Asia and spread to the world through Europe.
Synthetic Cannabinoids and Cannabinoid Receptors
As it is known, the cannabinoid system plays an important role in the regulation of some physiological processes in our body, such as the immune system, appetite, pain, sense of pleasure, mood, and memory. Cannabinoid receptors (CB) are an important part of the cannabinoid system. There are 2 subtypes of cannabinoid receptors, type 1 (CB1) and type 2 (CB2). CB1 is mostly blamed for its euphoric and anticonvulsant activity, while CB2 is responsible for the occurrence of anti-inflammatory effects.
CB1 and CB2 are G protein-coupled receptors that suppress adenyl cyclase activity. CB1 suppresses intracellular adenyl cyclase and cAMP levels through the G protein. Activation of G protein-coupled receptors suppresses voltage-dependent Ca + 2 channels and activates K + channels. As a result of these changes, intracellular presynaptic hyperpolarization, decrease in cellular excitability, and release of neurotransmitters occurs.
CB1 is densely found in the cortex, hypo-campus, cerebellum, substantia nigra region of the basal ganglia and pars reticulate regions, ventromedial striatum, nucleus accumbens (Nac), and CB2 is found in cells that are mediated by the immune system. In some studies, it is suggested that CB1 activation is the basis of the behavioral and neuronal effects of cannabinoids.
CB1, located in the cortex and hippocampus, is associated with learning and memory functions, while CB1 in the basal ganglia and cerebellum is associated with impairment of motor functions. Studies show that activation of CB1 causes pain, anxiety, depression, post-traumatic stress disorder, postmenopausal osteoporosis, cancer and neurodegenerative diseases, and obesity, diabetes, liver diseases, cardiometabolic complications, alcohol-drug addiction, and postmenopausal osteoporosis. It has been shown that the treatment of such diseases can be provided.
Toxicity of Synthetic Cannabinoids
In acute poisoning due to synthetic cannabinoids, unlike cannabis, more stimulating and similar side effects to those seen in symptomatic substance use can be seen. These side effects frequently consist of symptoms such as sweating, tremor, mydriasis, nausea, vomiting, appetite changes, hypertension/hypotension, chest pain, tachycardia, bradycardia, respiratory depression, confusion, psychomotor agitation, and sedation.
Synthetic cannabinoids have been shown to bind to CB1 with an affinity 100 times higher than cannabis. It is suggested that these different findings are probably due to stronger stimulation of CB1 receptors. In addition, the clinical features emerging after the use of synthetic cannabinoids may differ depending on the content of the substance (such as active substance, amount) used by the patients, and serious intoxication symptoms may occur depending on the amount and purity of the substance used.
It is difficult to precisely predict the clinical effects that may be seen, as they generally do not contain the plant materials specified in the package. In the literature, there are publications about the consequences of long-term use of synthetic cannabinoids. Although there is not much data, they are known to have cannabis-like psychoactive effects, and they may cause problems including cardiovascular symptoms such as red conjunctiva, pupillary dilatation, impaired motor, and cognitive activity, mild tachycardia, and increased blood pressure.
According to some studies, 68% of people using synthetic cannabinoids have been shown to experience at least one side effect, and in another study evaluating 316 synthetic cannabinoid users, the most common side effects were indicated as decreasing motor coordination (38%), tachycardia and arrhythmia (33%), dissociation (22%), dizziness (20%), paranoia (18%), confusion (18%), headache (18%), panic (14%), speech disorder (14%), sweating (%) 14), nausea or vomiting (9%), depression (4%) and psychosis (4%).
In a study they conducted, researchers reported that 23 (2.4%) of 950 cases using synthetic cannabinoids experienced immediate medical assistance immediately after substance use. In another study, it was found that users who received emergency medical help were younger than those who did not, and the reasons for applying to health institutions were mostly caused by symptoms such as panic, anxiety, paranoia, and breathing difficulties.
- Metabolic Side Effects
Synthetic cannabinoids can also cause serious metabolic complications such as increased glucose (25%), leukocytosis (9%), hypokalemia (2.3–3.4 mmol / L) (27%), respiratory / metabolic acidosis (n = 4).
- Withdrawal Symptoms
Although there is not much research about the problems that may arise due to the long-term use of synthetic cannabinoids, it has been determined that they have a higher addiction potential than cannabis and cause withdrawal symptoms due to their rapid development of tolerance. In some studies, it has been reported that psychiatric and physical symptoms similar to those seen in cannabis users are observed in those who use synthetic cannabinoids for a long time.
