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Introduction
On June 19, 2017, in the Official Gazette of the Federation, reforms and additions were published regarding the use of tetrahydrocannabinol (THC), as well as isomers and stereochemical variants, pharmacological derivatives of Cannabis sativa, indica and Americana (hereinafter marijuana). The controversy that has developed in the political and academic sphere, as well as the concerns that have arisen in the population in relation to known and poorly-known effects of the use of marijuana, have allowed the writing of this work. Herein, a review is made of reported therapeutic applications with the use of cannabis derivatives, emphasizing on the role cannabinoids play, and thereby contributing to the understanding of the probable therapeutic use of this plant and its derivatives.1
The cannabis plant
The cannabis plant is a term that groups the genus Cannabis, which comprises the Cannabis Sativa, Cannabis Indica, Cannabis Americana and Cannabis ruderalis plants. In general, cannabis is known as marijuana and has at least a bit more than 100 different synonyms; Table 1 presents some.1
Table 1 Marijuana synonyms
| Aceite (oil) | Alfalfa | Chora | Coffe | Chabela | Chíchara | Chipiturca |
|---|---|---|---|---|---|---|
| Churro (joint) | Churro de la buena (joint of the good stuff) | De la verde (of the green stuff) | Diosa verde (green goddess) | Doña diablo | Dama de la ardiente cabellera (lady with the burning hair) | Flor de Juana (Juana flower) |
| Goma (gum) | Grifa | Grilla | Güera (blond) | Hierba (grass) | Join | Juana |
| Juanita | Mala hierba (bad grass) | María | Mari | Mariana | Mary Poppins | Mois |
| Mora | Mota | Motivosa | Motocicleta (motorcycle) | Mole | Mostaza (mustard) | Nena (baby) |
| Nalga de ángel (angels buttock) | Orégano (oregan) | Orégano chino (Chinese oregan) | Oro verde (green gold) | Pasto (grass) | Petate (palm straw) | Pachola |
| Pepita verde (green nugget) | Porro (joint) | Soñadora (dreamer) | Tónico (tonic) | Tostada (toast) | Tronadora (thundering) | Trueno verde (green thunder) |
| Verdolaga (purslane) | Yerbabuena (spearmint) | Yerba de oro (golden grass) | Yerba del diablo (grass of the devil) | Yerba santa (holy grass) | Yesca (tinder) | Zacate (grass) |
García-Robles J. Antología del vicio. Aventuras y desventuras de la mariguana en México. Mexico: Laberinto; 2016.1
Worldwide prevalence of marijuana consumption is estimated to be 3.8 %, which means there are approximately 183.3 million users. One of the central problems is the consumption of marijuana by individuals under 18 years of age. In 23 member countries, the Organization for Economic Cooperation and Development has estimated that 9.3 % of 15-year-old men used marijuana in the previous 30 days, as well as 6.3 % of women of the same age.2,3 In Mexico, the prevalence of marijuana use once in life in the population of 12 to 65 years of age is 8.6 %, 2.1 % in the previous year (1.8 million are estimated in that age group) and 1.2 % in the previous month. In the population aged 12 to 17, 5.3 % reported having consumed marijuana.4 In a sample of secondary and high school students in Mexico, a prevalence has been reported of marijuana use sometime of 10.6 %, 12.9 % by males and 8.4 % by females.5
Cannabis, specifically the sativa species, is an herbaceous plant that grows spontaneously in tropical and subtropical regions and contains between 400 and 537 chemical components and nearly 100 cannabinoids.6,7 It is difficult to pinpoint the moment any Cannabis sativa preparation started being used. Its origin is located in Central Asia and its use has been described in the Chinese pharmacopoeia as part of traditional medicine. It was an Iranian physician, Sir William B. OShaughnessy, a Calcutta resident, who for the first time scientifically assessed the therapeutic value of the plant; he published his findings in the early 19th century.8,9
The use of its compounds throughout history has shown variants, as it occurs with the healing properties associated with its consumption, within the existing medical knowledge framework of every era. The effects it produces, mainly on the brain, were associated with religious practices. Currently, its consumption is widely spread all over the world, without having any relationship with religious aspects as in the past. Its main use, due its psychotropic effects, is ludic, although therapeutic properties are associated.10-13
