Life and Drugs (part 2), The Cannabis

Cannabis is the most consumed substance in Europe by 15.1% of the population aged 15-34 with 2.1 % being daily cannabis users (EMCDDA European Drug Report June 2023). And 97 000 users entered for drug treatments related to cannabis use in 2021 and were involved in 25% of the acute toxicity presentations, usually mixed with other substances. Cannabis is with alcohol the gateway to drugs for young people leading to the universe of drugs.

Cannabis is a dioecious plant (plant female and plant male). Cannabis has 3 subspecies: Cannabis sativa sativa L., is 1.80 m to 3 m high, with long fibers for industrial use (named as “hemp”), with a flowering time of 60-90 days; the smaller C. s. indica (1m), flowers more quickly 50-60 days and the C. s. ruderalis, a wilder type. France is the top hemp producer in Europe and third in the world.

From a drug use point of view, only the flowers of sativa and indica are interesting because richer in cannabinoids located in numerous small vesicles, the trichomes, more located around the flower for a protection against the predators in the context of food chain vs. species survival!

Initially the C. sativa was considered for its euphoric effects, producing the “high” while the C. indica produces a relaxation of the cerebral activity, creating an effect “stone”, which sticks. According to the UNODC, Morocco, in the Rif, is the world’s largest producer of psychoactive cannabis plants for the production of hashish (resin form) but since 2021 the culture is regulated.

The Cannabinoid substances were discovered in the 1960s in Israel by the team of Raphael Mechoulam. More than 113 substances have been isolated in the plant but the majority of the effects and their functions are still under study. They are all soluble in lipids, alcohols and organic solvents but almost insoluble in water.

There are 3 types of cannabinoids: – phytocannabinoids of the fresh plant; they are transformed under the action of heat, light, and during drying; – synthetic cannabinoids developed in the laboratory; – endocannabinoids: 8 are currently listed. They are produced by certain organisms, derived from fatty acids in cell membranes, they constitute the endocannabinoid system.

A) Among the phytocannabinoids (molecules with 21 carbon atoms): -CBG (Cannabigerol) is derived from cannabigerolic acid (CBGA), a combination in the plant of olivetolic acid and geranyldiphosphate. CBGA, which is acidic, is easily broken down into CBG with the loss of CO2. The CBG (less than 1% of the plant) is considered as the “cannabinoid strain” with a low boiling point (52°C) and therefore easily transformable! Should be non-psychotropic. -THC (TetraHydroCannabinol). Delta 9-THC is the psychotropic drug responsible for the euphoric high and its weaker psychotropic isomer, the Delta 8-THC. THC is derived from the non-psychoactive acid : THCA.  -HHC (HexaHydroCannabinol-a hydrogenated THC) has also been isolated in small quantities in seeds and pollen, synthesized in 1947 by Adams Roger. Its psychotropic action is comparable to THC, it alters the perception of time. In 2023 HHC is already illegal in several EU countries (See also infra).

Let’s remember that unlike alkaloid psychotropic molecules as cocaine and morphine, the Delta 8-THC and Delta 9-THC are tricyclic terpenoid drugs. The cannabinoids are a class of lipophilic molecules, storing in fatty bodies including the brain (60% of lipids) and easily crossing phospholipid cell membranes. Thus, THC is detectable up to 14 days in the blood, 30 days in the urine and 3 months in the hair. -The famous CBD (Cannabidiol) which was discovered in 1940 is present in the plant. It also derives from the cannabigerolic acid (CBGA) but with a synthesis route different from the THC. The CBD oil can be extracted from the flowers either by cold pressing or by using cold carbon dioxide (CO2) or by chemical solvents (ethanol, butane,…) or by natural solvents (olive oil, coconut oil,…). CBD oil is the subject of important advertising and marketing campaigns praising its health benefits.

CBD was not considered addictive if it is pure, but in 2016 Merrick J. et al. had shown that in an acidic environment, CBD slowly transforms into Delta-9 and Delta-8 THC. And what is the gastric environment if not an acidic environment! Moreover, it has been shown by Czégény et al, 2021, that 25% to 52% of CBD used in e-cigarettes (temperature around 300 ° C) is transformed into THC. Similarly the works of Love C.A. et al, 2023, highlight the potential respiratory health risks for the users of CBD vaping products. There is also the idea of combining CBD and THC in therapeutic cases, with CBD attenuating the deleterious psychotropic effects of THC. Todd et al (2017) show that if a co-administration could be beneficial in the very short term, on the contrary it would have a potentiating effect of the THC in the long term.