In the literature, there is a case with withdrawal symptoms consisting of tremors, headache, nightmares, nasal discharge, desire to use substances, hypertension, and tachycardia on the fourth day of hospitalization after discontinuation of synthetic cannabinoids. Dependence and physical withdrawal symptoms have also been reported in some cases with repeated use of synthetic cannabinoids at relatively high doses (3 mg/day).
People using synthetic cannabinoids experience various withdrawal symptoms such as paranoia, anxiety, panic attacks, fear of death, extreme irritability, difficulty concentrating, disorientation, tachycardia, insomnia, difficulty breathing, headache, constipation, nausea, decreased appetite, and weight loss. In the treatment of symptoms related to the use of synthetic cannabinoids; intravenous fluid administration, benzodiazepines for the control of irritability, agitation, and anxiety, and oxygen delivery are used.
- Mortality Rates
As a result of the toxicological analysis of forensic death cases between 2008-2012, 4.37% of synthetic cannabinoids were detected and it was reported that the cause of death of 0.6% of these cases was due to synthetic cannabinoids. 95.2% of death cases directly related to any drugs are men and 4.8% are women. This distribution shows that drug use is more common among men.
In cases of death associated with synthetic cannabinoids, the main findings as a result of postmortem examinations; It has been reported as obstruction (congestion) in the lung, liver, spleen, and kidney associated with extensive pulmonary edema, intense granulomatous inflammation. Since death cases are in their 20s, it is claimed that synthetic cannabinoids used for a long time cause hypertension and excessive cardiac functions.
Effects of Synthetic Cannabinoids on Health
- Effects on Mental Health
Some of the pharmacological effects of synthetic cannabinoids that occur through cannabinoid receptors are cognitive impairment, learning, memory disorders, euphoria, hallucinations, sleep disorders, and appetite increase. Synthetic cannabinoids and cannabis can trigger the onset of a psychotic disorder, causing individuals with previous psychotic disorders to experience new symptoms or worsen symptoms. It is reported that synthetic cannabinoids are frequently used together with substances such as alcohol, cigarettes, and marijuana. Psychoactive findings related to synthetic cannabinoids are often euphoria, anxiety, agitation, irritability, psychosis, and impairment in cognitive skills.
In the long-term use of synthetic cannabinoids, psychotic symptoms such as auditory, visual hallucinations, paranoid delusions, thought block, disorganized speech, anxiety, insomnia, stupor, and suicidal ideation can be seen. It is stated that some synthetic cannabinoids contain oleamide, a fatty acid, which is known to increase the risk of psychosis by activating CB1. Again, it has been emphasized that the use of synthetic cannabinoids worsens the underlying psychosis or accelerates its development in individuals with a predisposition.
New-onset psychosis has been reported in 10 previously healthy men who have used synthetic cannabinoids more than once. In the light of the present findings, if a new and sudden onset psychosis has developed in a person under urine toxicology follow-up, or if the person shows signs of cannabis intoxication but the urine screening is negative, the abuse of synthetic cannabinoids should definitely be suspected.
There are publications in the literature claiming that there is a significant increase in the rates of suicidal ideation and suicide attempt due to the use of synthetic cannabinoids. In 2 male cases who did not have a history of previous psychiatric disorders, a suicide attempt was reported shortly after the use of synthetic cannabinoids, and as a result of the analysis of the cases, it was stated that no drug or substance other than synthetic cannabinoids (JWH derivatives and AM-2201) was found.
Synthetic cannabinoids are considered a risk for serotonin syndrome. JWH-018 and similar Synthetic cannabinoids are theoretically able to “Serotonin receptor activation” since they contain an indole moiety that is structurally similar to serotonin. In addition, it is emphasized that by taking high doses of synthetic cannabinoids, weak monoamine oxidase inhibition may occur, thus increasing the risk of serotonin syndrome.
- Effects on the Respiratory System
It is reported that when synthetic cannabinoids are taken by inhalation, they are instantly absorbed from the lungs, spread to other organs such as the brain within a few minutes, and their effects begin within minutes. However, it is stated that synthetic cannabinoids cause an increase in resistance in the bronchi and a decrease in the respiratory rate. In addition, dry cough, burning and stinging in the mouth and throat, laryngitis, pharyngitis, sputum discharge, chest pain, frequent lower respiratory tract infections are common findings.
Another possible harm associated with the long-term use of synthetic cannabinoids is the carcinogenic potential, especially of naphthyl group metabolites, so chronic obstructive lung disease and lung cancer are reported to occur 5 times more than smoking in chronic users. Especially in young adults, its relationship with head and neck cancers has been proven, and an increase in blood cancer, brain and muscle tumors has been observed.