The actions that have been developed for marijuana legal consumption have been diverse and include its growth, marketing and use. Several legal changes have been made in relation with cannabis personal possession and consumption, such as possession and consumption legalization and decriminalization. Table 2 shows the various provisions that have been adopted in some countries of the European Union.14
Table 2 Legal status of the use and consumption of marijuana in countries of the European Union
| Country | Legal situation | Regulatory law | Amount of drug allowed |
|---|---|---|---|
| Germany | Use and possession for personal consumption | BtMG Law | 6 g of marijuana and up to 0.5 g of heroin and cocaine. |
| Spain | Use and possession for personal consumption | Organic law 1/1992 | Marijuana: 25 g of resin and 200 g of grass; 7.5 g of cocaine, 2.4 g ecstasy and 3 g of heroin. |
| Portugal | Legalization and decriminalization | 30/2000 law | 25 g of marijuana, 5 g of cannabis resin, 2 g of cocaine, 1 g of heroin, 1 g of ecstasy. |
| Finland | Use and possession for personal consumption | Law ss. 3, 27 | 1 plant or 3 g of cannabis or cannabis resin for personal consumption. |
| Italy | Use and possession for personal consumption | Fini law | 500 mg marijuana, 250 mg of heroin, 750 mg of cocaine. |
| Belgium | Administrative sanctions, misdemeanor | Col. 2/2005 | 1 plant or 3 g of cannabis or resin for personal consumption. |
| Czech Republic | Administrative sanctions, misdemeanor | Offense act 30/1/j/law 40/2009 | 15 g of marijuana, 1.5 g of heroin, 1 g of cocaine, 2 g of methamphetamine, 5 ecstasy pills. |
| The Netherlands | Legalization and decriminalization | Opiumwet Opium Law | No amount limit for self-consumption. |
European Monitoring Centre for Drugs and Drug Addiction. The state of the drugs problem in Europe. Luxemburg: European Monitoring Centre for Drugs and Drug Addiction; 2011.14
In Mexico, on June 19, 2017, in the Official Gazette of the Federation, reforms and additions were published with regard to the use of THC, as well as isomers, stereochemical variants and pharmacological derivatives of Cannabis sativa, indica and Americana (marijuana). Article 235 Bis of the General Statute of Health states that [.] the Ministry of Health shall design and implement public policies that regulate the medicinal use of Cannabis sativa, indica and Americana, or marijuana, pharmacological derivatives, including THC, its isomers and stereochemical variants, as well as to regulate research and domestic production thereof.15
Cannabinoids
In the study and research of cannabinoids and their pharmacological properties, at least three stages are recognized:
Research on Cannabis, encompassing from its description in the Chinese pharmacopoeia, circa year 200, until the decade of 1940, where cannabidol synthesis by Adams stands out (1940).
The second stage, which focuses on cannabinoid research and goes from the Adams report until 1993, the year in which Munroe reports the finding of the clone CB2 receptor.
The last stage, whose emphasis is on research on endocannabinoids, where the report of enzymes that biosynthesize endocannabinoids and the launch onto the market of some synthetic cannabinoids such as Sativex® stand out.
The first Cannabis sativa isolated cannabinoid was cannabis resin cannabinol (Wood, Spivey and Easterfield, 1899); however, its structure was characterized several years later (Adams, Baker and Wearn, 1940). Cannabidiol was isolated a few years later (Adams, Hunt and Clar, 1940) and was subsequently characterized by Mechoulam and Shvo.16
In the 1940s and 1950s, research around cannabinoids increased, so that compounds with cannabinomimetic activity were synthesized, among which Δ6α, 10α-THC hexyl (pirhexyl or sinhexyl) stands out. Subsequently this compound was documented to differ from THC only in a double bond between 6α and 10α and in that it has an N-hexyl in the side chain, instead of N-pentyl.17
In this context of the development of research on cannabis derivatives, it has been established that this plant has psychotropic and therapeutic effects mediated by cannabinoids. Out of these, three main types stand out:
Phytocannabinoids, directly extracted from Cannabis sativa and Cannabis Indica, which possess cannabinoids with psychotropic effect such as delta-9-tetrahydrocannabinol (Δ9-THC) and others without psychotropic effects but with some potential therapeutic effect.