CBD is the object of a powerful marketing network to the public. However, in June 2022 the EFSA (European Food Safety Authority Panel) considering the significant uncertainties and data gaps, concludes that the safety of CBD as a Novel Food cannot currently be established: there are insufficient data on the effects of CBD on the liver, gastrointestinal tract, endocrine system, nervous system and on people’s psychological well-being. NOTE: The semi-synthetic cannabinoids HHC (Hexahydrocannabinol) is already found in 20 European countries as ‘replacement for cannabis’ and also 3 new ones: the HHC-acetate, the HHcannabiphorol and the Tetrahydrocannabidiol all produced using the CBD extracted from low-THC cannabis (EMCDDA Report 2023). Their availability is raising concerns about the youth and public health and HHC is already illegal in several EU countries.

B) The synthetic cannabinoids are the most consumed such as Spices at the origin of suicides, the Buddha Blues, not expensive, equivalent to 95% of psychoactive substance, very popular with teenagers, circulates in colleges and high schools. Other names : Black Mamba, AK-47, Shooting Star, Yucatan, Moon Rocks,… Vaporized or ingested, the synthetic cannabinoids cause convulsions, cardiovascular and neurological disorders and psychosis. The peak of action is between 2 and 5 hours until 20 hours.

Manufactured from the 1960’s initially to search for receptors in the brain, they are lipophilic molecules of 22 to 26 carbons, having a higher binding affinity up to 100%, selective or not, for the same receptors as THC and the ones of the endogenous ligands. Thus we have 18 families listed in 2019 among which the CP (cyclohexylphenols), HU (the HU-210 a structural analog of THC is 100 times more powerful), JWH, AM, AB-FUBINACA, XLR, etc.

Studies of the Scientific Reports (2017, 7:10516), suggest that these synthetic cannabinoids exert serious side effects as well as proconvulsive properties (Schneir A.B. et al, 2012) where other authors show anticonvulsive effects in cases of severe epilepsy (Devinsky O. et al, 2016).

NOTE: The THC content of festive (and illegal) cannabis is typically 15% up to 30% compared to 0.2-0.3% of the original plant before genetic manipulation. Synthetic THC is 100 times more potent and produces zombies.

C) The EndoCannabinoid System (ECS) is one of the most important and complex communication systems of the body that contributes to homeostasis. It is phylogenetically very old, present from invertebrates to vertebrates except in protozoa and insects (Silver R.J., 2019). The ECS is composed of:

1) Membrane receptors consisting of 7 transmembrane helices with 3 extra and 3 intracellular loops. The NH2-terminal is extracellular and the COOH-terminal intracytoplasmic. Receptors couple with G proteins (a guanosine triphosphate binding) located on the internal side and which transmit the signal. They are : a)-The CB1 Receptor, discovered in 1988 (William et al.) and then identified by Matsuda L. et al. (1990). It is mainly located in the neurons of the Central Nervous System and weakly in the brainstem. In the periphery, it is present in the lungs, the gastrointestinal system, the testicles and ovaries. Its localization is mainly pre-synaptic. It is involved in psychotropic effects. The exogenous agonist is THC. Sagan S. et al. (2008), show that glial cells (astrocytes) have also G protein-coupled receptors, activated by cannabinoids, but distinct from the CB1 receptor. b)-The CB2 receptor (1993 by Munro S. et al.) is more peripheral. Mostly related to the cells of the immune system, including the spleen and amygdala. More involved in immunomodulatory effects.

2) Endogenous ligands. In the same way that the endogenous opioid system uses endorphins, the endocannabinoid system has its own signalling molecules: the endocannabinoids (8 are listed). These are neuromediators and neuromodulators synthesized in nerve cells and astrocytes “on demand” immediately with the entry of calcium into the neuron and they are not stored in vesicles. They are synthesized in the neuronal membrane from phospholipids. They have an inhibitory effect on the emission of dopamine, serotonin, glutamate and others. They have a retrograde synaptic signaling (from the postsynaptic neuron to the pre-synaptic). The most studied are: a)- the AEA for N-ArachidonoylEthanolAmide called Anandamide (from the Sanskrit ananda=felicity) isolated in 1992 by Mechoulam’s team; AEA is highly expressed in the hippocampus, cerebral cortex and cerebellum and also in the hypothalamus and brainstem. AEA has a high affinity for the CB1 receptor and a low affinity for CB2. AEA also acts on other systems such as vanilloid, peroxisome and glutamate receptors and activates transcription factors through the MAP-kinase pathway. AEA was also found in the cacao (di Tomaso E. et al, 1996). b)- the 2-AG for 2-Arachidonoylglycerol, a monoglyceride ester or ether, isolated in 1995. Has a high affinity for CB2 receptors, also for CB1. The binding of a ligand (AEA or 2-AG) on its receptor (CB1 or CB2) and the activation of the G-protein (GTP/GDP) are the first two steps required for the transmission of a signal inside the cell via a cascade of reactions. Also involved are adenylate cyclase, modulation of ion channels including calcium (Ca 2+) and potassium (K+), and the intervention of the phospholipase C.

