Cannabis, marijuana, hashish, natural and synthetic cannabinoids. Mechanism of action, drug addiction and associated risk factors



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Abstract

It has been shown that the grass, stems, leaves and inflorescences of wild and cultivated cannabis contain cannabinoids, which, like synthetic cannabinoids, have a hallucinogenic effect. The continuing increase in the abuse of hallucinogens from the group of natural and synthetic cannabinoids among young people, the widespread use of cultivated and wild cannabis, as well as the medical use of cannabinoids as drugs in the treatment of cancer and mental disorders, pose a risk of developing mental dependence and the prevalence of drug addiction in society. It is indicated that among drug addicts and youth, the names cannabis, marijuana and hashish refer to drugs made from cannabis herb (Cannabis sativa or Cannabis indica). Due to the fact that cannabinoids are not destroyed by high temperature (they do not burn in fire) and hydrochloric acid of gastric juice, they retain a hallucinogenic effect when inhaled as part of smoke and ingested as part of extracts. Most often, the cannabis is used to produce smoking mixtures known as spice, aroma mix, macon, as well as resin known as hashish. Hashish and the glandular trichomes of the flowering tops of female cannabis plants contain more cannabinoids than other cannabis plant products. It is indicated that inhalation of smoke from smoking mixtures into the body and enteral administration of liquid cannabis extract causes drug addicts to improve their mood and allow them to have fun. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). It has been shown that after inhaling smoke with natural or synthetic cannabinoids, the narcotic effect in drug addicts begins to develop after 15-20 seconds, reaches its maximum value after 10-30 minutes and lasts up to 1-3 hours, but can be prolonged by repeated smoke inhalation (smoking). After ingestion of cannabinoids in effective doses, the narcotic effect can begin to develop after 30-60 minutes, after which it usually reaches a maximum after 1.5 – 2.0 hours and lasts up to 6 hours (sometimes longer). At the same time, a person experiences dizziness, weakness throughout the body, auditory and visual hallucinations, loses coordination in movements and the ability to think correctly.

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Introduction

In recent years, cannabinoids have become increasingly widely used and available both in medicine (in psychiatry and oncology) and among ordinary youth in many countries of the world [1, 2]. Cannabinoids have gained particularly high popularity among young people due to their intoxicating and hallucinogenic effects. Therefore, the information base that allows an adequate assessment of their safety and effectiveness remains highly relevant [3, 4].

 Cannabis sativa has been cultivated throughout human history for food and intoxicating effects on the body. Breeding has resulted in marijuana varieties for intoxicating effects and hemp varieties for fiber and seed production [5]. The excavation of the Yanhai Tombs near Turpan in China's Xinjiang-Uygur Autonomous Region uncovered a 2,700-year-old grave of a Caucasoid shaman, as well as clothing and equipment that included a cache of cannabis [6, 7]. This archaeological find indicates that Cannabis was used as a medicinal or psychoactive substance or divination aid in the early era even before the discovery of the Silk Road.

The use of cannabis in Western medicine began in 1839 thanks to surgeon W. B. O'Shaughnessy, who, working in India for the British East India Company, gained experience in achieving analgesic, sedative, anti-inflammatory, antispasmodic and anticonvulsant effects using cannabis [8]. At the same time, he was the first to give a drawing of the plant Cannabis indica in article in the Journal of the Asiatic Society of Bengal (Figure 1).

 

Figure 1. Drawing of Cannabis indica featured in O’Shaughnessy’s article on the plant in the Journal of the Asiatic Society of Bengal (1839). (Reproduced with permission from Public Domain Image Archive from the Public Domain Review.  https://pdimagearchive.org/images/2e9409ba-4962-4517-8830-71a2de99481c/)

 

Despite the fact that the use of cannabinoids for medical purposes is very limited due to the likelihood of developing mental dependence, they are used in many countries in the treatment of cancer and mental disorders [9-12]. In addition, cannabis continues to be used for food production. [13-16]. One of the first countries to allow the industrial cultivation of cannabis for food production is Canada [17].

Due to the use of cannabinoids in medicine in the treatment of cancer and mental disorders, as well as due to the large area of land planted with cannabis for food production, there remains a danger of uncontrolled use of cannabis and cannabinoids, complicated by the development of mental dependence [18]. In addition, in recent years, there has been a growing interest among young people not only in herbal, but also in synthetic cannabinoids. The abuse of new psychoactive substances (NPS) among young people is growing at an unprecedented rate worldwide and creates social problems [19-24].

