Drug Of Abuse Cannabis Biology Essay

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Cannabis is a genus of flowering plant, that is produced by three purative species 1 Cannabis Sativa, 2 Cannabis Ruderalis under different conditions. This plant produces a variety of substances which is known as cannabinoids. One of the major active constituent of cannabis is tetrahydrocannabinol (THC). Cannabis or Marijuana is one of the most frequently used illicit drugs in the western world.

Cannabis is also known as Marijuana, Marihuana and Ganja. It is used in dried herbal form as a drug and resinous form of the drug is known as hashish. The herbal form is of the flowers and subtending leaves and stalks of mature pistillate or female plants.

1.a. History

Cannabis was first reported in 2735 B C by Shen-Nung, a Chinese emperor and said that it has properties against malaria and rheumatism. Cannabis was well known as herbal remedy before the birth of Christ in Indian subcontinent and the Arabian peninsulla. In Germany during 500BC, cannabis was reported to have properties as a narcotic drug. Much later was used as an aphrodisiac to treat impotence as a remedy to treat upset stomachs and headaches and also as a carminative (for flatulence). It was also used in combination with opium to produce sleep and its extracts to clear ear canals. A drink was made from cannabis named as 'Soma' was used in religious ceremonies to liberate sins in the Indian subcontinent and was also used to aid in medication. Concentration of cannabis was called by different names such as Ma-Yo (Chinese), Qunuba, Qunabu, Kannapu (Assyrian) and Bhang (Indian). The dried oily resin known as Hashish derive from Arabic and also called as dagga in Southern Africa. Other forms of cannabis include hashish (resin), the oil (hash oil) and thai sticks. Modern names used for cannabis are weed, grass, dope and pot.

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Cannabis was criminalized in various countries such as in South Africa (1911), in Jamaica (1913), in United Kingdom and Newzealand (1920s) and in Canada (1923).

1.b. Different Forms of Cannabis:

Cannabis [herbal form]

Hashish

Hash oil

Kiet:

CHEMISTRY OF CANNABIS:

1.c. Active Constituents of Cannabis

Major constituent of cannabis plant is tetrahydrocannabinol (THC). Other constituent include cannabidiol (CBD), cannabinal(CBN), and tetrahydrocannabivarin(propyl analog of THC).

∆9-tetrahydrocannabinol (∆9-THC) ∆8-tetrahydrocannabinol (∆8-THC)

Cannabinal(CBN) Cannabidiol (CBD)

Pharmacokinetics

The main aspect of the pharmacokinetics of active component of cannabis (THC) is the absorption, bioavailability, half-life and metabolic fate.

ABSORPTION AND BIOAVAILABILITY

Cannabis constitution i.e. THC or other cannabinoids are absorbed by different routes such as by inhalation, smoking or by using a bong or a water pipe or by ingestion of baked cannabis product significant absorption of THC will not be performed by eating fresh cannabis leafs, science it is activated by a heating process or by a dicarboxylation reaction.

2.1.a. Oral Consumption: -

Ingestion of THC by ingesting cakes or other sweet products or using a seeds or the oil of the cannabis plant is insufficient because it bioavailability after oral absorption is 6% and its peak concentration occurs at 1-5 hours after consumption. After ingestion of 20mg cookies, the peak concentration ranges from 4-11 ng/ml THC.

2.1.b. Smoking: -

Smoking cannabis produce much quicker absorption with maximum plasma concentration with a few minutes absorption is much higher than with ingestion and it shows bioavailability of 14-50% the amount absorbed will depend on the technique use to smoke the cigarette and how much is inhaled.

If a cigarette contains 1.75% THC (16mg) than it give peak plasma concentration of 80ng/ml, with plasma concentration range of 50-130ng/ml within 15 minutes of smoking correspondingly, so the concentration is directly proportional to THC content .

After absorption from lungs THC is rapidly distributed to tissue due to low water solubility and high affinity for fatty tissue, there will be higher concentration in adipose tissue. Its distribution will lead to decrease in blood plasma THC concentration.

So the elimination half life of THC is reported to be 4.3 days or within a range of 3-13 days. Its half life is longer than the action of cannabis is shortened. A quick peak level is produce for first hour by a rapid distribution phase and than slow down after one hour. In pharmacokinetic of THC there is a little difference in men and women. If dose of

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11-nor-∆9-tetrahydrocannabinol-9-carboxylic acid (carboxyl-THC)

It is one of the metabolite of THC found in the blood of cannabis users. THC measurement is difficult, so inactive metabolite is measured. Plasma concentration of unconjugated carboxyl-THC gives 1.97% THC cannabis cigarette peak at 43ng/ml at 20min after smoking. Plasma concentration falls to 13ng/ml by 6 hours.