3) Synthesis enzymes such as N-acyltransferase, phospholipases A2 and C.

4) Degradation enzymes. According Cravatt B.F. et al. 2001; Ueda N. et al. 2000, the 2 main ones are : a)-Fatty acid amide hydrolase (FAAH) with a single transmembrane domaine, it degrades the bioactive fatty acid amides class including AEA (anandamide) and the 2-AG. FAAH is localized in the post-synaptic neurons. b)-Monoacylglycerol lipase (MAGL) inactivates 2-AG (2-Arachidonoylglycerol) at 85% and also AEA .

Thus, studies have been shown that the EndoCannabinoid System is involved in: memory, mood, appetite, sleep, pain response, nausea, emotions, thermoregulation, immunity, male and female fertility, reproductive activities, the reward system and the use of psychoactive substances.

Psychoactive substances act on this ECS circuit by modifying the chemical balance of the Nervous System, which, not being naturally and correctly regulated, will influence the control of movements and emotions, creating this euphoria and illusion of well-being and generating dependence more or less slowly, according to Thorndike’s Law of Effect (1911): “A response is more likely to be reproduced if it leads to satisfaction for the organism and abandoned if it results in dissatisfaction”.

The psychoactive substances interfere with specific areas of the brain, which is composed of 3 basic parts that according to the theory will define our personality and character traits according to their respective influence:

-a reptilian or archaic brain dating back circa 400 million years. It is quite reliable, fast, manages basic perceptions and functions including: food, sexuality, homeostasis, survival reactions (attack or flight), but is compulsive. -then comes the limbic brain of mammals, 100 million years ago with 2 parts: Paleolimbic of lower mammals and the Neolimbic which distinguishes the good from the bad. It develops the learning, memory and emotions, it is the heart of the reward and punishment system in humans. -and finally the cerebral cortex or neo-cortex of primates and then human beings. It is the place of analysis, decision-making, intelligence, creativity, has a notion of future, and made the language possible. The brain is composed of some 90 billion cells, composed of highly plasticated neurons and glial cells. Its development ends around the age of 25 with a significant transition during adolescence, the change from the dependence of childhood to the autonomy of adult.

At the brain level, the Ventral Tegmental Area (VTA) of the mesolimbic midbrain is one of the primitive regions of the brain. Its neurons synthesize the neurotransmitter dopamine which their axons direct to the nucleus accumbens. The VTA is also influenced by endorphins and is the target of opiate drugs (morphine and heroin). -The nucleus accumbens plays a central role in the reward circuit (Klawonn A.M. and Malenka R.C., 2018). Its activity is modulated by dopamine which promotes craving and reward while serotonin has an inhibitory role. This nucleus is also connected to other centers involved in the reward system, including the hypothalamus. -The prefrontal cortex, a more recent region, is a significant relay of the reward circuit. Its activity is also modulated by dopamine. -Two other centers of the limbic system participate in the reward circuit: the hippocampus, which is the pillar of memory and the amygdala, which records perceptions.

-The neurotransmitter dopamine (pleasure molecule) plays a central role in positive reinforcement and contributes to addiction. -The GABA (gamma-aminobutyric acid), an inhibitor that is very present in the neurons of the cortex, participates in motor control and regulates anxiety. -The amino acid Glutamate is the most abundant excitatory neurotransmitter in the brain. It is associated with learning and memory. It regulates the release of dopamine in the nucleus accumbens. (Glutamate is also a food additive: E621). Its membrane receptor is the NMDA (N-methyl-D-aspartic).

The origin of the “high” or euphoria is due to the properties of THC which binds more stably than AEA to CB1 receptors (60% vs. 20%) resulting in an excessive increase in dopamine release and a prolonged excitation of meso-limbic dopaminergic neurons, meso-accumbic (the nucleus accumbens) and meso-cortical neurons of the brain, in the reward system and providing pleasure, which will lead to the drug search and then dependence.

