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We have designed this section as an educational resource to help you learn about cannabis and its various applications in health, wellness and industry.

CANNABIS IN HISTORY

Highlights on the timeline

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Cannabis

Evolution and Migration

The cannabis or hemp plant has been known since ancient times and grows in almost all parts of the world, but it’s mainly known as a useful source of fiber for the manufacture of textiles and ropes. In most fiber-producing areas, the plant was not used as a drug. Geographical and climatic factors modify the content of pharmacologically active material in the plant, and only in some regions this content was high enough to discover that the plant, and especially its resin, has important pharmacological actions. Knowledge of these actions appears to have first emerged in the Himalayan region of Central Asia and gradually spread from there to India, Asia Minor, North Africa, and traversed the desert to sub-Saharan Africa and the rest of the African continent.

In India, the plant was used as medicine and in other practices. Its social and religious uses were mainly related to the Durga Puja festival. On some other occasions during the year it was also used in family celebrations, such as marriages and births, to induce a relaxed and social mood and a good appetite. Only the weakest preparations were used: ‘bhang’ (comparable to marijuana) was taken orally, and the slightly stronger ‘ganja’ preparation was smoked, but the more potent preparation, ‘charas’ (known elsewhere as hashish), was not used for these purposes. , the use of charas was not socially approved for any purpose, and its devotees were considered ‘bad characters’ or marginalized.

Cannabis was also part of the therapeutic arsenal of traditional Indian medicine, and many of the uses were similar to those currently recommended in our own society. Among its stated benefits are sedative, relaxing, anxiolytic and anticonvulsant actions, all of which also made it useful in the treatment of alcohol and abstinence of opiates,analgesia, stimulation of appetite, antipyretic and antibacterial effects, and relief of diarrhea.

The introduction of the effects of the cannabis drug in Europe in the 19th century followed different routes for medical and non-medical uses. In France, general interest focused on the non-medical application of psychoactive effects, while in England the interest was primarily medical. During the Napoleonic invasion of Egypt in 1798, De Sacy and Rouyer, two French scholars who accompanied the army, described the plant and the practice and effects of smoking, and collected samples of the material to bring to France for further study. The famous French psychiatrist Moreau de Tours made further observations of its effects on the mood during his travels through North Africa in the 1830s. He later described in detail the mental effects of high doses of hashish, and advanced the hypothesis that dreams, insanity, and drug intoxication involve similar mechanisms. He proposed the use of hashish to produce a “model psychosis” for scientific study, a century before this concept was proposed in North America in relation to the hallucinogens lysergic acid diethylamide and mescaline. In Paris, the ‘Club des Haschichins’ flourished in the 1850s, with members such as the poets and authors Baudelaire, Gautier and Dumas. They served as subjects for Moreau’s experiments and popularized hashish in his writings as a route to aesthetic self-actualization, as did Ginsberg and others in the United States a century later.

In the United Kingdom, on the other hand, the medical and scientific writings of O’Shaughnessy, a British doctor working in India as a professor of Chemistry and Medical Matter in Calcutta, sparked interest in cannabis and observed the use of cannabis in India in traditional medicine, for the treatment of spastic and convulsive disorders such as ‘hydrophobia’ (rabies), tetanus, cholera and delir-ium tremens. He sent supplies of the material to a pharmaceutical company in London for analysis and clinical trials. Cannabis extracts were adopted in the British Pharmacopoeia and later in the American Pharmacopoeia, and were widely used in the English-speaking world as sedative, hypnotic, and anticonvulsant agents in the late 19th and early 20th centuries.

However, when cannabis was removed from the British Pharmacopoeia in 1932 and from the American Pharmacopoeia in 1941, its clinical use had virtually disappeared and its formal banishment sparked little or no protest. One of the reasons for this loss of favor was that the plant material was too variable in composition, its shelf life was too short and unpredictable, and had been increasingly replaced by pure opiates and new, more reliable synthetic drugs invented in the first part. Thus, cannabis would have to be substantially improved as a drug to regain clinical interest.

Ancient and modern chemical studies.

In North Africa the very high lipid solubility of materials responsible for the effects of cannabis on drug use was known, where a common practice was to heat the leaves and the upper part of the plant in a mixture of butter and water. The active drugs were concentrated in the butter phase and, as the mixture cooled, the butter could be separated from the water and used in preparations to be taken by mouth to produce the desired effects. In 1857, the Brother Brothers of Edinburgh prepared a non-alkaloid fraction with a high level of pharmacological activity, and the alcoholic extracts or the dry residues obtained from them were later standardized for their biological activity, forming the basis of pharmacopoeial preparations. In 1899 Wood, Spivey, and Easterfield attempted to isolate the active agents from such preparations, but their “cannabinol” had very little pharmacological activity and turned out to be a mixture rather than a single compound.

It was not until the 1930s and 1940s that Todd et.al In the UK and Adams et. al. In the United States they isolated pure cannabidiol and various tetrahydrocannabinoles (THC), and showed that the latter were responsible for the psychoactive effects. Of the numerous chemical compounds isolated from cannabis, only three have the typical psychoactive effects for which cannabis is used non-medically: ∆9-THC, ∆8-THC, and (very weakly) cannabinol. A fourth natural cannabinoid, cannabidiol, has other types of pharmacological activity but is not psychoactive.

Finally, Mechoulam et.al. In Israel, and Claussen and Korte in Germany achieved the complete synthesis of the pure compounds, established their molecular structures and developed the study of their structure-activity relationships. This work led to the synthesis of new cannabinoid derivatives and analogs that do not exist in nature. Armed with these pure and powerful chemicals, Devane et.al. Identified specific binding sites (cannabinoid receptors) in the brain, and demonstrated the receptor binding affinities of the different compounds parallel to their respective potencies of biological activity.

Because cannabinoids themselves do not exist in the brain, the existence of the receptors implies that other endogenous materials in the brain normally bind to them. Devane et.al. later reported the isolation of anandamide (arachidonyl ethanolamine), a lipid material related to prostaglandins, which is formed locally in the brain and binds to receptors, exerting actions similar to those of cannabinoids but less potent. Arachidonyl-glycerol and several other similar materials have been subsequently identified.

