Cannabis sativa, or Indian hemp (subfamilyCannaboideaeof family Moraceae), is an annual herbaceous plant native to central and western Asia. The plant is cultivated for itsmedicinal properties and as a natural textile fiber.²

       
           
       
Fig.1

Cannabis is a complex plant with over 400 chemical entities of which more than 60 of them are cannabinoid compounds approximately 80 are biologically active, some of them with opposing effects. Cannabis is also the most widely used illicit drug in the world and its use has been associated with various mental health problems, particularly in the young.1

Parts of the cannabis plant

       
           
       
Fig.2

Flower

The flowers of the female marijuana plant can be identified by their small teardrop structures, which consist of pistils attached to bracts. Cannabis flowers are usually covered with a frosty-looking coating of trichomes, with a heavier density of trichomes making for a more desirable flower.

Cola

The main part of the flower, at the end of a female plant's stem is composed of manysmall floral clusters. In general, the bigger, heavier, and more densely covered in trichomes a cola is, the better quality it will be, although some cultivars will naturally grow flowers that are more loosely structured and airy.

Bracts

The small leaves that surround the reproductive cells of a female weed plant. When a female plant is exposed to pollen from a male marijuana plant, the bracts surroundand shield the seed pod.

Trichomes

Marijuana trichomes are hairlike appendages found on the surface of the cannabis plant. Trichomes protect the plant from external stressors and contain resinous glands that create flavonoids, cannabinoids and terpenes—the chemical compounds that

give the marijuana plant its unique features and effects. Trichomesgive cannabis buds a crystal-like sheen and make them sticky feeling.

Node

The point at which the stem and leaf intersect. Nodes can hold one or more leaves or offshoots. As explained below, nodes are important to be familiar with, as they are where cannabis plants begin to grow either pollen sacs (male cannabis plants) or pistils (female cannabis plants). Understanding the sex of a marijuana plant is crucialto the final product, since only female plants produce flowers and since non- pollinated flowers are far superior than pollinated buds when it comes to consumption.

Fan leaves

Leaves are important components of a weed plant, and there are actually a couple types of marijuana leaves. The large, protruding leaves that appear along the lengthof the plant are called fan leaves. Theses leaves are essential to the living plant's photosynthesis, but are always removed from the finished, harvested product.

Stem

The main support structure of the marijuana plant, the stem transports fluids, nutrients, and information from the roots to the rest of the weed plant. The stem provides a foundation to give fan leaves access to the light they need to facilitate growth and carries the weight of heavy colas. The most relevant cannabis compounds are cannabinoids, which are formed by a terpene combined with resorcinol (or a benzopyranic ring system, according to a different nomenclature). There are about 60 cannabinoids. The most important psychoactive compound is tetrahydrocannabinol (THC), particularly the isomer delta (?9-THC).

Different parts of the cannabis plant have different concentrations of these phytochemicals. For example, leaves and glandular trichomes in the bark contain the most potent cannabinoid metabolites. Flower buds are primarily rich in THC, CBD, CBC, and CBG.3

While THC is psychotropic, CBD, another phytocannabinoid present in the Cannabis sativa plant, is non-psychotropic and has witnessed widespread acceptance for the symptomatic treatment of various medical conditions. CBD has antipsychotic, anxiolytic, anti-seizure, and anti-inflammatory properties and potentially mitigates some of the adverse psychotropic effects of THC by acting as a negative allosteric modulator of CB1 receptor.4

Classification Of Cannabis

       
           
       
Classification Of Cannabinoid

       
           
       
MORPHOLOGY

1. LEAF MORPHOLOGY

This investigation into the morphological characteristics of cannabis leaves during their development from seed germination to maturity revealed a distinct and organized pattern of leaf morphogenesis. After the expansion of cotyledons, the first true leaves (L1) were each one single serrated leaflet, which served as an initial stage of leaf development. Subsequently, the second true leaves (L2) emerged, featuring three serrated leaflets each, marking a notable increase in leaf complexity. Nodes 3 and 4 produced leaves with five serrated leaflets (L3 and L4), further highlighting the progressive trend in leaflet formation. At nodes 5 and 6, the number of serrated leaflets continued to increase, resulting in leaves with seven (L5) and nine (L6) serrated leaflets, respectively. This developmental sequence depicted in Fig.3 clearly demonstrates the stepwise progression of leaflet complexity during the early stages of cannabis growth.7

During the growth under the long-day photoperiod, nodes 2–4 exhibited the presence of axillary buds, accompanied by a pair of leaves at each node showing the plants were in the juvenile phase ……Additionally, two stipules were observed flanking the base of the leaf petiole in node 5 and node 6, demonstrating the transition of the plants from the juvenile phase into the mature phase⁷

           
       

Phase-transition-related morphological changes. (A) Cannabis plants with stipules and opposite phyllotaxy, showing the vegetative phase; (B) Cannabis plants with bracts and solitary flowers, signifying the transition of the plants into the reproductive phase; (C) Cannabis plants with alternate phyllotaxy (red arrows show the alternate arrangement of leaves).