Endocannabinoids, which are synthesized in the brain or peripheral tissues and act on cannabinoid receptors.
Synthetic cannabinoids, synthesized in laboratories with a similar structure to that of phytocannabinoids and endocannabinoids and that act through similar biological mechanisms.18
The identified cannabinoids have been classified in 10 subclasses according to their chemical structure:19
Endocannabinoid system
To understand the physiological and pharmacokinetic effects of any of the three types of cannabinoids, the cannabinoid system or endogenous cannabinoid system has to be understood, which is a complex endogenous signaling system constituted by four elements:
CB1 and CB2 cannabinoid receptors coupled to G-proteins.
Endogenous endocannabinoids that target these and possibly other receptors.
Enzymes that catalyze endocannabinoid biosynthesis and metabolism.
Specific mechanisms involved in accumulation of specific endocannabinoid cells.
The most widely investigated are cannabinoid receptors CB1 and CB2, located in the neuronal cell membrane, especially at presynaptic terminals.20
Currently, a broad definition of the endogenous cannabinoid system is being used, and using the term endocannabinoid-like mediators is preferred.21,22
Cannabinoid receptors CB1 and CB2 are differentiated by the way they transmit the signal and by their distribution in different tissues. Cannabinoid receptors activation results in adenylatocyclase inhibition, which prevents the conversion of ATP to cyclic AMP; on the other hand, their interaction with some ionic channels activity has been demonstrated. Both CB1 and CB2 belong to the broad family of protein G-coupled receptors.21 CB1 receptor activation results in effects on memory processing, mood, sleep, motor regulation, appetite and pain sensation, while CB2 activation does not produce said effects. CB1s are mainly found in the cortex, spinal cord and peripheral nervous system neurons, although they are also present in certain peripheral organs and tissues, such as endocrine glands, salivary glands, leukocytes, spleen, the heart and in certain areas of the reproductive, urinary and gastrointestinal systems.22
There are CB1 receptors in both central and peripheral nerve terminals, which inhibit the release of some neurotransmitters. Thus, CB1 receptors activation protects the nervous system against over-activation or over-inhibition elicited by neurotransmitters. CB1 receptors are found in the regions of the brain responsible for movement (basal ganglia, cerebellum), memory processing (hippocampus, cerebral cortex) and pain modulation (certain parts of the spinal cord, periaqueductal grey), while their presence in the brainstem is low, which may explain the absence of adverse effects at this level as a result from cannabis use. The brainstem, among other functions, controls breathing and circulation. CB2 receptors are mainly found in immune cells, including leukocytes, the spleen and tonsils.23
One of CB receptors functions in the immune system is modulation of the release of cytokines, which are responsible for inflammation and immune system regulation. Since the compounds that selectively activate CB2 receptors (CB2 receptor agonists) do not cause psychological effects, they are increasingly becoming the target of investigation of cannabinoids therapeutic applications as analgesics, anti-inflammatory and antineoplastic agents. In fact, there is evidence of the existence of cannabinoid sub-receptors, such as GPR 55, and the orphan receptors coupled to a G-protein. Other receptors may be only functionally related to the well-known cannabinoid receptors, with a similar structure to that of CB1 and CB2.22
After cannabinoid receptors were identified, their endogenous ligands, known as endocannabinoids, were discovered. In the brain, they act as neuromodulators. Endocannabinoids so far identified include anandamide (N-arachidonoyl-ethanolamide), 2-arachidonoyl-glycerol, 2-arachidonyl-glyceryl ether (noladin ether), O-arachidonoyl-ethanolamine (virodhamine) and N-arachidonoyl-dopamine.23
Anandamide and N-arachidonoyl-dopamine not bind to cannabinoid receptors, but also share the ability of capsaicin, a component of hot peppers, to activate vanilloid receptors. Endocannabioid signaling is characterized because these molecules are not synthesized or stored in nervous cells, but are generated from their precursors and released on demand.24
Affinity for cannabinoid receptors
Cannabinoids show different degree of affinity for CB1 and CB2 receptors. Synthetic cannabinoids have been developed that act as agonists or selective antagonists for either receptor. Δ9-THC has about the same affinity for both CB1 and CB2 receptors, while anandamide has very low selectivity for CB1; THC and anandamide effectiveness is lower in CB2 than in CB1 receptors.25 Although most physiological actions of cannabinoids (behavioral, memory, euphoria, immobility, analgesia, hypothermia, sedation effects) are attributed to their action on CB1 and CB2 receptors, pharmacological studies and in CB1 or CB2-knockout animals reveal other possible sites of action for these compounds, both in the central nervous system and the periphery.26