Cannabinoid receptors were found to be of at least two different types, CB1 receptors are mainly present in various parts of the brain (cerebral cortex, cerebellum, basal ganglia, limbic system, hypothalamus, hippocampus) and CB2 receptors present exclusively in peripheral tissues such as the immune system, bone marrow, lung, pancreas, and smooth muscle. Both types of receptors are linked to the inhibitory G protein, through which they act to inhibit cyclase activity, preventing theactivation of various calcium ion channels in the cell membrane, while increasing the entry of potassium ions. Functional results vary on different types of neurons. Inhibitory neurons are activated, with increased release of GABA, while motor neurons, cellular excitability, andneurotransmitter release decrease. The isolation of the different types ofreceptors has allowed the development of fully synthetic compounds with high selective affinity for one type or another, some acting as agonists and others as antagonists. The availability of these receptor-specific ligands has allowed rapid advances in the analysis of the cellular mechanisms underlying the various pharmacological effects of cannabinoids.

Anatomy of the plant

When examining a cannabis flower, you will notice a complex knot of different parts: the fiery orange hairs, the sugary crystals, the thick bumps wrapped in small leaves. But what exactly are these formations and what functions do they fulfill?

Anatomy of the plant

Anatomy of the plant 2

This short guide to the anatomy of cannabis is intended to familiarize you with the plant in its full form.

Male and female plants

Male and female plants

Cannabis plants can be male, female, or both (hermaphrodite).

Female plants produce the large resin-secreting flowers that are trimmedinto round or pointed buds, while males produce smaller sacks of pollen near the base of the leaves. Male plants pollinate females to start seed production, but the powerful flowers we consume come from female seedless plants, called “sin semilla”, which produce large buds rich in seedless cannabinoids.

Rare hermaphrodite plants contain male and female sex organs that allow the plant to pollinate itself during flowering. This self-pollination is generally considered a nuisance among growers, as it spoils seedless seedless plants and transmits hermaphrodite genes.

Growers can ensure the sex of their plants by growing clones or genetically identical clippings of an original strain. Feminized seeds are also available through a special breeding process.

The cannabis plant is made up of several structures, many of which can be found in any common flowering species. Cannabis grows on long, slender stems with its large, iconic fan leaves that extend from areas called nodes. Cannabis really begins to stand out in its flowers, where unique and intricate formations occur.

Tail

Cola de cannabis

A tail refers to a group of shoots that grow close together. While the smallest tails occur along the budding sites of the lower branches, the main tail (sometimes called the apical shoot) forms at the top of the plant.

Stigma and pistil

Stigma and pistil

The pistil contains the reproductive parts of a flower, and the vibrant, hair-like filaments are called stigmas. Stigmas are used to collect pollen from males. The stigmas of the pistil begin with a white coloration and progressively darken to yellow, orange, red and brown throughout the maturation of the plant. They play an important role in reproduction, but stigmas add very little to the potency and flavor of the flower.

Bracts and calyx

A bract is what encapsulates the female’s reproductive parts. They appear as green teardrop “leaves”, and are heavily covered with resin glands that produce the highest concentration of cannabinoids of all parts of the plant. Enclosed by these bracts and imperceptible to the naked eye, the calyx refers to a translucent layer on the ovule at the base of a flower.

Trichome

Despite its diminutive size, the crystal resin blanket is hard to miss in a cannabis bud. This resin (or “kief” when dry) is secreted through translucent mushroom glands in the leaves, stems, and calyces. Trichomes were originally developed to protect the plant against predators and the elements. These clear bulbous balloons ooze aromaticoils called terpenes, as well as therapeutic cannabinoids like THC and CBD. The basis for the production of hashish depends on these trichomes and their powerful sugar-like resin.

Varieties

The words “indica” and “sativa” were introduced in the 18th century to describe different species of cannabis: Cannabis sativa and Cannabis indica. The term sativa describes the hemp plants found in Europe and western Eurasia, where it was grown for its fiber and seeds. Cannabis indica refers to the psychoactive varieties discovered in India, where it was harvested for its seeds, fiber and hashish production.

Although the cannabis varieties we consume come largely from Cannabis indica, both terms are used, even mistakenly, to organize the thousands of strains that are on the market today.

This is how the terms have changed since their first botanical definitions:

  • • Today, “sativa” refers to tall, narrow-leaf cannabis varieties, which are believed to induce energizing effects. However, these narrow leaf drug varieties were originally Cannabis indica ssp. Indicates
  • “Indica” has come to describe robust broad-leaved plants, believed to produce sedative effects. These broadleaf drug varieties (BLD) are technically Cannabis indica ssp. Afghan
  • • What we call “hemp” refers to non-intoxicating industrial varieties harvested primarily for fiber, seed and CBD. However, this was originally called Cannabis sativa.

With the massive commercialization of cannabis, the taxonomic distinctions between cannabis species and subspecies became upside down and calcified. But now we know that a strain has more than its indica, sativa or hybrid designation.

Hybrid cannabis

The hybrid strains are bred from descendant indica and sativa plants. Due to the long history of cannabis strain crossings, many of them historically made underground to evade authorities, strains that have purely indica or sativa lineages are truly rare. Most of the strains called “indica” or “sativa” are, in fact, hybrids, with inherited genetics from both subspecies.

Cannabis Híbrido

Cannabinoids and Terpenes

Cannabinoids and TerpenesBoth THC and CBD are considered the best known cannabinoids. There are hundreds of cannabinoids in cannabis and more than 65 cannabinoids have already been classified. I In total, there are over 480 natural components within the cannabis plant.

THC (tetrahydrocannabinol) is the part of the cannabis plant that produces a mental and bodily high. It has mind altering effects. THC works by binding to the brain’s natural cannabinoid receptors, which create a feeling of euphoria. Many people consume THC through oils, capsules, flowers, and food.

CBD is very different. CBD does not have a disruptive effect and is used to treat many different ailments. CBD comes from hemp and cannabis plants. Products are created by extracting CBD oils from the plant and turning them into a gel, jelly beans, oil, or supplement.