- Effects on the Endocrine System
In the long-term use of synthetic cannabinoids, it has been observed that there is a significant decrease in prolactin and luteinizing hormone (LH) levels, but no change in dopamine levels, by binding to the CB of the endogenous ligand and causing the activation of CB1. In experimental animals treated with cannabis acutely and chronically, it was observed that LH and testosterone levels decreased, and a significant increase in stress hormones was observed 60 minutes after acute cannabis administration, but a decrease in corticosterone release was observed as a result of stimulation with cannabis for 7 days. In another study, it was shown that active CB1 regulates the release of T3 and T4 thyroid hormones in rats, thus it was found that cannabinoid receptors have a regulatory effect on thyroid hormones.
- Effects on the Urinary System
A nephrotoxic effect occurs in the kidneys due to exposure to synthetic cannabinoids, as a result of this, cases with acute renal failure have been detected in addition to an increase in blood creatinine levels.
- Neurological Effects
It is known that cannabis prevents epileptic seizures and synthetic cannabinoids cause epileptic seizures. Some studies have reported epileptic seizures within 3-6 hours after substance ingestion. These are usually generalized tonic-clonic (JTK) seizures, usually multiple, and do not cause sequelae. In toxic patients, clinically severe headache, epileptic seizures, ischemic or hemorrhagic stroke, with or without neurological sequela, can return to normal within a few months, and progress with narrowing of cerebral arteries and vasospasm, which is called “reversible cerebral vasoconstriction syndrome” can be seen.
The resulting vasospasm picture may result in vasogenic edema in the brain by causing damage to the endothelial layer of the cerebral vessels associated with increased vascular resistance and decreased cerebral blood flow. In addition, it has been reported that 20% of the cases with intoxication developed mydriasis. In light of this information, physicians should consider the abuse of synthetic cannabinoids in the differential diagnosis in young male patients with JTK seizures for the first time.
- Effects on the Cardiovascular System
The main effects of synthetic cannabinoids on the cardiovascular system are tachycardia, bradycardia, hypertension, hypotension, syncope, chest pain, electrocardiographic changes, and cardiac ischemia. Recently, it has been emphasized that cannabis and similar substances can increase the oxygen consumption of the myocardium through the sympathetic stimulation system and cause coronary spasm. Since increased heart rate and blood pressure changes can be seen intensely, especially in the first hours after using psychoactive substances, the risk of a heart attack in substance users was found to be four times higher than normal.
In another study, it is stated that synthetic cannabinoids cause early atheroma plaques and these plaques may cause “acute coronary syndrome” by triggering early rupture. As a result, the use of synthetic cannabinoids may cause the sympathetic nervous system to be stimulated, causing hypertension and tachycardia, but it should not be ignored that these symptoms may be masked as a result of the sedative effects of these substances.
- Effects on the Gastrointestinal System
It has been reported that recurrent nausea, vomiting, excessive thirst, dry mouth, and colic-like abdominal pain are common in chronic cannabinoid users, and these complaints are typically relieved after hot baths or resolved with cessation of substance use. In a large-scale study involving 464 patients using synthetic cannabinoids, it was stated that the GIS side effects were 21.1%, and the most common symptoms were abdominal pain, flank pain, nausea-vomiting, anorexia/weight loss, diarrhea, dehydration, and bloody vomiting.
Effective Factors in the Frequent Use of Synthetic Cannabinoids
The existence of medical uses of cannabis has led researchers to research synthetic cannabinoids in the field of treatment. Abuse rates have increased rapidly with the discovery that the psychoactive properties of synthetic cannabinoids, which were previously determined to have pain-relieving effects, are much more intense and powerful than cannabis.
The fact that synthetic cannabinoids cannot be detected in standard substance screening tests due to their different chemical structures caused them to become attractive among users in a short time in cases where regular urine monitoring is required (driving license, forensic medicine, probation). In addition, the fact that they are easily accessible and economical is among the factors that increase the popularity of these substances.
In a large-scale study conducted in 2011, the rate of trying any illegal addictive substance at least once in the 15-64 age group population was 2.7% (3.1% in men, 2.2% in women), 1.5% in the 15-16 age group (2.3% in men, 0.7% in women). When the lifetime use of any substance in young adults was examined, it was seen that the prevalence was 2.9% between the ages of 15-24 and 3.1% in the 25-34 age group. In these cases, the mean age of first-time substance use was “13.88 ± 2.39” years.