 

High concentration and resistance of phytocannabinoids to acids and high temperatures as risk factors for drug addiction

"Cannabis" (cannabis sativa, cannabis indica) is mainly consumed as "weed" (dried leaves, flowers and stems), which is better known by its Mexican name "marijuana" and is more commonly used in the USA. Cannabis resin, imported from Morocco and known as hashish, is more widely used in France and Spain [25]. Regardless of the products obtained from plants (products of plant origin), there are products obtained by chemical synthesis (synthetic cannabinoids) [26, 27]. That said, natural cannabinoids continue to be used because they are more accessible to addicts than their synthetic counterparts.

Сannabis sativa grows almost everywhere. It is shown that hemp is not a fastidious plant, can grow on different soils, and can be grown by hydroponic cultivation methods [28].  It is important to keep in mind that cannabis herb contains a sufficient amount of narcotic substances that are not destroyed by burning (therefore, the herb can be smoked) and acid exposure (therefore, extracts of the herb can be ingested on an empty stomach) [29]. As such, addicts may use the harvested cannabis herb as a smoking mixture for smoke inhalation, or as raw material for extracting oral narcotic drugs from the herb [30]. In all cases, the botanical source is Cannabis sativa L., a member of the plant family Cannabinaceae. C. sativa is considered the only species of the Cannabis genus, although 35 synonyms are known. There are various subspecies, varieties (chemotypes) and varieties of C. sativa, which are strong determinants for their use [29, 31].  

Plant cannabinoids are referred to as phytocannabinoids. This is to distinguish them from endocannabinoids (endogenous neurotransmitters that bind to human cannabinoid receptors) and synthetic cannabinoids [31]. To date, 130 different phytocannabinoid structures have been identified among various cannabis plants [32]. It is reported that the resin and glandular trichomes of the flowering tops of female plants contain the highest amount of phytocannabinoids [29, 33]. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (Figure 2) [29, 34, 35].

 

Figure 2. Chemical structures of THC (left) and CBD (right). Reproduced from Woerdenbag HJ, Olinga P, Kok EA, Brugman DAP, et al. Potential, limitations and risks of cannabis-derived products in cancer treatment. Cancers (Basel). 2023 Apr 1;15(7):2119.

 

Tetrahydrocannabinol (THC) belongs to hallucinogens that can disrupt sensitivity, perception, cognitive and psychomotor functions, cause euphoria, relaxation and various sensory changes [36-38]. It is reported that THC has an effect on the human body similar to that of lysergic acid diethylamine (LSD), mescaline, psilocybin, ipomoea and nutmeg, phencyclidan and stinky datura, namely, it causes hallucinations in which a person sees and hears things that do not exist in reality.

Hashish is a cannabis concentrate product composed of compressed or purified preparations of stalked resin glands, called trichomes, from the plant. It is defined by the 1961 UN Single Convention on Narcotic Drugs (Schedule I and IV) as "the separated resin, whether crude or purified, obtained from the cannabis plant". Since hashish is produced illegally, each batch of this drug, even from the same manufacturer, is of different quality and contains different amounts of phytocannabinoids and THC. Moreover, different batches of hashish from one manufacturer and from different manufacturers may have different appearance and different physico-chemical properties. The quality, properties and appearance of hashish depend on the type and quality of the raw materials used and the hashish production technology. Hashish usually has a firm consistency and a dark brown color, although it can sometimes appear transparent, yellow, black, or red (Fig. 3) [8, 39].

           

                                           1                                                               2

Figure 3. Appearance of drugs derived from hemp. 1 - Trichomes isolated with ice-water extraction method. 2 - Hashish shown next to a 19-millimetre (3⁄4 in) diameter U.S. penny for scale. Reproduced from Hashish – Wikipedia. https://en.wikipedia.org/wiki/Hashish?ysclid=mbfzsjlzez357944253.

 

However, in any case, hashish oil contains more THC than cannabis herb and marijuana. Therefore, hashish use has a stronger narcotic effect than marijuana use [8, 40]. In particular, hashish can cause paranoia, anxiety, and other psychological problems that can last for several days. In addition, it must be borne in mind that hashish is made using butane. Therefore, hashish contains butane, which can affect the brain and nervous system, causing dizziness, palpitations and loss of consciousness. Inhaling butane in large doses can be fatal. In this regard, hashish oil is more dangerous than marijuana. Therefore, hashish use is more likely to cause the development of addictive behavior and more often requires treatment for dependence on cannabinoids.

Cannabis, marijuana and hashish are likened to “street drugs”, therefore they do not have a quality standard and cannot have a “standard” and/or the same mechanism of action. Therefore, the use of each new batch of cannabis, marijuana and hashish as a street drug by any consumer each time represents for each of them the experience of exposure to an “unfamiliar” drug [41-44]. Additionally, phytocannabinoids can be distributed in the criminal environment in the form of various smoking mixtures known as spice, aroma mix, macon, the effect of which varies widely [39, 45-50].