Generally speaking, CBD and THC help treat medical conditions and disorders. Large doses of THC can have some negative side effects, while large intakes of CBD are generally safe, as it is not a mental disorder.

CBD can help treat your furry loved one’s anxiety and help them calm down when they are stressed. You can give them CBD by getting treats, oils, and water drops.

According to studies, any CBD that is safe for human consumption should also be safe for pets and children. However, only a limited number of veterinarians actually recommend CBD for dogs, as there are a limited number of studies. More study needs to be done to see if it can work with both cats and dogs.

Cannabis Terpenes

Terpenos del cannabis

Cannabinoids and terpenes have many differences. Terpenes are natural essential oils that control how things smell and taste. You have been experiencing them all your life!

There are at least 20,000 different terpenes, and the cannabis plant contains more than 100 of them.

Both Indica and Sativa plants have terpenes. These terpenes help determine which plant or strain you have. The types of terpenes within plants can even tell you if it’s a Sativa, Indica, or hybrid.

One of the most important terpenes to know is myrcene. This terpene has anti-inflammatory and sedative properties. Any strain that has more than 0.5% myrcene is considered Indica, due to the sedative effect of myrcene when combined with THC.

Sativa plants contain less myrcene and sometimes high levels of pinene. Pinene also has anti-inflammatory properties, but it also increases your mood.

Humulene terpene is good for people who want to decrease their appetite and benefit from its antibacterial properties.

Caryophyllene terpene can make your marijuana have a pungent or pungent aroma. This terpene can benefit people who experience anxiety, depression, and inflammation.

Linalool terpene is best for those who want a relaxing and stress-relief experience. This terpene can actually help reduce anxiety about THC.

As mentioned earlier, terpenes control how we perceive taste and smell. Many times, people select their favorite variety for the taste or smell of the flower. If you know which terpenes are dominant in that strain, you can easily find other strains with the same profile.

THE ENDOGENOUS CANNABINOID SYSTEM

400 million years ago, during the Cambrian period, in animals with axial symmetry, a basically biochemical system appeared that influences different vital functions of the organism such as the endocrine, nervous and immune systems.

The ECS consists of cannabinoid receptors, their endogenous ligands (endocannabinoids), the enzyme systems responsible for their synthesis and degradation, intracellular signaling pathways (regulated by the cannabinoids themselves), and their transport systems.

How important is this discovery?

The endogenous cannabinoid system (ECS) has a wide tissue, cellular and subcellular distribution that allows acting and influencing various physiological processes of great importance such as appetite and intake,pain sensation, cardiovascular, respiratory and reproductive function, state of mind, neuroprotection and synaptic transmission, motor control, memory and learning, the immune system, inflammation, hormonal release and action, cell proliferation, adhesion and apoptosis, among others.

Importancia del descubrimiento de cannabinoide endógeno

Endocannabinoids: synthesis and degradation

Most endocannabinoids are products derived from polyunsaturated fatty acid chains. The most important, Anandamide (AEA) and 2-Araquidonyl-glycerol (2-AG), are derivatives of arachidonic acid and belong to the group of N-acylethanolamines (NAE’s) and 2-monoacylglycerols (MAG’s), respectively. Both are synthesized on demand through the remodeling ofphospholipids through the N-acyl-phosphatidyl-ethanolamine selective phospholipase D (NAPE-PLD) pathway, in the case of AEA; and of the alpha and beta Diacylglycerol-lipase (DAGL) pathway in the case of 2-AG.

Anandamida (AEA)

Its inactivation takes place mainly through FAAH (fatty acid amide hydrolase) that breaks down AEA to arachidonic acid and ethanolamine, and MGL (Monoacylglycerol lipase) that breaks down 2-AG into arachidonic acid and glycerol.

Estructura de una sinapsis química típica

Despite their similar chemical structure, both ligands have different enzymatic routes of synthesis and degradation, making up a much more complex machinery than that of classical neurotransmitters. Endocannabinoids are not stored in the body, but are synthesized, released, and degraded at their site of action. Its activity is controlled, like many other bioactive molecules, by its endogenous levels.

Endocannabinoids: mechanism of action, neuronal / non-CNS synapses

The synthesis of endocannabinoids is a process related to calcium homeostasis. An intracellular increase in calcium in the postsynaptic neuron activates enzymes that, in turn, synthesize the corresponding endocannabinoid from lipids in the cell membrane.

At the level of neuronal synapses, cannabinoids have an inhibitory function, being the only ones that act by modulating the level of neurotransmitters released from the pre-synaptic neuron (they are sent retrogradely from the post-synaptic neuron to the pre-synaptic). They do not act systemically, that is, they only do it where it is necessary, in the exact location of our body where a specific and selective effect is needed, depending on the type of cell in which the cannabinoid receptors are activated.

An important characteristic of the endocannabinoid system is that cannabinoids can have both inhibitory and excitatory behavior at the synaptic level, although their action is always inhibitory:

  • Inhibitory behavior: They inhibit the release of excitatory neurotransmitter from the pre-synaptic neuron (eg: glutamate) →promote inhibition.

  • Excitatory behavior: They inhibit the release of inhibitory neurotransmitter from the pre-synaptic neuron (eg GABA or Glycine) → promote excitement.

Outside the CNS, cannabinoids act through the same receptors, but their effects vary depending on the cell type on which they exert their effect.

Due to the extensive distribution of the endocannabinoid system in the human body we can act on multiple cell lines producing a wide range of effects. For example, activating receptors at the digestive tract level reduces gastric juice secretion and intestinal motility; in lymphocytes it reduces the production of proinflammatory cytokines; and in skeletal muscle tissue muscle tone decreases.

Cannabinoid receptors: CB1 / CB2

Endocannabinoids Mechanism of action

CB1 / CB2 Both CB1 and CB2 are G-protein coupled receptors with 7 transmembrane segments. They have an inhibitory function influencing, among others, Adenylate cyclase and the MAP-Kinase (MAPK) pathway, and in the case of CB1 also on certain ion channels.