Considering the results of this study, it is noteworthy that the prevalence of substance use is much higher in young adults (15-34 age group) compared to the general population (15-64 age group). In a study conducted in Australia, it was reported that 70% of the users are male and the average age is 27, 78% work in a job that generates regular income, and 7% use these substances every day. In 2009, in a different study conducted with 1463 students between the ages of 15 and 18 studying at schools providing general and vocational education, the rate of those who reported using synthetic cannabinoids at least once was 6%, and in a similar different study, it was 11.4%.
In another study examining 1898 cases using synthetic cannabinoids, the mean age of the users was determined as 23.32, and some life-threatening side effects were reported in 7.3% of these cases after substance use. In another study, the average age of those using synthetic cannabinoids was 26 years, and the rate of serious side effects after using synthetic cannabinoids was found to be 40%.
Analysis of Synthetic Cannabinoids
In general, urine, serum, blood, oral fluid, and hair samples of individuals are used to detect drug use. While the main substance is analyzed in the hair and oral fluid, its metabolites are detected in the urine. Some metabolites of synthetic cannabinoids have been determined as a result of chromatographic analysis with blood and saliva. The liquid chromatography-tandem mass spectrometry (LC-MS / MS) method is used for the detection of metabolites of synthetic cannabinoids in urine today. However, not all types of synthetic cannabinoids have yet been detected.
Synthetic cannabinoids are metabolized in the liver by conjugation and oxidation. They are mainly oxidized via the cytochrome P450 system. After hepatic cytochrome P450 oxidation, UGT (e.g. UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B4), which is a microsomal enzyme found in the smooth endoplasmic reticulum microsomes of hepatocytes, is excreted via glucuronic acid conjugation. When used orally, the onset of their effects may be delayed due to the first-pass metabolism.
The main psychoactive component affecting the central nervous system in natural cannabis is Δ9-THC. Although both cannabis (9-THC) and Synthetic cannabinoids show their effects mainly on CB1 and CB2, they are chemically and pharmacologically different. Since cannabis has a partial agonist and plateau effect, even if the amount of substance that is used increases, there is no difference in the intensity of the effect. However, since the increase in the doses of synthetic cannabinoids, which are full agonists, does not show a plateau effect, an increase in the intensity of the effect is observed.
Some varieties of synthetic cannabinoids that show high potency and affinity for cannabinoid receptors may produce longer half-life or more active metabolites. It has been reported that some metabolites of JWH-018 have an affinity at least as high as JWH-018 for CB-1. As a result, the duration of action of synthetic cannabinoids may be longer or shorter, but the onset of action is both faster and more intense than 9-THC.
According to the European Monitoring Center for Drugs and Drug Addiction, the number of Synthetic cannabinoids detected is increasing from year to year. It has been reported that by the end of March 2014, a total of 107 types of Synthetic cannabinoids have been detected. In a study examining the rates of synthetic cannabinoids retrospectively in 1200 herbal ingredients sent by judicial authorities in Istanbul and its surrounding, 98.3% of these components contain synthetic cannabinoids, where 99.4% of them JWH-018, and 65.9% is reported to be JWH-081. Although different classifications are made, Synthetic cannabinoids are divided into eight chemical groups:
- Naphthoylindoles (eg JWH-018, JWH-073, and JWH-398).
- Naphthylmethylindoles (eg JWH-185)
- Naphthoylpyrroles (e.g. JWH-369)
- Naphthylmethylindenes (eg JWH-176).
- Phenylacetylindoles (i.e. benzoylindoles, e.g. JWH-250).
- Benzoylindoles (eg AM-694)
- Cyclohexylphenols or non-classical cannabinoids
- Classic Cannabinoids (THC, other components of cannabis and their structurally related synthetic analogues).
Usage Ways of Synthetic Cannabinoids and Clinical Findings
Synthetic cannabinoids are smoked by using pipe, hookah, or wrapping on cigarette paper. It has been reported that it is also consumed by brewing. The mode of administration can also be oral. Its use by parenteral route has not been reported yet. There is not much research on absorption, distribution, metabolism, and excretion. After synthetic cannabinoids are inhaled, they are absorbed instantly from the lungs and spread to other organs such as the brain within a few minutes, and their effect usually begins within minutes.
After oral use, the effects may be delayed depending on food intake, digestive activity, and first-pass metabolism. These lipophilic molecules have high distribution capacity and are stored in fat-containing tissues in the body after chronic use. Although the duration of action may vary, it usually takes hours. It has been reported that the effectiveness of JWH-018 lasts 1-2 hours and the activity of CP-47,497-C8 lasts 5-6 hours. It is emphasized that some metabolites of JWH-018 have an affinity for CB-1 receptors as much as JWH-018. In general, they have a longer half-life compared to Δ9-THC, and their toxic effects last longer.