1. Floral Morphology

Upon transition to the short-day photoperiod, compacted inflorescences emerged at the apical regions of the main stem (after 10 days) and secondary- and tertiary-order branches (after 15 days). Cannabis inflorescences presented as complexly branched compound racemes. This distinctive structure is emblematic of monopodial growth, featuring an enduring apical meristem and indeterminate axillary inflorescences of higher orders. Flower development at the apical regions of the main stem is shown in Fig.5. During flower development, prior to stigma elongation, a profusion of glandular trichomes emerged on the perigonal bract encasing the ovary. As the inflorescences a reddish-brown shade Fig.57

       
           
       
Fig .5. Flowering progress in cannabis. Main flower after (A) 3 days, (B) 1 week, (C) 2 weeks, (D) 4 weeks, (E) 6 weeks, and (F) 8 weeks.

Chemical constituents of Cannabis sativa L. 47,48 Marijuana is the crude drug derived from the plantCannabis sativaL. a plant that is currently accepted as belonging to a family (Cannabaceae) that has only one genus (Cannabis) with only one

species (sativa) that is highly variable.

Cannabis has had a long history of use (over 5000 years) starting in Central and Northeast Asia with current use spreading worldwide as a recreational drug or as a medicine albeit unauthorized. Several historic reviews have been written onCannabisuse as a

Cannabinoids: 70 known (4 new)

The typical C21 group of compounds present inC. sativaL. is known as cannabinoids and includes their analogs and transformation products (Razdan, 1987). Five different numbering systems have been used for the cannabinoids (Fig. 1; Eddy, 1965). Compounds in this review will be numbered according to these systems, or if needed, by using the Chemical Abstract Index numbering.

The 70 known cannabinoids can be classified as follows:

Other constituents: 419 known (2 new)

The following chemical classes (number known) has been identified in marijuana: nitrogenous compounds (27), amino acids (18), proteins (3), enzymes (6), glycoproteins (2), sugars and related

compounds (34), hydrocarbons (50), simple alcohols (7), simple aldehydes (12), simple ketones

(13), simple acids (20), fatty acids (23), simple esters (12), lactones (1), steroids (11), terpenes

(120), non-cannabinoid phenols (25), flavonoids [23, including 2 new flavonol glycosides, namely kaempferol 3-O Mechanism of action

Until the mid-12th century, the existence of human cannabinoid pathways was not understood. The discovery of THC and CBD led to identification of the signaling pathways. Evidence that THC interacts with a particular mammalian target was uncovered in murine neuroblastoma cells, which expressed upregulated adenylate cyclase in response to exposure to the compound or its synthetic analogues. This finding paved the way for the isolation and cloning of a G protein– coupled receptor that subsequently was named cannabinoid receptor type 1 (CB1).8 Cannabinoid receptor type 2 (CB2) was later isolated from human leukemia cells.9CBD was shown to directly exert activity at the CB2 receptor. Identification of these receptors led to the hypothesis that an endogenous cannabinoid system in the mammalian body, known as endocannabinoids, might also exist. The first endogenous cannabinoid ligand was then isolated from pig brain and namedN- arachidonoylethanolamine (AEA) or anandamide10. The second endogenous ligand was also isolated from intestinal tissue and named 2- arachidonoylglycerol (2-AG).11,12 Both AEA and 2-AG are arachidonic acid derivatives produced from phospholipid precursors through activity-dependent activation of specific phospholipase enzymes.13 A number of other endogenous ligands have since been discovered, includingN-arachidonoyl dopamine,N arachidonoyl glycerol ether,

andO-arachidonoylethanolamine. 14

2-AG is mainly synthesized through activation of phospholipase C and subsequent production of diacylglycerol, which is converted to 2-AG by diacylglycerol lipase. 2-AG is primarily metabolized by monoacylglycerol lipase, leading to the formation of arachidonic acid and glycerol.14CB1 and CB2 receptors are certainly the most well-known targets for AEA and 2-AG, which activate them with different affinity.