2.1c. Intravenous

Intravenous administration of THC (5mg) will give peak concentration of 40ng/ml at 5-45min in frequent users and peak concentration of carboxyl-THC Infrequent marijuana users at 70ng/ml at 14-180min post-dose and 90ng/ml in frequent users.

METABOLISM AND BIOLOGICAL ACTIVITY OF METABOLITES: -

There are 20 metabolites obtained from the metabolites obtained from the metabolism of THC and only three of them are significance which are 11-hydroxy, the 9-carboxyl and the glucouronide of 9-carboxyl-THC. 8 and 2'-hydroxy THC metabolite exist in both the 8α and 8β isomers of which the β form has the most activity the 11-hydroxy metabolites has some activity like THC others hydroxylated metabolite and polar metabolite are occurred hydroxyl metabolites will be produce in larger amount if cannabis taken as oral administration due to first-pass effect. the major metabolites of THC is the conjugate form of 9- carboxyl metabolite with glucouronic acid is present in plasma and urine and is most often target in blood and urine analysis.

EXCRETION:-

After THC is metabolized and it is excreted as polar hydroxyl, carboxyl and conjugated forms in urine is 20% and in feces 40% of dose is excreted. 9-carboxyl THC is excreted as the glucouronide conjugate and 2% is excreted as the 11 hydroxyl form.

The average peak of urine concentration of carboxyl THC at 90 and 153ng/ml within 6 hours, when the smoking of 1.75% (16mg) and 3.55% (14mg) cannabis cigarette. After 10mg smoked and 5mg intravenous administration similar urine concentration is observed. Concentration of cannabinoids in urine can be variable that can take place due variable rates of metabolism, release of THC from Fats and tissue and variation in urine output. In urine, creatine measurement is used to correct for renal function. Drug excretion will also be affected by kidney function.

DURATION OF ACTION: -

The duration of action of cannabis in short and follows the blood THC concentration rather than the carboxyl-THC metabolite. After smoking the peak effect occurred about 15-30 min and the peak concentration THC is achieved with in a minutes where as decline after this peak. The pharmacological effect often last for 2-4 hours. The slower absorption and the greater concentration to the behavior effect by metabolites can cause longer duration of action therefore oral consumption of cannabis produce a duration of action of about 8 hours.

PHARMACODYNAMIC

3.a. Mechanism Of Action: -

The active constituents of cannabis act on specific receptors on the CNS. The cannabinoids receptors belong to G-protein coupled receptors. Activation of these receptors inhibits the enzyme adenylate cyclase and produced intracellular mediator. Movement of calcium through ion channels is also affected by these receptors.

The site of action for THC is the cannabinoids receptors which is located to specific region of the brain. There are two types of receptors CB1 and CB2, CB1 sites includes hippocampus and cortex for cognitive effect and basal ganglia and cerebellum, which controls balance and co-ordination. CB2 site is a peripheral binding site and plays its role in modulating immune response and inflammation.

These receptors are diluted by a number of neuronal systems for its physiological functions by other drug of abuse. Endogenous substance or endogenous cannabinoids includes anandamide and 2-arachidonyl glycerol, which are derivatives of arachidonic acid and act as a receptors and act as precursor for the formation of prostaglandins and related substance. Both of this substance interacts with cannabinoids receptors in both peripheral and central site to produce wide range of effects. Difference in the pharmacological action between THC and the endogenous cannabinoids may be due to either pharmacodynamic or pharmacokinetic difference.

3.b. PHARMACOLOGICAL ACTION: -

Cannabis produces an important range of physiological effects such as pleasant, dreamy state with impairment of cognitive and psychomotor function.

3.b.1. Acute Physiological Effects: -

Cannabis can increase heart rate, blood pressure and body temperature. Heart rate depends on dose of cannabis and can give 50% within 30 minutes of a dose. Blood pressure, there is particular increase in systolic pressure by 25mm/hg on administration of 5mg dose of THC. Body temperature also depends on a dose.

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Cannabis can also lower intracellular pressure , reduce lacrimation, reduce the conjunctivae and can cause photophobia by small increase in the size pupils and diminish reaction to light all physiological effect are due to behavioral changes that shows only a poor relationship with plasma concentration of THC.

3.b.2. Acute Behavioral Changes: -

Acute psychological behavioral changes of cannabis iv users include a transient euphoric effect associated with emotional and cognitive changes that are usually perceived as a high recent cannabis used by user can be suggestive if the blood concentration of THC is in excess of 5ng/ml.