CB1 and CB2 are G protein coupled receptors with 7 transmembrane segments

CB1 is found mainly in the central nervous system (CNS)

CB2 is found mainly in structures related to the immune system

CB1: CB1 receptors are found mainly in the CNS, most abundantly in the basal ganglion, cerebellum, neocortex and hippocampus, an essential area in learning and memory processes. They are located in areas related to cognitive functions, memory, anxiety, pain, sensory perception, visceral perception, motor coordination and endocrine functions. In lower concentrations they are also found in the immune system, peripheral nervous system, testes, heart, small intestine, prostate, uterus, bone marrow, and vascular endothelium.

CB2: CB2 receptors are predominantly found in structures related to the immune system: lymphoid line (B and T lymphocytes), myeloid line (monocytes, macrophages, granulocytes, mast cells), glial cells of the CNS and spleen. To a lesser extent, they are present in cells of other tissues and peripheral organs such as the heart, endothelium, bones, liver and pancreas. In the CNS, CB2 receptors are present, above all, in glial cells, increasing their presence significantly (about 100 times) in inflammatory processes or after tissue injury. Their presence has also been described in neuronal progenitor cells and neurons of the cerebral cortex, hippocampus, pale globe, limbic areas, and mesencephalic areas. CB2 receptors are believed to be responsible for the immunomodulatory properties of cannabis and their activation is unrelated to the psychoactive effect.

Main functions of CB1 and CB2 receptors

CB1 and CB2 inhibit activation in various cell groups by inhibiting adenylate cyclase.

CB1 and CB2 inhibit gene transcription pathways involved in neoplastic or proliferative processes such as MAPKs (MAP kinases).

GPR55 / GPR119 / GPR18 type receivers

GPR-type receptors are G protein-coupled metabotropic receptors that are candidates for consideration as part of the SEC. They are distributed in the adrenal glands, spleen, digestive system and widely in the CNS: Caudado and Putamen nuclei, Hippocampus, Thalamus, Hypothalamus, Prefrontal cortex and Cerebellum.

GPR55’s are located in regions of the brain involved in the control of functions such as memory, learning, and motor coordination, such as the dorsal striatum, caudate nucleus, and putamen, as well as in various peripheral tissues, including the ileum, testes, spleen. , tonsils, breast, omental adipose tissue; and even in some endothelial cell lines. Due to its wide distribution in the CNS, various functions are attributed to it that vary according to the location of the receptor.

  • CAUDED CORE:
    Innervated by dopaminergic neurons Learning and memory functions. Voluntary movement.
  • PUTAMEN CORE
    Functions related to learning and fine movement. Adiadochokinesia together with cerebellum.
  • HIPOCAMPO
    Memory. Spatial memory and orientation. Anxiety management. Hyperactivity.
  • TÁLAMO
    Filter all sensory stimuli less smell Connects with frontal lobe, emotions, hyperactivity-depression. Regulates visceral activity.
  • MORTGAGE
    Regulates the release of hormones in the pituitary. Food behavior, fluid intake, mating, aggressiveness. Automatic visceral-endocrine regulation.
  • BRAIN
    Motor functions, adiadochokinesia, balance. Cognitive functions, attention, language, music.
  • PREFRONTAL CORTEX.
    Personalization of the individual, feelings. Apathetic, depressive behaviors, compulsion. Attention processes

There is evidence indicating that the GPR55 receptor plays a relevant role in the regulation of bone metabolism, in the control of inflammatory pain, and in the proliferation of tumor cells Significantly higher expression has been observed in tumors of different origins compared to healthy tissues.

GPR119 receiver

The GPR119 receptor or glucose-dependent insulinotropic receptor shows a relatively narrow expression pattern, being found predominantly in pancreatic and intestinal tissues. Endocannabinoids are considered potential GPR119 ligands, with OEA (Oleylethanolamine) being its main known ligand.

Its location in the β-cells of the pancreatic islets and the intestinal L-cellsof the enterocrines focuses attention on the possible involvement of GPR119 in the control of glucose homeostasis and obesity.

The expression of GPR119 in pancreatic islet β cells has hypothesized that this receptor could play a role in modulating insulin secretion.

GPR119 stimulation exerts a double effect in the reduction of glucose in the blood, acting directly on the pancreatic β cell promoting insulin release and, indirectly, through enteroendocrine cells, releasing incretins such as GLP-1 or others. anti-hyperglycemic agents.

Available data on the effects of GPR119 agonists in animal models indicate that they could be important agents for the treatment of type 2 diabetes and obesity.

GPR18 receiver

The GPR18 receptor, together with GPR55 and GPR119, is part of the orphan cannabinoid receptor subtype involved in endogenous lipid-mediated neurotransmission. Its antagonist ligands are 2-Araquidonyl-glycine (main ligand), Anandamide, THC, Arachidonylcyclopropylamide, O-1602, and both CBD and AM-251 as partial agonists. O-1918 acts as the antagonist.

Vanyloid receptors

TRPV receptors are part of the TRP receptor family consisting of 28 members grouped into seven subfamilies (TRPC1-7, TRPM1-8, TRPV1-6, TRPA1, TRPP1-3, TRPML1-3 and TRPN). Of this group of receptors with TRPV alone, cannabinoid-mediated agonism or antagonism has been described. It is a family of ion channels that modulate the flow of ions through the cell membrane, thus influencing the conductivity of nerve impulses and the transmission, modulation and integration of harmful stimuli.

Receptores TRPV

Its distribution pattern in the human body is very wide, being present in practically all tissues, but especially in the central and peripheral nervous system. They are mediators of a wide variety of cellular functions such as the initiation of pain, thermoregulation, salivary secretion, inflammation, the tone of smooth muscles and homeostasis of calcium and magnesium, among others.

Currently, these receptors and their interrelation with the SEC are being investigated in order to develop new therapeutic targets aimed at analgesic treatment.

Physiological actions of cannabinoids

Physiological actions of cannabinoidsIn recent years, knowledge about cannabinoids and their relationships with different physiological systems has increased significantly. The endocannabinoid system can be described as a modulator system that influences three basic systems of physiological regulation: the neurotransmitter system, the immune system, and the endocrine system.