Work is currently underway on the development of synthetic endocannabinoid analogues without the CB1 and CB2-activation side effects, which trigger a therapeutic effect or recreational effect.27
Endocannabinoid system tonic activity
Endocannabinoids can behave as reverse agonists; they act when, in physiological conditions, the cannabinoid receptor is active without being bound to its direct agonist; the moment the reverse agonist binds to that receptor, it inactivates it and thus hampers its function. This way, sometimes, and only with a certain type of receptors, they can produce increased sensitivity to pain and trigger nausea, for example.28 This tonic activity may be due to endocannabinoids constant release or to the fact that part of cannabinoid receptors are naturally in an activated state. Endocannabinoid levels have also been observed to be higher in areas of the brain associated with pain (periaqueductal grey).29
Tonic control of spasticity by the endocannabinoid system is lost, for example, in cases of relapsing chronic experimental autoimmune encephalomyelitis in mice, a classic experimentation model in multiple sclerosis. The number of cannabinoid receptors has also been shown to be increased in models of chronic neuralgia due to neuronal damage in mice, as well as in models of intestinal inflammation. The same has been shown in terms of appetite control and vomiting in the emetic circuits of the brain.30
Δ9-THC is cannabis most pharmacologically active phytocannabinoid and has a psychotropic effect that generates addiction, both in its herbal form (marijuana or raw cannabis) and in the modality resin (hashish). THC was characterized in the 1960s (Gaoni and Mechoulam, 1964), which opened the door to scientific investigation on marijuanas biological and medical properties and served as the basis for the development of derivatives with therapeutic activity, where separating pharmacological from psychoactive properties was attempted.
THC pharmacological effects depend on activation, as direct agonists, of its specific receivers, both in humans and in laboratory animals, whereas its antagonists can block specific receptor activity (passive antagonism) or produce the opposite effect (active antagonism).31,32
Medicinal use of cannabis and its derivatives
In recent years, studies have been carried out on the usefulness of cannabis derivatives in several diseases. By means of controlled clinical trials, the role of these derivatives in spasticity has been investigated in multiple sclerosis and medullary lesions, chronic pain, essentially neuropathic, movement disorders (Gilles de Latourette, dystonia, levodopa-induced dyskinesia), asthma and glaucoma.33 With non-controlled clinical trials, their effect on Alzheimers disease, its role in neuroprotection, singultus or intractable hiccups, epilepsy, alcohol and opioid dependence and inflammatory processes have been assessed. Most studies have been carried out with approved and marketed synthetic substances; however, in most cases, cannabis has shown evidence of lower biological strength.34
Chronic pain is the reason for cannabis medicinal use most commonly declared by patients. It accounts for 90 % of medicinal cannabis authorizations in Europe and the United States.35 The use of cannabis can block nerve impulse transmission at different levels (peripheral neurons, spinal cord and brain). Cannabinoids have shown efficacy in some specific types of chronic pain, such as neuropathic pain associated with human immunodeficiency virus infection, spinal cord injuries, multiple sclerosis and pain of cancer origin; however, cannabinoids are not first-choice drugs in the treatment of chronic pain. They are considered third and fourth-line in the treatment of neuropathic pain.36
Neurological diseases, as well as psychiatric and oncological conditions, have justified cannabis acceptance for medicinal use in several countries around the world. Some cannabinoids have been approved; however, due to the lack of scientific evidence on safety or efficacy, others have not been approved. They can be topically administered, by using vaporizers or ingested as food or oil; the latter method is mainly used in children with epilepsy and other conditions.37
Cannabinoid medicinal use
With the evidence that has been published, different regulatory agencies of the world have approved drugs that act on cannabinoid receptors for human use.36
In 2005, a pharmacological mixture was approved in Canada, composed of THC and cannabidiol, for use in neuropathic pain in multiple sclerosis and, more recently, in pain caused by cancer.