 

New synthetic cannabinoids as risk factors for drug addiction

The use of new psychoactive substances containing synthetic cannabinoids (SCs) has been increasing worldwide in recent years. The recreational use of SCs is an illicit use. However, the level of recreational use of SCs is increasing, as many cheap brands are convenient and readily available [47-50]. It is important to note that, unlike phytocannabinoids, synthetic cannabinoids are not usually mixed with tobacco (most likely to avoid reducing the narcotic effect). Synthetic cannabinoids are reported to have a more potent effect on the body. In particular, with prolonged use, synthetic cannabinoids are more likely than phytocannabinoids to cause anxiety, agitation, psychosis, schizophrenia, insomnia, nightmares, withdrawal symptoms, suicidal thoughts, cognitive impairment, nausea, vomiting, loss of appetite, weight loss, breathing difficulties, hypertension, tachycardia, palpitations, pain chest pain, myocardial infarction, muscle twitching, skeletal muscle hypertonia, hyperflexia, hyperextension, sensitivity changes and fasciculation, as well as acute renal failure, abdominal pain, miosis, mydriasis, xerostomia, hyperthermia, fatigue, rhabdomyolysis, cough. It is no secret that repeated long-term use of synthetic cannabinoids can even result in death [48, 51].

It is reported that cannabinoid-based drugs are becoming increasingly popular among adolescents, despite the risks associated with their use [52, 53]. While the psychotropic effects associated with natural cannabis are associated with the presence of THC, SCs products contain a wide range of high-potency total cannabinoid receptor agonists that cause "THC-like" the effects, but they are more serious and persistent [54, 55]. While cannabis use usually causes psychotropic effects such as euphoria, relaxation, and a general pleasant feeling, the use of THC-like drugs can cause more undesirable effects such as agitation, irritability, confusion, hallucinations, delusions, psychosis, physical dependence, and death [56-66].

Characteristic symptoms of chronic poisoning by synthetic cannabinoids are conjunctival hyperemia, increased body temperature, increased appetite, dry mouth, decreased tone of smooth muscle formations of internal organs (stomach, intestines, bladder, rectum, uterus, gallbladder). decreased intraocular pressure, decreased testosterone levels in the blood and urinary retention. The diagnosis of drug dependence is made when a person develops withdrawal syndrome in case of withdrawal from a regularly taken drug [67-75].

 

Idealized ideas about the mechanism of action of cannabis, marijuana, hashish, natural and synthetic cannabinoids

All illegally produced narcotic products, including dried various parts of cannabis plants (roots, stems, leaves, inflorescences) and extracts from them, as well as synthetic cannabinoids, differ from each other not only in their appearance, but also in physico-chemical properties, doses taken, biological (and narcotic) activity, and ways of introduction into the human body. The fact is that the cannabis plant contains more than a thousand chemical components, all of which have different chemical properties that require different conditions for preservation during drying and extraction [76, 77]. At the same time, in practice, the process of drying vegetable raw materials is carried out in the air at different temperatures, humidity, and illumination, and the conditions and storage periods of dried raw materials are even more different (Fig. 4).

 

Figure 4. Air-drying (hang-drying) of the cannabis plant. Reproduced from Lazarjani, M.P., Young, O., Kebede, L. et al. Processing and extraction methods of medicinal cannabis: a narrative review. J Cannabis Res. 2021;3:32.

 

In turn, the chemical synthesis of cannabinoids, carried out in clandestine chemical laboratories using raw materials of varying quality without monitoring compliance with technological regulations, eventually leads to the appearance of a "dirty" product, which is a mixture of many different chemical compounds. It is impossible to isolate an absolutely pure cannabinoid from such a mixture [76].

Under these conditions, the information about the mechanism of action of drugs of the above group (as well as all drugs from different pharmacological groups) currently dominating in textbooks, reference books, encyclopedias and scientific articles is built on the idealized essence of chemically pure substances and the idealized essence of their interaction with an idealized virtual patient [78]. It has been reported that in pharmacy, pharmacology, chemistry, physics, and materials science, researchers traditionally substitute the substances (materials) under discussion with chemical elements and the structural formula of one molecule of exclusively only one chemical substance belonging to the group of so-called basic substances. Therefore, researchers assume that the substance under consideration is of ideal high quality and is completely free of any impurities.

The world's dominant information on the mechanisms of action of natural and synthetic cannabinoids and medicinal products is therefore idealized rather than real. This information is not directly related to specific drug products and medicines.