In some users, dysphasia occurs paranoia, panic and unpleasant feeling. Depersonalization and restlessness occurs in some users. Cognitive effect can also occur. Cannabis can induce acute paranoid or manic psychosis, which may lead to increase risk of aggression and violent act.

3.c. CHRONIC AND ADVERSE HEALTH EFFECT: -

Use of cannabis can produce a lot of adverse effect such as lung diseases, cancer, impair of short term memory, over all learning, schizophrenia, paranoia, maniform psychosis and organic psychosis. Other effects include abnormal menstruation and an ovulation in women, decrease testosterone, decrease sperm count and impaired sperm motility with abnormal morphology in men.

THERAPEUTICS USES

Cannabis drugs are classified under different category such as stimulant, depressant or hallucinogen. Cannabis as a mixture of all the above properties, so it is used in amelioration of nausea and vomiting, and stimulation of hunger and AIDS patient i.e. effective for treating glaucoma, general analgesic effect. It's used for medical as been legalized in thirteen states.

5. ANALYSIS

Marijuana can be detected in urine for 30 days after use, as its metabolites in urine are present up to 30 days. In urine, a small fraction of THC of a dose is excreted and a major inactive oxidation product i.e. 11-nor-δ-9-tetra-hydrocannabinol-9-carboxylic acid (11-COOH_THC) can be detected by immunoassays. Some of them are discuss bellow:

5.a. Radioimmunoassays:-

ABUSCREEN: It is a specific and sensitive test for detection of 11-COOH_THC at 5ng/mL. Cannabis has been tested against the assay at urine concentrations of 10,000ng/mL and no positive values greater or equal to the detection sensitivity of 5ng/mL occur. Some of the drugs tested are given bellow in table 1.

Table 1. Drugs did not interfere with the Roche Abuscreen RIA for cannabinoids at an added concentration of 10,000ng/mL.

Amitriptyline

diphenylhydantoin

Phenylpropanolamine

Amylobarbitone

fenoprofen

Dextromethorphan

Amphetamine

hydrochlorothiazide

Codeine

Ampicillin

ibuprofen

Cocaine

Aspirin

imipramine

Chlorpromazine

Atropine

MDMA

Chlorpheniramine

Benzocaine

methadone

Diazepam

Benzoylecgonine

methamphetamine

Penicillin G

Butobarbitone

methaqualone

Pentobarbitone

Caffeine

Morphine

Phencyclidine

Chlordiazepoxide

naproxen

Phenobarbitone

Chloroquine

oxazepam

Phenothiazine

Dextropropoxyphene

DPC:-

DPC radioimmunoassay for cannabinoids uses the double -antibody technique and has a detection limit of approximately 2ng/mL. and therefore no interference was found with the drugs listed below in table 2:

Table 2. Drugs not detected in urine by the DPC cannabinoid RIA when present in concentrations of 100,000ng/mL.

Acetaminophen

Fentanyl

Morphine

Amphetamine

Furosemide

Morphine 3-glucuronide

Aspirin

Ibuprofen

Nalorphine

Benzoylecgonine

Lidocaine

Normorphine

Buspirone

Methadone

Phenobarbitone

Caffeine

Methamphetamine

D-Proxyphene

Clonazepam

Methaqualone

Secobarbitone

Cocaine

Ecgonine

Diazepam

Codeine

Ethylmorphine

Cotinine

Fenfluramine

The cross-reactivity of other cannabinoids in the assay are shown in bellow table 3.

Table 3. Cross-reactivity of cannabinoids in the DPC RIA.

Compound

Concentration

Added

(ng/mL)

Concentration

Found

(ng/mL)

Cross reactivity (%)

11-nor-δ-9-THC-9-carboxylic acid

100

100

100

Cannabinol

10,000

100,000

3.4

24

0.03

0.02

Cannabidiol

10,000

100,000

5.5

21

0.06

0.02

Δ-8-THC

100

1,000

>250

>250

>100

>100

Δ-8-THC-11-oic acid

10

100

1,000

9.7

125

>250

97

125

>100

5.b. Enzyme Multiplied Immunoassay Technique (EMIT).

The Emit d.a.u. is available in the three kits with cut-off levels of 20ng/mL, 50ng/mL and 100ng/mL. the major metabolites of THC in urine is detected by this assay.