1) Regulation of neuronal plasticity

Cannabinoids are synthesized at the level of the postsynaptic neuron, are released into the synaptic cleft, pass through it, and bind to receptors located on the presynaptic neuron to perform its function (retrograde neurotransmitters). The activation of these receptors causes,through different intracellular signaling pathways and the modulation of ion channels, an inhibition of the release of excitatory and inhibitory neurotransmitters (GABA, Glutamate, Serotonin, Dopamine, Acetylcholine or Norepinephrine) in different regions of the brain.

2) Influence on the endocrine system

As in neurotransmission, the Endogenous Cannabinoid System (SCE) acts on the endocrine system in an inhibitory way, influencing the homeostasis of sex, thyroid, growth hormones and prolactin. An inhibitory modulating role of the hypothalamic-pituitary-adrenal axis of the SCE has been observed, showing that, at baseline, there is an inhibitory endocannabinoid tone that decreases ACTH and Glucocorticoid secretion. In this way, it inhibits axis activation against a stressful stimulus.

3) Involvement in metabolism and energy balance

Several studies demonstrate the relationship between hypothalamic CB1receptor activation and appetite regulation in mesolimbic areas [81]. The levels of endocannabinoids AEA and 2-AG increase in fasting situations and are under the influence of diet (AEA increases in diets rich in polyunsaturated fatty acids). On the other hand, endocannabinoids promote gluconeogenesis and fatty acid synthesis in peripheral tissues.

Exogenous Cannabinoid

The cannabis plant varieties contain around 500 different chemical compounds, of which approximately 100 are part of the family of phytocannabinoids. The most studied from a therapeutic point of view are Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), althoughthere are more and more studies showing the potential medical interest of other cannabinoids such as Cannabinol (CBN), Tetrahydrocannabivarine (THCV) or Cannabigerol (CBG).

⇒ The cannabis plant contains approx. 500 chemical compounds

⇒ > 100 of the different compounds are Cannabinoids

⇒ In the plant, Cannabinoids are found in their acid form → they require decarboxylation (application of heat) to transform into their active form

In addition to the cannabinoids contained in the plant, there are other chemical compounds with therapeutic potential, especially terpenes, which are attributed part of the organoleptic properties of cannabis. Other families of compounds of the cannabis plant such as flavonoids, alkaloids, phytosterols etc. That have practically not been studied yet

The presence of such a high amount of different compounds can be a source of possible pharmacological interactions between the constituents themselves, both synergistically and antagonistically. Studying these interactions, it has been observed that, in terms of efficacy and tolerability, the results of treatments with whole plant preparations have been more promising versus the use of isolated cannabinoids.

The main Phytocannabinoids

The most abundant phytocannabinoids present in the Cannabis plant aredelta-9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabinolic acid (CBNA), followed by cannabigerolic acid (CBGA), cannabichromanic acid ( CBCA) and cannabinodiolic acid (CBNDA).

1) THC: Delta-9-tetrahydrocannabinol

THC is the most abundant cannabinoid in most Cannabis strains and the one with the most powerful psychoactive effect. It is a partial agonist of the CB1 and CB2 cannabinoid receptors (with a more powerful effect on CB1), exerting an analgesic, anti-inflammatory, antiemetic, orexygen, antitumor, antiepileptic, antispastic and spasmolytic effect. Current studies have shown that, in addition to its effect on CB1 and CB2, THC acts on GPR55 receptors (low dose agonist and high dose antagonist) and on TRPV1-5 receptors, thus influencing thermoregulation nociception, salivary secretion, smooth muscle tone, heart rate and calcium and magnesium homeostasis.

2) CBD: Cannabidiol

CBD acts primarily as an agonist for 5HT1A receptors (predominant in the central nervous system, as well as in neuronal tissues of the digestive and cardiovascular systems), lowering blood pressure and heart rate by a central mechanism, by inducing peripheral vasodilation and by stimulating the vagus nerve.

The most important therapeutic effects are given by its anxiolytic, analgesic, antiemetic, antiepileptic, antitumor, antioxidant, anti-inflammatory, antipsychotic, immunomodulatory, antibacterial and antifungal, neuroprotective, antirheumatic and sleep-inducing properties. A synergistic effect of CBD is its ability to modulate the action of THC, increasing bioavailability and reducing its side effects.

3) CBN: Cannabinol

Cannabinol is a breakdown product of THC that acts as a partial agonist on CB1 and CB2. Its affinity is lower for CB1 and higher for CB2 with respect to THC. Mouse models have been able to demonstrate a muscle relaxing, sleep inducing and anticonvulsant effect. Other properties attributed to Cannabinol, based on studies with laboratory animals, are a certain antibacterial effect, appetite stimulator and reducer of intraocular pressure.

4) THCV: Tetrahydrocannabivarine

THCV acts as an antagonist at CB1 receptors and as a partial agonist at CB2 receptors. Recent studies have shown an involvement of THCV in lipid metabolism and homeostasis, a suppressive effect on hunger, and an effect on Leptin secretion and Insulin secretagogues. These properties could be of great interest in diseases such as metabolic syndrome, carbohydrate intolerance or in some types of diabetes.

5) CBG: Cannabigerol

CBG is the first cannabinoid synthesized by the plant and is the biochemical precursor to the other cannabinoids. Its function exerts on CB1 receptors (mild antagonist), 5HT1A receptors (antagonist), alpha-2 adrenergic receptors and CB2 (both agonists). The therapeutic effect of CBG is given by its properties as antibacterial and antibiotic, muscle relaxant, antidepressant, anti-inflammatory, analgesic, reducing intraocular pressure and certain antitumor and antimetastatic effects are attributed to it.

6) CBC: Cannabichromene

CBC does not act on CB1 and CB2 receptors, the signaling pathway by which it performs its function is still unknown. In addition to possessing Gram (+), Gram (-), antifungal and anti-inflammatory antibacterial effects, it acts as an antidepressant and mood modulator and activates neurogenesis in hippocampal neurons involved in the area of learning and memory. Especially this last characteristic promises great potential in the treatment of CNS neurovegetative and neurodegenerative diseases.

