Response To The FDA’s Warning Letter

The CBD market flourished after Hemp became federally legal across the U.S. in the 2018 Annual Agricultural Bill and became the largest ingredient in the cannabis market in the U.S. So far, the FDA has approved only one prescription drug containing cannabidiol – “Epidiolex” made by GW Pharmaceuticals that treats two rare forms of childhood epilepsy – Dravet syndrome and Lennox-Gastao syndrome. This British pharmaceutical company has invested a lot of effort and money in developing cannabis-derived drugs such as “Sativex” containing THC & CBD (at a ratio of 1:1).

The same company also tested the toxicity of high doses of CBD in humans and published results that showed that CBD is also safe at very high doses – 1,500 mg/ kg body weight. Over the past few years, the FDA has issued several warning letters to companies that market new unconfirmed drugs containing CBD. The FDA also tested the chemical content of cannabinoid compounds in some products, and many were found to not contain the CBD levels that manufacturers claim they contain. Some CBD oils containing harmful and addictive synthetic cannabinoids have been found.

Therefore, the FDA recently issued a revised consumer update detailing its new safety concerns regarding CBD products that are not properly regulated. Since these products are not yet FDA approved for the cure, reduction of symptoms, treatment or prevention of any disease – consumers should be wary of purchasing and using such products. Currently, CBD cannot be marketed as a dietary supplement, food or therapeutic drug.

The world is still waiting for the correct description of the CBD 

The FDA has raised serious concerns about potential damage to CBD products, including: liver damage, reduction in male fertility, sleepiness, diarrhoea and interactions with herbs and other medicines. The entire world accepts the FDA as the primary authority in deciding what we should eat, drink or put into our bodies in any form, as well as the medicines and add-ons that we can safely take. The FDA also regulates the safety of dermatological and cosmetic ointments and creams.

With such an important international duty, there comes a great responsibility.

Two main claims presented in the last FDA warning from November 25, 2019 are:

1. High doses of cannabidiol cause liver toxicity in mice (1).
2. Reducing testosterone levels in men reduces testicular size and reduces the amount of active seeds and sperm availability (2).

Both claims are very important for overall human health and should be carefully examined. Later in the article, I will try to show that both may be due to the same inhibitory effect of CBD on the same isisyms of the hemo-protein cytochrome P450 that metabolizes the sex hormones as well as cannabinoids and other xenobiotic substances (such as many common drugs) in both sexes.

Six other sub-claims were made in the warning letter:

1. The FDA claims CBD and alcohol [EtOH] together have a synergistic effect that can cause dangerous side effects.
2. CBD can cause fatigue and sleepiness during waking hours a day.
3. CBD causes gastrointestinal problems such as diarrhoea, abdominal pain and Irritable Bowel Disease (IBD).
4. CBD safety during pregnancy and lactation is not yet known.
5. Interactions with CBD and medications have not yet been thoroughly tested.
6. High dose CBD toxicity to the vascular system.

The original FDA warning letter can be found in the following link We will do our best to address each of these claims in a scientific and balanced manner.

Claim 1. CBD toxicity to the liver

Notes on the methodology: B6C3F1 mouse model

B6C3F1 mouse is a hybrid hybrid between: Male mouse strain C3H/HeJWhine female mouse strain C57BL/6J. This mouse strain (B6C3F1) exhibits a very high sensitivity to liver tumours spontaneously and chemically, in contrast to female mouse of the C57BL/6J variety very resistant to liver tumours. It will be interesting to test the effect of CBD on the liver of a mouse of the C57BL/6J variety – not only on the most sensitive strain – B6C3F1 that spontaneously develops malignant liver diseases.

In many biological tests of substances that cause liver cancer of the National Toxicology Programs (NTP) the mouse strain B6C3F1 is widely used that detects increased sensitivity to hepatocarcinogenesis (3). Chemicals (such as N, N-diethyl nitrosamine {DEN}) cause the development of pathological liver focal points = the spread of hepatocytes and / or apoptosis (planned cell death). The sensitivity of this mouse strain is hereditarily controlled by fundamental genetic differences [multiple genes] in the liver known as: liver sensitivity from cancer = Hematopoietic Stem Cells (HSCs). Separation and genetic link analysis indicate that at least 7 different genes of HCS may be highly susceptible to the liver tumour of this mouse strain B6C3F1. Chemicals identified as liver carcinogens in a sensitive mouse affect the decision-making process in assessing the chemical risk in cases of cancer (4).

In many aspects, mice and rats behave differentially and both differ from humans. The question of the relevance of the findings of studies in mice regarding human health and risk assessment for their health is still an unresolved problem in scientific and regulatory communities. It will be important to replicate the experiments of Ewing in other strains of less sensitive mice such as: C57 & Balb C (1). 