Table 4. Concentration of THC metabolites showing a positive response in the Emit d.a.u. cannabinoids 50ng assay

Compound

Concentration (ng/mL)

8-β-11-dihydroxy- δ-9-THC

1,000

8-β-hydroxy- δ-9-THC

1,000

11-hydroxy- δ-8-THC

1,000

11-hydroxy- δ-9-THC

1,000

11-nor- δ-9-THC-9-carboxylic acid

50

Table 5. Compounds shown to give a negative response with the Syva Emit d.a.u cannabinoids 50ng assay

Compound

Concentration tested (µg/mL)

Acetylsalicylic acid

1,000

Amitriptyline

1,000

Amphetamine

100

Benzoylecgonine

400

Chlorpromazine

12*

Meperidine

1,000

Methaqualone

500

Morphine

200

Oxazepam

300

Phencyclidine

1,000

Promethazine

125

Propoxyphene

100

Secobarbitone

1,000

5.c. Cloned Enzyme Donor Immunoassay (CEDIA)

The CEDIA d.a.u. multilevel THC system is very similar in performance to Emit in terms of sensitivity and specificity. This assay can detect about 10% fewer positives than the RIA techniques. Low concentrations of the target metabolite (11-COOH-THC) are found in false-negative sample. Cross reactivity of cannabinoids are shown in below table 6.

Table 6. Cross-reactivity of cannabinoids in the CEDIA THC assay.

Compound

Concentration (ng/mL)

Crossreactivity (%)

11-nor- Δ9-THC-COOH

50

100

11-nor- Δ8-THC-COOH

40

125

Δ9-THC

500

10.4

11-OH-11- Δ9-THC

125

43

8β-OH-11- Δ9-THC

1,000

2.8

8, 11-di-OH-11- Δ9-THC

500

8.4

1- Δ9-THC-glucuronide

62

72

Cannabinol

1,000

2.9

Cannabidiol

1,000

<0.1

This assay can be extended to blood sample by first extracting with acetone, evaporating the extract and then reconstituting the residue in a mixture of methanol and buffer. FPIA system can also adopt this process for blood analyses.

5.d. Fluorescence Polarization Immunoassay (FPIA)

The TDx kit for cannabinoids has a sensitivity for 11-COOH-THC of 10ng/mL in urine and better sensitivity of 2ng/mL. A range of THC metabolites in urine can be detected by this assay. In abbott TDx FPIA, cross reactivity of cannabinoids are shown in below table 7.

Table 7. Cross-reactivity of cannabinoids in the abbott TDx FPIA.

Compound

Concentration added (ng/mL

Concentration found (ng/mL)

Cross reactivity (%)

11-nor-δ-8-THC-9-carboxylic acid

100

109

100

1-hydroxy-δ-9-THC

200

100

50

96.8

56.7

31.5

48.4

56.7

62.9

8-β-hydroxy-δ-9-THC

200

100

50

57.5

50.6

40.3

28.8

50.6

80.6

8-β-dihydroxy-δ-9-THC

200

100

50

58.5

52.8

41.8

29.3

52.8

83.6

Cannabidiol

200 Not detected

Cannabinol

200

100 Not detected

15.8

7.9

Gas chromatography:

For cannabinoids, a confirmatory test is carried out by GC/MS.By this technique, a gas chromatogram of Δ9-THC, CBD, CBN and cannabichromene ( CBC) is obtained and the peak of this substaqnce is well separated by this technique but the CBC peak can overlap CBD peak. Peak of cannabinoids is not interfered by impurity on analyzing dried cannabis. As these technique is used for the detection of cannabis constituents by used of mass spectrometer and other technique with can be used for the detection of cannabis are LC/MS or LC/UV and TLC.

Case report:

This a case report of a man (25 year-old), driving his vehicle (A) through a red light of a controlled intersection, which collide with a vehicle (B) travelling through the intersection facing a green light but due to these collide the driver of vehicle (B) was died and the driver of vehicle (A) was in a shock state and was suffered from minor head and limb abrasions, he was treated in a local hospital. The blood sample of the driver (A) was taken after 2 hours of the accident, which showed the reading of 25ng/mL of a carboxy-THC (total). The accident occurred after 10 min of the start of his car. Before the accident, there was no evidence to suggest that the driver was driving abnormally.

A serious accident has occurred by a man, who had been taking cannabis. A positive concentration of the inactive metabolite of THC was reported by the toxicological evidence but the metabolite found was inactive. So the driver has not take the cannabis before the accident but might have take few days earlier.

Before the accident, the abnormal behaviors of driving was absent i.e. not obeying traffic signal may suggest that he was not so impaired to be incapable of proper control of motor vehicle. A clinical assessment of impairment would be better test performed by a trained physician or drug recognition expert. The illegality can only be proven by the driver is dangerous or reckless driving and failing to obey a traffic signal. To sustain a culpable driving charge this was not sufficient. Immediately after the accident, if an assessment of sobriety and a large positive THC level may conclude very recent use of cannabis associated with significant impairment by an expert.