Medical Analysis

Comprehensive Medical Analysis of Marijuana and Cannabinoids: Pharmacology, Testing Methodologies, and Clinical Implications

Introduction- marijuana

Marijuana is recognized under a vast array of street names and colloquial terms, including Canabins, Hashish, Bhang, Hemp, Kef, Kif, Charas, Ganja, Sensemilla, Dope, Hash, Grass, Pot, Blow, Draw, Stuff, May Jane, Tea, Weed, The weed, Gold, Skunkweed, Skunk, Reefer, Rope, Smoke, Gage, Boo, Charge, Jeev, Mootha, Pod, Wacky backy, Locoweed, Dagga, Zol, Green, and Mezz [1, 2]. The consumption ways and routes of administration for these substances vary widely among users, encompassing smoking through hand-rolled cigarettes known as joints, pipes, and water pipes or bongs; brewing the plant material into tea; baking it directly into foods such as brownies or cookies; inhaling via modern vaporizers, commonly referred to as vapes, vape pens, or weed pens; and utilizing it combined with molten substances [1, 2].

Botanically and pharmacologically, marijuana is derived directly from the dried flowers of the Cannabis sativa plant [1, 2]. It functions fundamentally as a cannabinoid, where cannabinoids represent several distinct structural classes of compounds found predominantly within the cannabis plant, as well as in most animal organisms—although insects notably lack such receptors—or produced as synthetic compounds [1, 3]. The two primary and most thoroughly researched cannabinoids are delta-9-tetrahydrocannabinol, commonly abbreviated as THC, and cannabidiol, known as CBD [3, 8]. These specific compounds are primarily responsible for mediating the psychoactive effects of cannabis [3, 4]. Following the consumption or use of marijuana, individuals typically experience initial sensations of euphoria and profound relaxation; however, the substance may simultaneously induce other dramatic psychological and physiological effects, including intense fear, acute panic, and overwhelming anxiety [4, 5].

Mode of Action of Marijuana

The pharmacodynamics and physiological pathways of marijuana dictate that its primary sites of action are localized within the central nervous system, specifically the brain and the spinal cord [3, 4]. Upon ingestion or inhalation, active cannabinoids bind to two major types of G-protein-coupled receptors, designated as CB1 and CB2 [6]. CB1 receptors are predominantly expressed within the brain and are densely located across the basal ganglia, cerebellum, hippocampus, association cortices, spinal cord, and peripheral nerves, which accounts for the profound alterations in motor control, memory, emotion, and sensory perception experienced by users [4, 6].

Compounds of cannabis

The chemical composition of cannabis encompasses a diverse spectrum of organic compounds categorized structurally [9]. Marijuana consists of dried leaves and flowering heads, whereas Hashish represents the concentrated resin harvested from upper leaves and flower buds [2, 9]. At the molecular level, cannabis constituents are divided into non-cannabinoids, isolated pure compounds, and true cannabinoids [9]. Within the cannabinoid category, compounds are further subdivided into psychoactive agents such as delta-9-THC and delta-8-THC, active but non-psychoactive compounds like cannabidiol, and over 60 additional compounds that remain largely inactive or are continually being studied for minor pharmacological properties [6, 9].

Metabolites of Marijuana

The metabolic pathway of cannabinoids in the human body involves a series of enzymatic biotransformations primarily occurring in the liver [3, 5]. The primary psychoactive constituent, delta-9-THC, is initially hydroxylated into its active intermediate metabolite, 11-OH-THC [3, 15]. This active metabolite is subsequently oxidized into 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, widely referred to as THC-COOH [14]. To facilitate renal excretion, THC-COOH undergoes further phase II metabolism, conjugating with glucuronic acid to form THC-COOH glucuronide [15, 16].

Indications – Marijuana

The clinical, forensic, and administrative indications for marijuana testing are extensive and multifaceted [12, 20]. They include forensic or legal purposes, such as investigating accidents or workplace incidents where there is a strong suspicion of illegal drug use [12]. Testing is heavily mandated in safety-sensitive jobs, including transportation, construction, and healthcare sectors, where personnel need to be entirely free from the abuse of these substances to ensure the safety of all workers and the public [12, 20]. Random workplace testing and pre-employment testing serve as standard pillars of employment screening [12, 20]. Clinical assessments may also require toxicology screens when drug involvement is suspected [20]. Furthermore, testing is strictly enforced for sports and athletes, where cannabis use is classified as illegal, as well as for post-accident investigations, monitoring abstinence and adherence to therapeutic treatment programs, and fulfilling court-ordered mandates for probation, parole, and social services [12, 20].