On the other hand, dronabinol, a synthetic form of THC, was approved by the Food and Drug Administration in 1986 and, therefore, marketed in the United States for the treatment of nausea and vomiting caused by chemotherapy and anorexia-cachexia syndrome (extreme thinness and lack of appetite) associated with acquired immunodeficiency syndrome. In addition, it has also been used in the control of certain types of pain, since it enhances morphine derivatives analgesic effect.38
On July 31, 2013, with 50 votes in favor, 46 against and three absences, in Uruguays Chamber of Deputies, the draft to legalize marijuana sale and self-cultivation was approved. On Tuesday, December 10, 2013, the Uruguayan Senate passed the 19/172 law, which was finally enacted by the executive branch on Tuesday, December 24, 2013, in Montevideo, Republic of Uruguay.39 Regulations in different places have their differences for possession, consumption, cultivation and marketing (Table 3).40
Table 3 Comparison of the first three jurisdictions in the world that legally regulate the use of marijuana: Colorado, Washington and Uruguay
| Item | Colorado | Washington | Uruguay |
|---|---|---|---|
| Level of law | State constitution, laws and regulations | State law and regulations. | National Law and Executive Order |
| Regulatory agency | Colorado Department of Revenue | Washingston State Liquor Board (LCB) | Institute for the Regulation and Control Cannabis (a public, non-state entity) |
| Definition of marijuana | All parts of plant, seed, resin extracted from any part of the plant, and every compound, manufacture, salt, derivative, mixture or preparation of the plant, its seeds or its resin, including marijuana concentrate, which is cultivated, manufactured, distributed or sold by a certified or licensed retail marijuana establishment. Does not include industrial hemp or the weight of any another ingredient combined with marijuana to prepare topical or oral administrations, food, drink or other product. | All parts of the plant with a THC concentration greater than 0.3% on a dry weight basis; the seeds thereof; the resin extracted from any part of the plant and every compound, manufacture, salt, derivative, mixture or preparation of the plant, its seeds or resin. | Flowering tops with or without the fruit of the female cannabis plant, except the seeds and leaves separated from the stem, including the oils, extracts, preparations for potential pharmaceutical use, syrups and the like, to which the natural tetrahydrocannabinol content is equal to or more than 1% of its volume. |
| Quantity for personal possession | 1 ounce (28.5 g). | 1 ounce (28.5 g). | 40 g (1.4 ounces). |
| Domestic cultivation for personal consumption | 6 plants, with 3 in flower and possession of the marijuana produced by plants at the cultivation site | None | Up to 6 flowering plants per household with a maximum production quantity of 480 g per year. |
| Minimum age | 21 | 21 | 18 |
| Retail transaction limitation | 1 ounce (28.5 g) of marijuana or its equivalent in retail marijuana product to Colorado residents. Up to a quarter of that amount for out of state residents. | 1 ounce (28.5 g) usable marijuana, 16 ounces of marijuana-infused product in solid form, 7 g of marijuana-infused extract for inhalation and 72 ounces of marijuana-infused product in liquid form | 40 g (1.4 ounces) of marijuana per month. |
| Residency requirements | For its purchase, see above. For obtaining a license, a minimum of 2 years residence is required. | None for purchasing. For obtaining a license, a minimum of 3 months residence is required. | For purchasing, domestic cultivation and membership in cannabis clubs, Uruguayan legal or naturalized citizenship or permanent Uruguayan residency is required. None specified for licenses. |
| User registry for non-medical purposes | None. | None. | Registration with the Institute of Regulation and Control of Cannabis is required for purchase in pharmacies, domestic cultivation or membership in cannabis clubs. |
| Consumption in public spaces | No open and public consumption. Smoke free zones included. Drug petty offense of USD $ 100 and fine 24 hours community service. | Unlawful to use marijuana in view of general public. USD $ 50 civil fine. | Consumption in the public spaces is with the exception of closed public spaces, workplaces, public transportation, educational centers, health establishments or sports institutions |
| Driving under the influence of marijuana | New THC 5 ng/mL blood per se driving under the influence of drugs (DUID) creates a rebuttable presumption. | New THC 5 ng/mL blood per se DUID. | Zero tolerance. |
| Outdoor commercial cultivation | Allowed | Allowed | Allowed for those registered for domestic cultivation, cannabis clubs or authorized producers. |
| Commercial cultivation | Licensed marijuana cultivation facilities. | Licensed marijuana products. | Licensed marijuana producers. |
| Commercial retail outlets. | Licensed retail marijuana store. | Licensed dealer. | Licensed pharmacies. |