Liver enzymes are responsible for the transformation of synthetic cannabinoids. Some synthetic cannabinoids have a long half-life. For example; JWH-018 can be detected in blood for up to 24 hours and in saliva for up to 12 hours after use. The dose used is reported to be low, ranging from 0.5 to 5 mg. Synthetic cannabinoids are mixed with other substances and are present in very small amounts compared to these substances. Therefore, measurements that will detect synthetic cannabinoids should have sufficient sensitivity.
Since synthetic cannabinoids are rapidly converted into unknown metabolites by the body, urine analysis is also not sufficient for detection. In addition, since many different synthetic cannabinoids are converted into similar metabolites, the results of urine analysis cannot show which synthetic cannabinoids are used. The fact that most metabolites of synthetic cannabinoids maintain their CB1 receptor affinity and show various levels of intrinsic activity cause serious side effects and safety problems.
Clinical Findings Related to Synthetic Cannabinoids
Long-term use of synthetic cannabinoids has been reported to cause addiction syndrome, withdrawal symptoms, and psychiatric symptoms similar to cannabis use. In acute poisoning, it is more similar to those seen in the use of stimulant and sympathomimetic substances, unlike cannabis. Due to the presence of synthetic cannabinoids in different combinations and ratios in the mixtures sold in the market, the estimation of the clinical effects is also difficult.
The psychoactive effects of synthetic cannabinoids have been reported as pleasant, euphoria and anxiety, agitation, irritability, psychosis, and changes in cognitive skills, while acute physical effects are sweating, nausea, vomiting, appetite changes, hypertension/hypotension, chest pain, tachycardia, and bradycardia. It is described as respiratory depression, confusion, psychomotor agitation, somnolence, and sedation. While some people experience sedation after the use of synthetic cannabinoids, agitation, nausea, hot flushes, burning in the eyes, dry mouth, mydriasis, tremor, and tachycardia are observed in others.
Although most people using synthetic cannabinoids have mild symptoms, there are sometimes convulsions and myocardial infarction. Numerous cases of convulsions due to synthetic cannabinoids have been reported. These are generalized tonic-clonic (JTK) seizures and do not leave any sequelae. It was stated that the abuse of synthetic cannabinoids should be considered in the differential diagnosis in young male patients who had JTK seizures for the first time in the emergency service. It was also emphasized that people with negative urine screening should be suspected of synthetic cannabinoids abuse, even though they show symptoms of cannabis intoxication.
It has been reported that synthetic cannabinoids can cause serious medical problems such as acute renal failure, acute vision loss, and Wernicke Syndrome. Synthetic cannabinoids can also put the user in dangerous positions due to hallucinations and dreams. Recently, an increase in the number of suicides related to them has been reported. It has been reported that most people have increased activity in intoxications, and patients are at risk of rhabdomyolysis, increased creatine kinase levels, and subsequent renal failure.
In the long-term use of synthetic cannabinoids, psychotic symptoms such as auditory, visual hallucinations, paranoid delusions, thought block, disorganized speech, anxiety, insomnia, stupor, suicidal ideation are observed. New-onset psychosis has been reported in 10 previously healthy men with more than one use of synthetic cannabinoids. It has also been emphasized that the use of synthetic cannabinoids worsens the underlying psychosis or accelerates its development in individuals with a predisposition.
Tolerance and withdrawal findings have been reported after the long-term use of synthetic cannabinoids. It has been reported that tolerance develops rapidly and withdrawal symptoms include inner restlessness, intense sweating, substance craving, tremor, headache, nightmares, insomnia, irritability, difficulty concentrating, and nausea.
In animal experiments, it has been reported that synthetic cannabinoids show their effects on the CB1 receptor and cause changes in mood (causing anxiety and panic), memory, visual and auditory perception. In addition, it has been reported to cause hypothermia, hypoalgesia, and hypomotility.
Studies in mice have found that JWH-018 shows the quadruple effect of THC (analgesia, catalepsy, hypomotility, hypothermia), and depending on the dose, it causes analgesia at a dose of 0.009 mg/kg and hypothermia at a dose of 1.47 mg/kg. It has been reported that after repeated doses of JWH-018 given to mice (0.1-10 mg/kg), it caused severe lethargy and unresponsive catatonic period in mice, and one mouse died of respiratory depression.
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