Signs of overdose (Marijuana Intoxication)

Acute marijuana intoxication or overdose presents with a wide-ranging spectrum of physical, psychological, and behavioral manifestations [4, 5]. The clinical presentation is captured comprehensively in the symptom matrix below:

Methods Of Estimation

The laboratory detection and quantification of cannabis and its metabolites rely on an array of advanced analytical techniques [10, 12]. These methods include Liquid Chromatography-Tandem Mass Spectrometry, Gas Chromatography-Mass Spectrometry [12], HPLC-MS (High-Performance Liquid Chromatography coupled with Mass Spectrophotometry) [10, 12], CE-MS (Capillary Electrophoresis coupled with Mass Spectrophotometry), ultra-violet spectrophotometry, infrared spectrophotometry, paper chromatography, thin-layer chromatography, spectrophotofluorometric methods, standard immunoassays, lateral flow chromatographic immunoassays, and Enzyme-Linked Immunosorbent Assay methods [10, 12]. It is worth noting clinically that no special preparation is required for standard testing procedures.

Methods of collection

Marijuana – Cut Off Value in Various Samples

Organ/System Effects

The systematic physiological and pathological impacts of cannabis consumption affect multiple organ systems across the human body [4]. In the central nervous system (Brain), effects include euphoria, relaxation, altered perception, impaired memory, anxiety, and high-dose-induced psychosis [4]. Cardiovascular manifestations encompass tachycardia, short-term blood pressure elevations, orthostatic hypotension, and cardiac arrhythmias [4]. Respiratory impacts feature acute bronchodilation alongside chronic bronchitis, persistent cough, and localized airway inflammation [4]. Gastrointestinal effects involve increased appetite commonly referred to as the munchies, nausea relief, and cannabinoid hyperemesis syndrome associated with chronic heavy usage [4].

Effects of Cannabis – Slide No. 2

Limitations

When interpreting drug screen results, several analytical and clinical limitations must be taken into account [12, 20]. Gas chromatography/mass spectrometry stands as the preferred confirmatory method due to its high specificity [12]. However, technical or procedural errors, as well as the presence of other interfering substances in urine specimens, may cause erroneous results [12, 20]. Furthermore, chemical adulterants such as bleach or alum introduced into urine specimens can produce false results regardless of the analytical method employed [12, 20]. Dilution or substitution practices also pose a significant risk of producing false negative outcomes [12, 20]. Clinicians must recognize that a positive test result merely indicates the presence of the parent drug or its metabolites, but it does not measure the exact level of intoxication, the route of administration, or the precise concentration profile in urine [12, 20]. The testing approach is also constrained by high costs and the reality that advanced resources cannot be available everywhere [12, 20].

Additional challenges include a lack of specialized expertise, which can limit diagnostic utilization [12, 20]. The natural variability in the metabolism and excretion of the drug from person to person heavily influences its detection window, complicating interpretation [3, 14]. A negative result does not necessarily certify a drug-free biological sample, as negative findings occur when drug components remain present below the established cut-off threshold of the assay [12, 20]. Interpretation protocols must account for the fact that urine concentrations vary extensively based on fluid intake and other biological variables [12, 14, 20]. Finally, standard immunoassays that yield a single unified result in the presence of a drug and its metabolites cannot fully quantify the individual concentrations of separate chemical components [12, 20].

Refer Legal & Police Prospective Aspects

For further operational guidance, medical and legal professionals are directed to review the specific presentation titled: Drugs – Sample Submission for Legal Side & Police Department.

For Non-Medicos

Understanding Marijuana and Cannabinoids

Marijuana, commonly known by street names like weed, pot, or hash, comes from the Cannabis sativa plant [1, 2]. It contains active compounds called cannabinoids—most notably THC, which makes users feel high, and CBD [3, 8]. When consumed through smoking, vaping, or eating infused foods, these chemicals bind to specific receptors in the brain and spinal cord, triggering feelings of euphoria, relaxation, or sometimes anxiety and panic [1, 4, 6].

Testing Methods, Sample Collection, and Cut-Off Values

Drug testing utilizes various biological samples depending on the investigative window needed [12, 17]. Urine tests can spot metabolites days to weeks after use, blood tests measure active intoxication, hair tests show long-term history up to three months, and saliva tests check for immediate roadside use [11, 13, 14, 17]. Laboratories apply strict cut-off limits—such as above 15 ng/ml for urine and 1 to 5 ng/ml for blood—to confirm positive results using advanced equipment like mass spectrometry [11, 12, 14].