AEA has the highest affinity in both cases.14 Physiological or pathological stimuli induce synthesis and release of endocannabinoids, which can subsequently activate cannabinoid receptors. Therefore, endocannabinoids are synthesized and released “on demand” through the cleavage of membrane phospholipid precursors.

THC and CBD of the phytocannabinoid system can also bind to G protein–coupled cannabinoid receptors CB1 and CB2. CB1 receptors are particularly abundant in the frontal cortex, hippocampus, basal ganglia, hypothalamus, cerebellum, spinal cord.15,16 and peripheral nervous system.15 They are present in both inhibitory GABAergic neurons and excitatory glutamatergic neurons.15CB2 is most abundantly found on cells of the immune system, hematopoietic cells,17 and glia cells.16 CB2 is mainly expressed in the periphery under normal healthy conditions; in conditions of disease or injury, this upregulation occurs within the brain and CB2 is therefore expressed in the brain in unhealthy states.11 CB1 and CB2 are also widely distributed in the cardiovascular system.18 Synthetic cannabinoids are typically consumed through smoking or in a concentrated liquid form. The negative effects of synthetic cannabinoids include palpitations, paranoia, intense anxiety, nausea, vomiting, confusion, poor coordination, and seizures. Interestingly, some individuals reported strong compulsions with persistent cravings to reuse a week after cessation and some reported withdrawal symptoms

such as headache, nausea, and vomiting.19

Uses of Cannabinoids46

Pain

Helping to Decrease Opioid Use Anxiety

Epilepsy Glaucoma

HIV/AIDS Symptoms Inflammatory Bowel Disease Irritable Bowel Syndrome

Movement Disorders Due to Tourette Syndrome Multiple Sclerosis

Nausea and Vomiting Related to Cancer Chemotherapy Posttraumatic Stress Disorder (PTSD)

Sleep problems

Pharmacology of cannabidiol

PHARMACOKINETICS OF CANNABINOIDS

The pharmacokinetics of cannabinoids are reviewed by Agurell et al49. and Maykut and others. About 50% of the THC in a joint of herbal cannabis is inhaled in the

mainstream smoke; nearly all of this is absorbed through the lungs, rapidly enters the bloodstream and reaches the brain within minutes. Effects are perceptible within seconds and fully apparent in a few minutes. Bioavailability after oral ingestion is much less; blood concentrations reached are 25-30% of those obtained by smoking the same dose, partly because of first-pass metabolism in the liver. The onset of effect is delayed (0.5-2 hours) but the duration is prolonged because of continued slow absorption from the gut.

Once absorbed, THC and other cannabinoids are rapidly distributed to all other tissues at rates dependent on the blood flow (Fig.6). Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4-5 days.

They are then slowly released back into other body compartments, including the brain. Because of the sequestration in fat, the tissue elimination half-life of THC is about 7 days, and complete elimination of a single dose may take up to 30 days50..

Clearly, with repeated dosage, high levels of cannabinoids can accumulate in the body and continue to reach the brain. Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas

• • PHARMACODYNAMICS OF CANNABINOIDS

Cannabinoids exert their effect by interaction with specific endogenous cannabinoid receptors, discovered by Devane et al⁵¹.Neuronal cannabinoid receptors are termed CB₁ receptors and have been found in rat, guinea pig, dog, monkey, pig and human brains and peripheral nerves. A second cannabinoid receptor, the CB₂ receptor, was identified by Munro et al. in macrophages in the spleen and is also present in other immune cells. The distribution of CB₁ receptors is very similar to that of injected THC and includes cerebral cortex, limbic areas (including hippocampus and amygdala), basal ganglia, cerebellum, thalamus and brainstem⁵²

Two similar endogenous fatty acids have since been isolated (Fig. 7) and it now appears that there may be a whole system of multiple cannabinoid receptors and anandamide-related substances. Their physiological function has yet to be⁵³. appears that both anandamides and their receptors reside within neuronal lipid membranes and act as neuromodulators through intracellular G-proteins controlling cyclic adenosine monophosphate formation and Ca²⁺ and K⁺ ion transport. In this role the system may have important interactions with other neurotransmitters, including?-aminobutyric acid, opioid systems and monoamines. In particular, THC has been shown to increase the release of dopamine from the nucleus accumbens and prefrontal cortex⁵⁴.

This effect, which is common to many drugs of misuse (including heroin, cocaine, amphetamine and nicotine), may be the basis of its reinforcing properties and its recreational use. It is reversed by naloxone, suggesting an opioid link

Overview of CBD pharmacological effects