In this regard, it should be borne in mind that, to date, the authors of scientific articles discussing the mechanism of action of natural and synthetic cannabinoids are most often in an illusory world (a world represented by individual chemical molecules in pure form), whereas the real world (the world of real batches of cannabis, cannabis herb, hashish and other products produced by specific manufacturers and in specific batches of goods) is represented by all sorts of mixtures of different substances of different quality in different ratios. It must therefore be assumed that the idealized nature of cannabinoids may sometimes be far removed from the nature of the actual products used illicitly. The fact is that the chemical name and chemical formula are merely the symbol of a single molecule of a chemical element, reflecting its idealized chemical essence, but not the essence of the actual batch of cannabis, marijuana, hashish synthetic cannabinoid. This is why today in idealized pharmacology, toxicology, addiction science and pharmacy, the term “cannabinoid” refers to any chemical substance, regardless of structure or origin, that binds to the body's cannabinoid receptors and has effects similar to those produced by the cannabis plant.

On the other hand, people who use cannabinoids also differ from each other. Important differentiating factors are body weight, age, frequency and duration of previous use of biologically active substances, including alcoholic beverages and drugs, and the presence of addiction and dependence to cannabinoids. However, when describing the mechanism of action of cannabinoids, the authors most often mean (although they do not specify) not a real person, but a virtual person of “average” sex, average age, average health, with a body weight of about 70 kg [78].

In its most general form, the mechanism of action of cannabinoids on an adult addicted to cannabinoids can be presented as follows [79]. It is reported that an addict (i.e., a person addicted to cannabinoids) inhaling smoke from cannabis mixtures and/or enterally injecting liquid cannabis extract improves mood. At the same time, the addict enjoys it, because the grass, stems, leaves and inflorescences of cannabis contain phytocannabinoids that cause euphoria. An addict gets a similar result of exposure when taking synthetic cannabinoids. It has been shown that 30-60 minutes after the introduction of a normal dose of a natural or synthetic cannabinoid into the stomach of an adult addict, he develops drug intoxication. The maximum depth of intoxication develops after 1.5 – 2.0 hours. This causes dizziness, weakness throughout the body, auditory and visual hallucinations, loss of coordination in movements and the ability to think correctly. This condition persists for about 6 hours or more, and repeated use of the cannabinoid prolongs this condition. It has been shown that smoking cannabis, marijuana, hashish, spice, or a mixture of aromas can cause a narcotic effect after 15-20 seconds, while the maximum effect develops after 10 to 30 minutes, and the duration of the narcotic effect lasts 1-3 hours [79]. The plasma half-life of THC has been reported to be 1 to 3 days in occasional users and 5 to 13 days in chronic users [80].

At the same time, in recent years, cannabinoids have been widely used for recreational purposes by young people and adolescents and are increasingly being used therapeutically in psychiatry and in the elderly and the elderly in the field of oncology [80-84]. That said, the responses of adolescent and elderly bodies to cannabinoids are different from those of adult addicts who are addicted to cannabinoids. There is much more research to be done in the future to elucidate in detail the age-related pharmacodynamics and pharmacokinetics of natural and synthetic cannabinoids.

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About the authors

Aleksandr L. Urakov

Izhevsk State Medical Academy

Author for correspondence.
Email: alurakov@bk.ru
ORCID iD: 0000-0002-9829-9463
SPIN-code: 1613-9660

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Izhevsk

Aleksandr V. Samorodov

Bashkir State Medical University

Email: avsamorodov@gmail.com
ORCID iD: 0000-0001-9302-499X
SPIN-code: 2396-1934

Dr. Sci. Med., assistant professor, head, Department of Pharmacology

Russian Federation, Ufa

Lyubov V. Lovtsova

Volga Medical Research University

Email: lovcovalubov@mail.ru
ORCID iD: 0000-0003-1480-183X
SPIN-code: 8333-8772

Dr. Sci. (Pharmacology), assistant professor

Russian Federation, Nizhny Novgorod

Inessa Ya. Moiseeva

Penza State University

Email: moiseeva_pharm@mail.ru
ORCID iD: 0000-0003-1168-2871
SPIN-code: 9607-0306

Doctor of Medical Sciences, Professor, Head of the Department of General and Clinical Pharmacology

Russian Federation, 440026, Penza, Krasnaya St., 40

Mithun Rudrapal

School of Biotechnology and Pharmaceutical Sciences Vignan’s Foundation for Science, Technology & Research

Email: drmr_pharma@vignan.ac.in
ORCID iD: 0000-0002-8172-6633

MD, Dr. Sci. (Medicine), Professor

India, Vadlamudi, Guntur

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