| Market integration | Allowed. | Prohibited. | Allowed by the law, but not implemented. |
| Taxes | 15 % excise tax from cultivation to processing or retail. 10% excise tax on sale, in addition to any existing local or state sales tax. | 25% excise tax at each stage of sales (producer to processor to retailer to customer). | Taxed by Value Added Tax under a VAT suspension regime, allowing the producers to deduct VAT from their purchases and preventing the transfer of the tax to the final price. There is no tax on agricultural assets. |
| Production and distribution limits. | As of September 2014, establishments must grow at least 70% of the marijuana they sell and sell no more than 30% of what they grow to other outlets. | Producers, processors and retailers are limited to 3 licenses, no more allowed to hold more than 33% of the allowed licenses in any county or city. Maximum cultivation is 2 million square feet statewide. Maximum limit of retail licenses issued by LCB is based on population. Currently at 334. | Not specified in the law or regulations. The regulatory body will define the authorized production quantity. |
| Packaging and labeling regulations | Yes: quantity, serving size, ingredients, potency. | Yes: quantity, serving size, ingredients, potency. | Yes: specifications, safety conditions and maximum quantity 10 g. |
| Product warning labels of health effects. | Yes. | Yes. | Yes. |
| Child-resistant packaging | Required for final sale of marijuana retail product. | Required for marijuana-infused products meant to be eaten, swallowed or inhaled. | To be established during the call for applications for production licenses. |
| Advertising | Permitted but restricted to avoid reaching minors under 21 for retail establishments. Signage permitted at place of business in compliance with local ordinances. | Restricted to no more than a sign for retailers at place of business. Prohibited for producers and processors. | Not permitted. |
| Advertising warnings | Not misleading or safety claims can be made. | Detailed and required. | No advertising allowed, either directly or indirectly. |
| Internet sale | Prohibited. | Prohibited. | Prohibited. |
| Security systems | Required and detailed. | Required and detailed. | Required and to be specified during the call for applications for production licenses. |
| Cannabis clubs | Not permitted. | Not permitted. | Permitted. Between 15 and 45 members can collectively grow up to 99 plants, proportional to the number of members, with the maximum annual allotment of 480 g of dried product per year per member. |
| Medical marijuana | Yes, continuing in existence with new laws and are tax exempt. Prorated fees when converting medical retailer to non-medical. | Yes, continuing in existence with new laws. | Yes, regulations currently being prepared. |
| Taxes and fee distribution | First $ 40 million dollars to Public School Capital Construction Assistance Fund; remainder to General Fund to later be distributed to local governments. The established Marijuana Cash Fund will be used to pay for enforcement of rules and regulations. | Dedicated marijuana fund run by Washington State Liquor Control Board. $ 125 thousand to Healthy Use Survey; $ 50 thousand to social and health reports; $ 5 thousand to the University of Washington for web-based marijuana education; $ 1.5 million to State Liquor Control Board; remainder: 15% to drug treatment; 10 % for drug education; 1 % to state university research; 50% to Washington Health Plan; 5 % to community health care; 0.3 % to building bridges program; remainder to General Fund. | Not specified |
| Administrative sanctions or fines for violations or noncompliance | Yes, tiered schedule that includes up to $ 100,000 fines and suspension and/or revocation of license. | Yes, tiered schedule that includes up to $ 2500 fine and suspension and/or cancellation of license. | Yes, fines of up to $ 63,000, seizures, and suspension or withdrawal of license. |
| Prevention and treatment | Yes, law mandates that state agency will establish educational materials regarding appropriate retail marijuana use and prevention of marijuana use by those under 21. | Yes, some taxes generated will go to treatment | Yes, the national health and education systems required to promote treatment and prevention. |
| Monitoring and evaluation | Yes, required by law for Department of Health to monitor health effects every two years, starting in 2015. | Yes, required by law to independently by Washington State Institute for Public Policy to evaluate policies and impacts related to health, security, economic effects, etc., starting in 2015 until 2032. | Yes, by a specialized independent unit to evaluate the impact of the policy year by year. |
Comparison of the worlds first three jurisdictions to legally regulate marijuana: Colorado, Washington and Uruguay. USA: Drug Policy Alliance; 2014.40 Prepared with the input of Adrián A. Gutiérrez of Rueda Abadi Pereira Consultores, based on the framework provided by Bryce Pardo of the Inter-American Drug Abuse Control Commission.