Terpenes and Flavonoids

As part of the advances in research on the cannabis plant and its therapeutic use, more and more active ingredients are being found whose functions are still little studied. It has been shown that, at the same dose, the effects produced by the administration of pure cannabinoids are different from those produced by administration of extracts from the whole plant. These facts lead us to the conclusion that the cannabis plant contains other active ingredients with pharmacological action and that they act synergistically and / or asynergically with cannabinoids. The two groups found so far are terpenes and flavonoids.

Flavonoids are natural pigments derived from phenylpropanoids present in vegetables. Its functions in the plant kingdom are both the attraction of pollinators and symbiotes and the protection against excess UV light, environmental contamination and certain microbes or herbivores. In vitro studies attribute numerous therapeutic properties such as antioxidants, anti-inflammatory and anti-allergy, among others.

Terpenes are organic compounds derived from isoprene (hydrocarbon of 5 C atoms) that originate from the enzymatic polymerization of two or more isoprene units (Monoterpenes binding of two isoprene molecules, Sesquiterpenes binding of three, etc.).

Myrcene

Myrcene, or Beta-myrcene, is one of the most abundant terpenes in nature, being present in hops, lemon and myrcia, among others. In cannabis plants it is mainly present in indica varieties. Its main therapeutic effects are:

– Sedative, hypnotic and muscle relaxing effect

– Analgesic effect

– Anti-inflammatory effect

– Anti-tumor effect

Pinene

With the name Pineno it refers to two isomeric bicyclic monoterpenes: Alpha pinene and Beta-pinene. Therapeutic effects such as:

– Anti-inflammatory effect

– Bronchodilator effect

– Antibacterial effect

Limonene

Limonene is present especially on the skin of lemons and other citrus. In addition to its own therapeutic effects, it facilitates the absorption of other terpenes, thus enhancing its effects. Its therapeutic properties are:

– Antibacterial effect

– Anti-tumor effect

– Antidepressant and anxiolytic effect

Caryophyllene

As Caryophyllene we mean the mixture of 3 compounds: Alpha-caryophyllene, Beta-caryophyllene and Caryophylene oxide. All components are present in the cannabis plant, with Caryophyllene Oxidebeing the substance detected by police dogs trained to find cannabis. In addition to cannabis, they are also present in hops, cloves and black pepper, among others. Its therapeutic properties are:

– Antifungal effect

– Gastric cytoprotective effect

– Anti-inflammatory effect

Synthetic Cannabinoids

The first synthetic cannabinoids were developed in order to explore and understand the pathways of the endogenous cannabinoid system. So far,more than 120 substances with different degrees of affinity for CB1 and CB2 receptors have been created, but with stronger pharmacological effects than THC.

Most belong to the group of indoles, with only a few being structurally related to THC. Some of the synthetic cannabinoids, such as Dronabinol and Nabilone, are being used in the medical field for their orexigenic properties to treat nausea and vomiting caused by treatment with chemotherapy or in cases of anorexia caused by immunodeficiencies.

CANNABINOIDS IN CLINICAL PRACTICE

The therapeutic effect of a cannabis variety is determined by the percentage of cannabinoids, terpenes, flavonoids and other active substances that we find in the different species of the plant.

Terpenes modulate and complement the effects of cannabinoids, as well as providing the flavor and smell of each variety.

Cannabinoids are chemically terpenophenols, so it is predictable that terpenes themselves act in the same way as cannabinoids; in some cases through receptors of the endocannabinoid system.

Terpenes and cannabinoids are volatile or semi-volatile substances, so their quantification is carried out by chromatography, a technique that serves to characterize compounds from a complex mixture. Currently, High Precision Liquid Column Chromatography, or HPLC, is the most accurate technique for quantifying cannabis components. The result of a chromatography indicates the quantity of each cannabinoid or terpene analyzed and is expressed as a percentage with respect to 100% of the total weight:

If we had, for example, 1g of plant material whose chromatography indicates 10% THC, we would know that this sample contains 100mg of THC, that is, in 100mg we would have 10mg, and so on.

Since the different cannabinoids and terpenes have different effects, knowing the amount of both components that the different varieties of the plant contain, we can use one or the other depending on the disease or symptoms presented by the patient.

In a way, this allows the treatment to be individualized, something that is not easy since the final effect of cannabis depends on multiple factors such as: body weight, previous exposure, metabolism and tolerance, among others.

Due to the variability in the percentages of different cannabinoids, when we use the whole plant or derivatives of it (and not isolated cannabinoids) it is difficult to have a regular supply of herbal product to follow the treatments. It is vitally important to use standardized and correctly analyzed products to know the exact percentage of cannabinoids and terpenes that we are administering to the patient. It is also important to control the possible presence of contaminants such as heavy metals, pesticides, fungicides, bacteria, fungi, etc. If the herbal material is properly analyzed, it can be precisely used and dosed for inhalation by vaporizer or for oral dissolution and administration, for example.

ROUTES OF ADMINISTRATION

The routes of administration of a drug should be used following certain

criteria to achieve painless administration, regular absorption and thus obtain the highest bioavailability of the product, in this case cannabinoids.

Oral – sublingual route

We can administer cannabinoids generally dissolved in olive or sunflower vegetable oil or, in some cases, in ethanol for sublingual or intraoral administration, through the mucosa of the oral cavity. Ethanol is a good solvent for cannabinoids, although for some patients its taste can be unpleasant, in addition to generating an oropharyngeal burning sensation.

The intraoral and sublingual mucosa allows advantages such as rapid absorption and good control of the amount administered, although it also entails some disadvantages such as variations in the bioavailability of the administered substances. It can take us about two weeks to stabilize a treatment in relation to the doses. Therefore, it is important to start with low doses, especially when using THC, until the minimum effective dose is found, especially if we use the oral route. Another problem is that the effect can take between half an hour and up to two hours after the shot. Variability depends on each individual and also on the time of day, food intake and individual activity.