Dose of CBD tested: Various studies have examined the dose of CBD in the range of: 5mg / kg BW through vein up to 10mg / kg BW orally (5),

The study on which the FDA relies used ridiculously high doses and completely irrelevant of: 615-2,460mg / kg equal to 4-17 full containers of “Epidiolex” !! (Epidiolex is a 100ml container containing 100mg / ml of CBD insulated). In calculating 70kg BW for an adult patient, it will take several months for an average epilepsy patient to consume a full container and therefore 17 such containers are excessive doses.

Altmetric Scale [AS] ALLOMETRIC SCALING

Small animals, like a mouse or songbird, are more active than large animals, like humans. It is not only a matter of physical movement – the metabolism is faster even among small animals. A mouse liver will clean drugs from its system faster than a person. This is one of the main reasons why the dose of medicines is not the same between laboratory animals and humans in the clinic.

An alumetric scale is a useful rule of thumb that helps overcome this problem. It is assumed that a drug dose scale can be changed from one animal to another based on body weight and body mass index (BMI). 

To convert a dose of animals in mg / kg to a dose equivalent to a person [HED]:

Calculation of human equivalent dose based on body area: Based on: Nair, A & Jacob S, 2016. doi: 10.4103/0976-0105.177703

This almatric scale factor is often used to find an initial dose for drugs that have never been tested in humans, which is not the case for CBD, a compound with established human safety documentation. The use of an altmetric scale should be justified to reinterpret preclinical work. And in fact, an almetric scale of toxicity may not be related to cannabinoids. The linear scale factor is based on properties that these oily compounds do not have. For example, it works best when the drug being tested solublely dissolves in the bloodstream and floats freely in the bloodstream, but however over 99% of CBD (and THC) is related to protein (albumin), and not free. Moreover, the ridiculously high doses in this study will bring to the body’s metabolic mechanisms ‘satiety’, and prevent relevant dose extrapolations. Undoubtedly, the dosage used in the B6C3F1 mouse experiment is not translated directly into a human dose. (The aforementioned calculation might have been correct if it were a water-soluble molecule).

However, by choosing a poor scale factor, the authors’ report on the “human equivalents” becomes irrelevant. Recall that the THC study indicates that we can increase the dose of THC for primates up to 10 times the dose of rat without toxicity, the opposite of what an almetric scale suggests. All of this only underscores the importance of limiting the conclusions to what we can establish. Research on which the FDA’s warning letter is based shows that igniting huge doses of CBD – 0.25% of its weight – is harmful to mice. For comparison: For a person weighing 100 kg, this is about ingestion of 250 grams of pure CBD! (In an estimated calculation of NIS 50 per gram, it will cost such a consumer about NIS 12,500 per day for the consumption of 250 grams. Alternatively, he will be able to “drink” 125 bottles of CBD oil 20%) The findings in mice say nothing about humans and say nothing about realistic dosage.

Acute toxicity trials 

It is important to note that only in six! B6C3F1 mice are used in each treatment group. This strain of mouse is highly susceptible to heptocracygenesis [genetic background] and develops spontaneous liver tumours. The high doses of CBD resulted in an increase in total glutathione [{GSH} glutathione], increase in total bilirubin and a small increase in alanine and aspartame transamins [ALT & AST, respectively]. Gene expression systems of the ftotoxies have revealed that high doses of CBD differentially regulate more than 50 genes, many of which have been linked to oxidative stress responses, and are associated with enzyme pathways that perform drugs and drugs. Liver toxicity caused by extremely high doses of CBD in a lot of olive oil in this sensitive mouse strain was of a choleraty nature – far from a natural phenomenon.

Cholestatosis is a condition in which bile fluid cannot flow freely from the liver to the duodenum [part of the small intestine]. This condition can be caused by blocking or mechanical obstruction in the tube (as a result of gallstone or malignant) or metabolic – disorders in the formation of bile (genetically or purchased by medicines). Taking high doses of CBD combined with a lot of olive oil as a carrier has the potential to cause acquired cholestasis that harms mice sensitive to B6C3F1.

Sub-acute toxicity experiments

The lowest doses of CBD used for this part of the study [61.5mg/kg] are still ten times higher than those used for human clinical trials and have resulted in loss of appetite and body weight loss in some of the mice treated. The effects were observed only in extremely high doses of CBD [615mg/kg] that are irrelevant to a real scenario.