It should be emphasized that there is a clear difference between the use of cannabinoids as a therapeutic tool and the therapeutic use that has been wanted to give to marijuana, either smoked, ingested prepared with certain meals or topically applied. The differences are shown in Table 4.41
Table 4 Examples of the association between endocannabinoid receptor localization, probable physiological function and potential effect of marijuana
| Normal endocannabinoid receptor location | Endocannabinoid regulation of normal physiological function | Potential effects of marijuana |
|---|---|---|
| Cerebral cortex, hippocampus, limbic system | Judgment, cognition, memory, state of alertness, mood and behavior, perception of time/color/sound | Impaired judgment, cognition, memory, alertness status, mood and behavior swings, altered or distorted, deteriorated perception of time/color/sound |
| Basal ganglia, cerebellum | Coordination, movement | Loss of coordination |
| Hypothalamus | Appetite | Increased appetite |
| Bone marrow | Nausea and vomiting | Nausea and vomiting reduction |
| Dorsal afferent spinal cord and peripheral nociceptors | Pain perception | Reduced pain perception |
| Visual system | Intraocular pressure | Intraocular pressure reduction |
| Cardiovascular system | Heart rate, blood pressure | Increased heart rate and blood pressure in sitting or decubitus position |
| Gastrointestinal system | Motility | Decreased intestinal motility |
| Immune system | Immunity | Variable stimulation or suppression |
Source: Schrot RJ, Hubbard JR. Cannabinoids: medical implications. Ann Med. 2016;48 (3):128-141.41
Cannabinoids clinical applications
There are different forms of cannabis products that are available in some countries to be used for medical purposes, for example, in Canada; some of them are dronabinol (pill), nabilone (pill) and nabiximol (spray).42 Some pathological entities where there is more experience on cannabinoids medical use are described in Appendix 1,43-60 which indicates the level of evidence these drugs have by pathological entity according to the Grade system (Appendix 2).
Other therapeutic applications
In addition to those previously commented, a significant number of possible therapeutic benefits of cannabis and its derivatives is currently under study. For example, CB1 receptors activation by the synthetic cannabinoid compound WIN 55212-2 has been shown to produce an interesting antitussive effect. On the other hand, cannabis administered as an aerosol would produce a significant bronchodilator effect for asthmatic patients; this route of administration would avoid the detrimental effects to the lungs caused by smoked cannabis. In contrast, cannabinoid CB1 receptor block is being investigated as a possible strategy in obesity prevention and in the treatment of addiction to various drugs of abuse (tobacco, cocaine, heroin, etc.).60
Conclusions
Current knowledge suggests that cannabinoids appear to be a new alternative to combat pain and other symptoms that fail to respond or partially respond to classical drug treatment. There is a need for more studies to be carried out in order to demonstrate the efficacy of this pharmacological group and thus integrate it into daily clinical practice, since, to this moment, there are few primary indications for its prescription due to the scarcity of available evidence. The scope of cannabinoid drugs appears to range from palliative use to therapeutic purposes. New lines of research point to a likely anti-tumor effect, which would open an alternative for cancer treatment; however, further evidence is needed in this field. Thus, cannabinoids seem promising in a wide range of pathological entities, but there is still a long way to go for their acceptance and use in routine clinical practice.
Approval of Cannabis sativa derivatives for therapeutic purposes in Mexico requires informing the health group, as well as the population, on what cannabinoids are and the therapeutic agents that can be used. The National Academy of Medicine of Mexico issued a position document for the use of Cannabis sativa derivatives for therapeutic purposes, where ailments feasible to receive this type of treatment and the actions that have to be deployed to carry out a healthy and regulatory management of these compounds are defined. It is necessary for the generation of scientific evidence of the benefit or impact deriving from the use cannabinoid-based drugs to be promoted in our country.