Inhaled via vaporizer

In the case of cannabis, the route with the best bioavailability is undoubtedly the inhaled one, and the effect is quickly obtained. If a competent vaporizer is used, the path is clean, there is no combustion and, consequently, there are no toxic or carcinogenic substances derived from it. Currently there are competent vaporizers on the market that guarantee us precision in the vaporization temperature. This is important because, the more temperature range that can be selected, the better the plant is used and, in addition, it allows to select, in a certain way, the cannabinoids to inhale.

THC vaporizes at 157o-165oC and CBD at 178o-190oC. Therefore, if we inhale at 157oC, we are not in this case inhaling CBD, only THC, from which we can deduce that there will be more psychoactive effect and predominance of the effects produced by THC. If we want to get the most out of the plant to be able to inhale the greatest number and quantity of cannabinoids, terpenes, flavonoids, etc. We must work at about 200o-220oC, and checking that there is no combustion. In general, the terpenes of the cannabis plant vaporize in a range that goes from 156oC to 219oC, so we would put this figure as a maximum. Because the effect is very fast, the patient can assess after each inhalation whether the dose is sufficient. This fact helps to personalize the dosage of the treatment, which offers an important advantage when it comes to therapeutic use.

Transdermal or percutaneous route

Another route of application, which may be useful in some patients, is transdermal administration, that is, through the skin. Because cannabinoids dissolve well in fats, due to their lipophilic characteristics, they are absorbed efficiently to treat local pathologies without having to resort to other routes. It is easy to prepare creams for topical application that can be used both in chronic pathologies such as osteoarthritis, fibromyalgia, rheumatic diseases, and in acute pathologies such as sprains, contusions, arthritis, tendinitis, muscle pain, etc.

CBD-rich preparations have an anti-inflammatory and anti-proliferative effect, so they can be an effective tool in cases of psoriasis, hyperkeratotic dermatitis or dry eczema.

If we associate terpenes, such as Limonene, with cannabinoids, we can improve transdermal absorption, since this terpene has the function of facilitating the diffusion through the skin of other compounds, among other actions. Valuable blood levels are not detected after the topical application of cannabinoids, so it does not cause a psychoactive effect in the patient.

Rectally

Rectal absorption is variable and depends on various factors such as the amount of fecal content or the state of the rectal mucosa, among others. This route supposes that the drug skips the hepatic passage since it is absorbed by the middle and inferior hemorrhoidal veins, passing directly to the general circulation. By avoiding the hepatic passage, in the case of THC, the first metabolic step is decreased by hydroxylation to 11-hydroxy-THC (which has a psychoactive potency up to 4 times greater than THC), so this route would theoretically be an alternative to administer THC in high doses, minimizing its psychoactive effect.

The major disadvantage of this route of administration is given by the slow absorption due to the hydrophobicity of THC. To solve this problem, research is being carried out with pro-forms of THC bound to hemisuccinate that promise greater bioavailability than the oral route.

DOSING PRINCIPLES

The dosage of cannabinoids is based on calculating the amount to be administered per kilogram of weight. Depending on the products we use and their concentration, we can calculate the dose more or less accurately.

In general, CBD treatments are started for a variable period of time, depending on each case, and we will assess the joint use of THC in increasing doses until the desired effect is achieved. In this way, we can modulate the psychoactive effect of THC and minimize the tachycardia and anxiety that can be generated, especially at the beginning of treatment.

Regarding THC, doses of 0.5 to 4 mg / Kg / day are administered, managing the majority of pathologies in a range of 0.5 to 2 mg / Kg / day, with the exception of cancer patients, in whom dose in a range of 2 to 4 mg / Kg / day. It should be borne in mind that no clinical trial has been carried out so far that provides us with the exact doses, the treatment cycles or the most effective combinations between cannabinoids, so it is dosed in relation to the preclinical data available.

In the case of CBD, doses of 0.5 to X mg / Kg / day are administered, the maximum dose of CBD that has generated toxicity at the moment is not known. Most pathologies could be treated with doses in a range of 0.5 to 2 mg / Kg / day, and in patients with refractory epilepsy, up to 25 mg / Kg / day of pure CBD have been administered.

RECOMMENDATIONS FOR CLINICAL USE

The response to cannabinoid treatments is, in many cases, difficult to predict since their effectiveness depends on many factors, including being able to reach the necessary doses without the patient having side effects. Above all, when we use THC, we refer to the psychoactive effect (“high”).

If there are no contraindications, it is advisable to start CBD treatment, evaluating the effectiveness with the initial doses in about 10 days and considering whether or not to use joint THC, if necessary. The possibility of using THC or CBD as monotherapy or together, in one or the other ratio, must be evaluated in each case.

Another factor to take into account is if the patient has previously used cannabis in his life, since if he knows the psychoactive effect of THC, we can use higher initial doses than in the case of a non-consumer patient. In the case of chronic consumers it is difficult to calculate the doses since they can generate greater tolerance due to continued use.

Previous forecast

We have to assess the prognosis at the time of starting cannabinoid treatment since most patients access cannabis treatments at very advanced stages of their pathologies. We must also bear in mind that a good result, in many cases, can be a better quality of life for many patients.

We have to offer reasonable expectations since cannabinoid treatments have their therapeutic limitations.

Tolerance

We know that chronic cannabis users require increasingly higher THC doses to achieve the same effect. We refer to this phenomenon as tolerance. CBD does not seem to generate the same problem, since, in clinical practice, maintained doses generate the same effect without the need to increase them.

Active consumer

Patients who have previously used cannabis know its effects and may or may not have had positive experiences, so we have to be especially careful with patients who have had bad experiences with cannabis and the psychoactive effect.

In chronic consumers it is very difficult to dose since tolerance to THC is generated due to its continued use.

Cannabinoid ratios

The patient must tolerate the treatment well, without presenting a psychoactive effect and generating a comfort area that reasonably meets his expectations depending on the pathology we are treating.

As long as we work with ratios close to 1/1 we will minimize the psychoactive effect of THC; if we increase THC, the psychoactive effect increases by exceeding the amount of CBD.