Health Impacts and Limitations of Drug Screening

Heavy or chronic cannabis use impacts multiple body systems, leading to rapid heart rates, breathing issues, memory problems, and impaired motor coordination [4]. While drug screens are vital for workplace safety, legal proceedings, and clinical assessments, they come with limitations [12, 20]. Factors like sample dilution, chemical adulterants, individual metabolic differences, and hydration levels can occasionally alter test accuracy or fail to reflect the true level of ongoing intoxication [12, 14, 20].

References:

1. World Health Organization (WHO). Cannabis: a health perspective and research agenda. Geneva: World Health Organization; 2016.

2. United Nations Office on Drugs and Crime (UNODC). Recommended methods for the identification and analysis of cannabis and cannabis products. New York: United Nations; 2009.

3. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770-1804.

4. Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001;178(2):101-106.

5. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327-360.

6. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta-9-tetrahydrocannabinol, cannabidiol and delta-9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.

7. Mauriias S, et al. Cannabinoid receptors as therapeutic targets. Prog Neurobiol. 2009;89(2):142-162.

8. Mechoulam R, Hanuš LO. Cannabidiol: an overview of some chemical and pharmacological aspects. Phytother Res. 2019;33(10):2483-2489.

9. ElSohly MA, Slade D. Chemical constituents of cannabis sativa: the constituents and their analytical chemistry. Life Sci. 2005;78(5):539-548.

10. Brenneisen R. Chemistry and anaylsis of phytocannabinoids and other cannabis constituents. Forensic Sci Handb. 2007;2:17-80.

11. Toennes SW, et al. Comparison of cannabinoid metabolite concentrations in whole blood and plasma after consumption of cannabis. J Anal Toxicol. 2008;32(7):496-501.

12. Lowe RH, et al. Analytical methodology and interpretation of cannabinoid drug tests in biological fluids. Clin Chem. 2006;52(4):618-627.

13. Cone EJ, et al. Testing for drugs of abuse in hair: experimental observations on the adsorption of delta-9-tetrahydrocannabinol and its metabolites. J Anal Toxicol. 1993;17(6):386-391.

14. Heustis MA, Cone EJ. Urinalysis of cannabinoids: excretion patterns of delta-9-tetrahydrocannabinol-11-oic acid. J Anal Toxicol. 1998;22(6):445-453.

15. Schwope DM, et al. Identification of recent cannabis use: whole blood and plasma free and glucuronide cannabinoid pharmacokinetics following controlled smoked cannabis administration. Clin Chem. 2011;57(10):1405-1413.

16. Desrosiers NA, et al. Phase II cannabinoid disposition in human plasma following controlled oral cannabis ingestion. Clin Chem. 2014;60(4):631-640.

17. Verstraete AG. Detection time of drugs of abuse in blood, urine and oral fluid. Ther Drug Monit. 2004;26(2):200-205.

18. Niedbala RS, et al. Detection of marijuana use by oral fluid and immunoassay evaluation. J Anal Toxicol. 2001;25(7):514-520.

19. Barnes AJ, Huestis MA. Pharmacokinetics of cannabinoids. Handb Exp Pharmacol. 2005;(168):213-241.

20. American Association for Clinical Chemistry (AACC). Guidelines for substance abuse and clinical toxicology testing. Clin Chem. 2015;61(1):120-134.

FAQ’s:

• What is marijuana?
  Marijuana is a cannabinoid derived from the dried flowers of the Cannabis sativa plant.

• How does marijuana act?
  It binds to CB1 and CB2 receptors in the central nervous system.

• What are main active compounds?
  The primary active cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

• What are its primary metabolites?
  Key metabolites include 11-OH-THC, THC-COOH, and THC-COOH glucuronide.

• What indicates acute intoxication?
  Symptoms include tachycardia, panic attacks, chest discomfort, hallucinations, and impaired motor skills.

• What collection types are used?
  Samples include urine, blood, hair, and saliva collected for laboratory testing.

• What is the urine cut-off?
  The cut-off value to label urine test results as positive is greater than 15 ng/ml.

• How does cannabis affect systems?
  It impacts the central nervous, cardiovascular, respiratory, gastrointestinal, and reproductive systems.

• What affects test accuracy?
  Chemical adulterants, dilution, substitution, and individual metabolic variations can cause false test results.

• Which method confirms drug use?
  Gas chromatography/mass spectrometry (GC/MS) serves as the preferred confirmatory method due to high specificity.