The Adolescence:

Adolescent behavior is often characterized by impulsivity, sensation-seeking and risk-taking behavior. This is related to the sequential brain maturation with the accelerated maturation of limbic structures (sensitivity to emotional and social signals) and then of the prefrontal cortex (rational and plans ahead) which evolution towards maturity is slower and therefore delayed (Giedd, J.N. et al. 1999; Casey, B.J. et al. 2008). Therefore, teenagers can have deep and complex emotions but they cannot fully control them. Hence the risk-taking and impulsiveness without yet assuming the consequences. This makes adolescence a perilous time of life, but also full of possibilities and with a great adaptability thanks to brain plasticity and synaptic pruning.

The Pathologies :

Cannabis has been associated epidemiologically with significant fetal malformations and cancer induction in children and adult populations.

1) Testicular cancer is most common in youth between the ages of 15-35 using cannabis according to the Cancer Research Foundation. There is an increased risk of testicular germ cell tumor (Gurney J. et al. 2015) by deregulation of the hypothalamic-pituitary axis. Indeed, CB1 and CB2 receptors are present in:

-the hypothalamus where THC blocks the hormone that controls sexual maturation at puberty and fertility, the ovulation hormone lutein and the testosterone;

-on testicular tissue, THC reduces testosterone production in Leydig cells and has a pro-apoptotic effect on Sertoli cells;

-on spermatozoa, THC alters concentration, count and motility with problems of infertility and impaired spermatogenesis (Gundersen T. D. et al. 2015). THC would be able to damage the DNA until the chromotripsis (bursting) of the chromosome with possibility of genetic transmission ( Reece A.S. and Hulse G.K. 2016).

2) Dong et al. 2019, already highlighted the neural and immune impact of cannabinoids on fetal and offspring development.

3)Hjorthoj C. et al 2023, clearly demonstrated an association between cannabis use disorder and schizophrenia affecting the way a person thinks, feels and behaves.

4)With a 20-year hindsight, the therapeutic legalization of cannabis in Colorado in 2000 has shown (Reece and Hulse, 2019) in women under 24 years of age consuming THC during their pregnancy, a 5-fold increase in teratogenic incidence in newborns such as spina bifida, microcephaly, trisomy 21, absence of partitions between the heart atria or ventricles, etc. These abnormalities may be correlated with the action of cannabinoids known to modify histones (including H3) as well as the methylation of Cytosine-Phosphate-Guanine sites of DNA, thus altering the regulatory systems of gene expression.

Costentin J. (CNPERT, 2020) reminds that THC consumption leads to epigenetic modifications that affect the immune system, cognitive activities, brain maturation, with the development of psychiatric disorders. In abortion products from cannabis-using mothers, the nucleus accumbens (in the limbic system) of these fetuses shows a decrease in mRNA (RNA messenger) coding for the dopaminergic D2 receptors and a rarefaction of these receptors. This under-expression altering the reward circuit would facilitate later the interest for drugs by the youth.

So, as far as the cannabis-youth relationship is concerned, -we need to tackle this widely popular substance very seriously and gather evidences against the harmful influence of biased and commercial arguments, -we need to make these data widely known to protect the young public and for the sake of future generations.

There are a large number of possible influences on adolescents such as protective and/or risk factors. They are : family, school and teachers, peers, neighborhood, leisure, media, culture and legislation. But the main one remains parents and parenting practices. Indeed, they can help (or not) to protect children by listening to and leading them by example.

Based on the contacts established across Europe by our volunteers with young people, parents, associations, teachers, social workers, health professionals, local and national leaders, security and police officers, The Truth About Drugs campaign was actively developed. This is a prevention campaign with education on health risks, aimed at youth and public awareness on the potential harms of marijuana and other illicit drugs, so that the risks are clearly understood.

« It is ignorance that blinds and misleads us. Open your eyes Ô miserable mortals » said Leonardo Da Vinci (1452-1519). Thus, empowered with the real facts on drugs, young people will be able to face with lucidity the different aspects of life problems related to drug use, to make the right decision and be able to fully realize their own potential.

This approach perfectly fit with the 2023 theme of the UN International Day: “People first: stop stigma and discrimination, strengthen prevention” .

“If things were a little better known and understood, we would all lead happier lives” L.Ron Hubbard (1965)

References:

Consult also the regulation in the EU: -Recreational use of cannabis – Laws and policies in selected EU Member States https://www.europarl.europa.eu/RegData/etudes/BRIE/2023/749792/EPRS_BRI(2023)749792_EN.pdf

-International Day against Drug Abuse and Illicit Trafficking – EU action against illicit drugs https://www.europarl.europa.eu/RegData/etudes/ATAG/2022/733548/EPRS_ATA(2022)733548_EN.pdf

About the drugs visit: www.fdfe.eu ; www.drugfreeworld.org