Chronic exposure to high concentrations of CBD in oral conditions has been found to reduce appetite and body weight and increases liver weight relative to body weight (1). The high standard deviation values [SD] shown in all experiments are a clear result of small experimental groups with 6! Mice only. If you want to seek FDA approval to add CBD as a new dietary ingredient [NDI – new drug ingredient] or generally recognize it as safe [GRAS– Generally Regarded As Safe], the results of additional toxicity studies should be shown more detailed and accurate in humans. 6, 7, 8, 9

Liver Protection with CBD

Hepato-protection by CBD About a decade ago, many scientific papers examined the therapeutic and medical effects of CBD – focusing on the liver. The protective effect on the liver of CBD is evident in ischemia / re-paraphrasia [I/R] and it suppresses the release of inflammatory substances (cytokines, interlaukins, chemocenes) that damage liver tissue. Ischemia / re-paraphrasia I / R leads to changes in markers of liver damage (serum transaminase), oxidative / nitritic pressure in the liver, disorder of mitochondrial function and inflammation (production and release of TNFα monocyte and cyclooxygenase [COX-2]). Moderate doses of CBD have been found to protect rodents’ liver from I/R as a result of a decrease in liver cell mortality (hepatocytes) (10). Many studies prove that CBD suppresses inflammation of the liver.

Immuno-histochemical analysis revealed that CBD reduced the expression of the enzyme Nitric Oxide synthase [iNOS – Inducible Nitric Oxide synthase], cyclooxinase [COX-2], [TNF-α], nuclear factor [NFkB] Fas ligand & caspase-3, liver tissue I / R. Caspaise -3 causes the breakdown of proteins in cytosol, leading to the death of hepatocytes (10).

CBD has reduced the deterioration in the biochemical parameters measured and have a potential therapeutic effect in protecting the liver from injury (11). CBD has been found to cause apoptosis of hepatic stellate cell [HSCs]. The spread and activation of HSC is the main cellular event in the development of fibrosis in the liver when they produce excess collagen, which leads to the accumulation of the scar matrix (connective tissue instead of the ptocytes) and fibrotti liver, less active (12). CBD has recently been found to reduce the formation of fibrotic scars (connecting tissue) in the liver, allowing normal liver cells to reproduce and heal the liver after injury. The Endo-cannabinoid System (ECS) is activated in the liver as a result of liver function disorder.

CBD has been found to reduce the amounts of fats within hepatocytes and together with its anti-inflammatory and antioxidant properties it protects the liver. It has recently been found that CBD cures liver diseases such as: Hemohromatosis (Haemochromatosis-Iron Buildup) Wilson’s disease (copper buildup) Primary analysticcholangitis (autoimmune disease in bile ducts) Primary birrhosis Budd-Chiari syndrome (liver vein obstruction) Glycogen storage disease (Glycogen storage disease)) Gilbert’s syndrome is high in the blood. In our opinion, the therapeutic effects of CBD on the gallbladder and liver should be taken into account before the FDA decides to remove the CBD from the shelves, claiming that it damages the liver.

CBD against liver cancer 

CBD causes apoptosis (planned cellular death) in neuroblastoma, cappucci sarcoma, bladder cancer, colon cancer and liver cancer (13). CBD reduces the volume of cancerous tumour in the human prostate and inhibits the angiogenesis of the blood vessels within them. CBD stimulates the activity of a tissue inhibitor of the enzyme meteoproteins from the protein joint [TIMP-1 – Tissue Inhibitor of Metalo Proteinase] and therefore reduces the penetration of metastatic cells into healthy tissues. TIMP1 is a metaloprotogenic protein inhibitor molecule (MMP) that plays a crucial role in the composition of the extracellular medium (ECM), wound healing during pregnancy and metastasizing. In pregnancy, TIMP1 plays a regulatory role in the implantation process, especially during the invasion of the cytotropobblast (fertilized egg) into the endometrium of the uterus. In addition, it plays a role in the tainting of the proteins of fetal tissue and placental associated with the early stages of pregnancy.

Studies attribute this role to a mechanism involved in the chromatin structure in the promoter region of TIMP1 (14). Monitoring of TIMP1’s activity is involved in the development of cancer. Thus, CBD may prevent and cure cancer in the bladder, brain, mammary gland, prostate, skin, lungs, colon and blood (leukemia) (15).

Hereditary test for different types of CYP 450

Three subtypes of these enzymes are particularly important: 2C9, 2C19, 3A4 Patients with low activity of these enzymes should be advised and those with very high activity should be advised to calculate the CBD dose accordingly. “Do no harm” , is a very important motto for modern medicine. Millions of people all over the world use CBD in many forms and ways for extended periods of time without serious and noticeable side effects that cause the treatment of Phyto-cannabinoids to stop.