Rescate

Whole plant vaporization is a very interesting resource since it gives us an almost immediate effect. Furthermore, if the plant is analyzed we can, by weighing it, prepare the doses with acceptable precision. A patient who is taking a prescribed treatment with THC and CBD, orally, for example, can vaporize as a rescue on demand, since, noticing the effect quickly, he can dose as needed more or less effect.

PHARMACOLOGICAL INTERACTIONS

As with any drug, knowledge of the metabolic pathways of both cannabis and the drugs in use is crucial to make a correct prescription and offer a treatment adapted to each patient.

Cannabinoids inhibit cytochrome P450 (CYP), a huge and diverse family of hemoproteins that constitutes one of the most important enzyme systems for the metabolism of endogenous and xenobiotic substances. Specifically, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, are responsible for the metabolism of more than 60% of the drugs in clinical use today.

So far, no serious case of drug-cannabinoid interaction has been found that has reached the properly documented medical literature, which in no case should relax the use of cannabinoids and other drugs without previously ruling out possible interactions derived from their joint use.

Drug interactions

Although no case of serious drug interaction related to the use of cannabinoids is known so far, it is known that they can interfere with the metabolism of numerous drugs due to their ability to inhibit cytochrome P450 (CYP450), especially affecting the CYP3A4 and CYP2C19.

Cannabinoids and inhibitors

Cytochrome inhibitors block one or more CYP450 subtypes, thus slowing down the metabolism of their substrates, causing an increase in the drug available in the blood and, in turn, a high risk of side effects and overdose. This reaction is especially important when CYP inhibitors are given together with drugs whose metabolism depends on a single enzyme or which have a narrow therapeutic window.

Cannabinoids and inductors

CYP450 inducers increase the metabolic activity of the enzyme complex by increasing the synthesis of the enzyme. Unlike the action of inhibitors, the increase in activity appears with a variable delay (up to days) depending on the half-life of the inducing drug. As mentioned in the previous section, attention must be paid when administering inducers together with drugs whose metabolism depends on a single enzyme or which have a very narrow therapeutic window. In the case of administration of prodrugs, it is crucial to monitor blood concentrations since the inducing drug can significantly increase the transformation from prodrug to drug, thereby increasing the risk of adverse reactions and signs of overdose.

In conclusion, it can be said that the drug interactions related to the modification of cytochrome activity are not exclusive to the use of cannabinoids, but to the majority of drugs that we use on a daily basis. Doctors and healthcare professionals should pay attention when prescribing both cannabinoids and any other medicine that inhibits / induces CYP450. Taking into account the metabolism of different drugs and adjusting the dose, only in special cases will it be necessary to replace a prescribed drug when introducing cannabinoids to treatment.

Cannabinoids and opiates

Chronic pain is one of the conditions most recognized as susceptible to being treated with cannabinoids. Cannabinoids and opiates influence nociception at the level of the posterior horn of the spinal cord, enhancing the effects of both. By blocking CYP complexes (especially CYP2D6 and CYP3A4), which are important for opioid metabolism, cannabinoids can increase blood concentrations of opioids, potentiating their side effects such as drowsiness, constipation, hypotension and depression. respiratory, among others. Drugs or substances that use or inhibit CYP enzyme pathways can also potentiate and prolong the effects of opioids such as Hydrocodone and Oxycodone.

Cannabinoids and chemotherapy drugs

In the administration of cannabinoids to patients undergoing chemotherapy, it is crucial to pay attention to possible interactions, since the high toxicity of chemotherapeutic agents requires very precise dosing to avoid reaching their toxic range. Despite being one of the classic and proven indications for the therapeutic use of cannabis, it is still unknown at what level cannabinoids initiate the inhibitory effect at the liver level, although no serious case has been reported so far as a direct consequence of its use concomitant. Another aspect to consider is the use of different doses of THC and CBD depending on whether the intention of the treatment is palliative, treating the symptoms (nausea, vomiting, associated pain, etc.) or if the intention is to “try” to reach an antitumor range ( something that, according to the current state of research, is only verified in cultures of human cells or laboratory animals).

Cannabinoids and antiepileptics

n the specific case of treatment of refractory epilepsies with CBD, as in the combined treatment with opioid analgesics, interactions between CBD and antiepileptics may appear, causing an increase in the level of the drug in the blood and, thus, a possible appearance of side effects from the overdose resulting from the antiepileptic.

The list of antiepileptics whose metabolism depends on CYP complexes is long and includes, among others: Phenytoin (CYP2C19), Clobazam, Valproate (CYP inhibitor), Etosuximide, Lamotrigine, Topiramate, Tiagabine (CYP3A), Oxcarbamazepine (inhibits CYP2C19 and induces CYP3 ), Zonisamide (CYP3A4), Felbamate (CYP3A4 and CYP2E1), Peranpanel, etc.

Cannabinoids and anticoagulants

In 2017, a case report was published on the possible drug interactions between CBD and Warfarin, a vitamin K-dependent oral anticoagulant. Due to its narrow therapeutic range, and its inter-individual variability in dosage, Warfarin requires episodic INR monitoring to maintain an appropriate anticoagulant effect. The anticoagulant is composed of 2 stereoisomers that are both metabolized by CYP450 (S-stereoisomer by CYP2C9 and stereoisomer-R by CYP3A4, mainly), which causes any change in the activity of these enzymes to cause changes in plasma levels of the drug.

Cannabinoids and other drugs

In modern medicine, a combination of Cannabis with other medications could also be beneficial for different therapeutic indications. Cannabis has been used illegally by individuals suffering from various diseases and, in conjunction with a large number of prescribed medications. No clinically significant unwanted side effects have been observed to date.

Some medications can enhance or decrease the effect of Cannabis and / or THC, while the effects of certain drugs may be increased or decreased by the action of cannabinoids. We will put some examples:

Anandamida Gardens publishes these contents for educational purposes, therefore, they do not represent any therapeutic recommendation for any person, for which the follow-up of their indications is of individual responsibility along with the guidance of a health professional, and not the creator of this content.