“The train has already left the station” and the FDA must focus on quality control, training and training for doctors, pharmacists and patients. Instead of warning letters to CBD oil producers, the FDA should focus on studies that will hereditaryly value a patient’s sensitivity to high doses of CBD – according to subtypes of his liver enzymes. A list of common medications not to be taken along with high doses of CBD will contribute to the health of the general population. As a rule of thumb – do not take any medication that should not be taken together with grapefruit with CBD.

CBD & Drug Interactions There are currently eight main interactions between cannabidiol and pharmaceuticals (and 504 moderate interactions):

• Alcohol – Alcohol (EtOH)
• Aspirin
• Benadryl (diphenhydramine)
• Simbalta (Delkastin) Cymbalta (dulextine)
• Lyrica Pergablin- Lyrica
• Tylenol acetaminophen
• Zoloft (Sarterlin) 
• Zyrtec (cetirizine)

Moya-CBD’s full list of cannabinoids and drug collisions

CBD interactions with various human diseases

CBD and liver damage

CBD has been found to increase the activity of liver and serum transminas and therefore serum transminas (ALT & AST) and overall bilirubin levels should be measured in all patients who suffer liver damage before starting CBD treatment. It is recommended to adjust the dose to people suffering from liver impairment. It may be necessary to perform a slower titration (calibration) in the dose. Patients who develop symptoms that indicate liver dysfunction (nausea, vomiting, fatigue, anorexia, jaundice) must stop treatment for CBD. It is always recommended to consult your doctor before starting or discontinuing any medication (16). Most medication withdrawal must be done in stages and gradually and not all at once.

Cannabis research in rodisers is not a good fit for the human Endo-cannabinoid System.

Most cannabinoid studies are conducted on rodents. However, the rodent model does not fit well with the way cannabis behaves in the human body. There are differences in CB2R genes between humans and rodisers (17).

Comparing the species, it was found that the CB2 gene of the human genome, rat and mouse differ in gene structures and isoform expression patterns – different forms of their receptor protein. Moreover, the structure and activity of CB2R in rats differ from those of mice. Evolutionary changes in CB2R including its coding sequences, and the genetic regulatory elements may contribute in part to the differential effects of CB2R ligands on the self-management of cocaine consumption (18).

The effects of Phyto-cannabinoids can vary between males and females (gender differences). THC causes damage to nonspatial memory in humans but not rodence. A recent review estimated how often animal studies matched human results and found that only 37% were replicated in humans. Furthermore, about 18% of the results of the study examined were found to be contrary to the findings of these studies in humans. Legalization in other countries will clear the way for large clinical trials in humans in the future. Eye-level and impartial education is the common goal of all of us.

Claim 2. CBD causes a reduction in testosterone levels.

THC & The functioning of the male reproductive system

The effect of marijuana versus tobacco smoke on the male reproductive system was recently studied by Dr. Jorge Halkel and her colleagues in Brazil found that levels of free radicals (ROS) increase among people who smoke cannabis and tobacco (19,20) (2).  Moreover, a reduction in sperm count, advanced motility as well as morphology and DNA integrity were affected by heavy chronic smoking. The study was very small (24 men) and evaluated the sperm quality only of men who sought clinical support for fertility. The picture in the general population may be completely different. This 40% reduction in sperm concentrations may make it difficult for men with sperm counts already affected and make them less fertile. One study by the same group of researchers in Brazil also found a poor acrosum response that can lower fertility (ACROZOME – the part at the top of the sperm that breaks through the egg shell).

Each cannabinoid directly linked to CB1 and CB2 receptors – such as THC – will have a negative effect (at least while present in the bloodstream) on male reproductive function, since the endocannabinoid system plays a modular monitoring role in the hypothalamus pituitary gonads HPG axis. THC has been shown to lower testosterone synthesis (T) by suppressing the enzymatic activity of Leydig cells in the testicles, and actually acts as a type of endocrine disorder (2).

However, these studies have shown no significant change in plasma testosterone levels when smoking marijuana, so we need to look at all this research in its broader context. CBD, which slows down T production, but at the same time it also suppresses the metabolism and breakdown (oxidation) of testosterone in the liver, and does not lower serum T levels in the bloodstream. The interplay between the endocannabinoid system and the HPG axis actually appears to be a complex and of limited physiological importance in man  (21).

• It seems that THC in high concentrations does not help the health of the male reproductive system since THC binds directly to CB1 and CB2 receptors and causes a modular reaction in these tissues (hypothalamus, pituitary, testicle).
• Some studies have also shown that marijuana use does not affect serum testosterone levels. While other studies have shown it is.
• CBD is not directly associated with CB1 and CB2 receptors – so its effects are more positive for the male reproductive system than isolated THC. Reducing damage to the reproductive system is very important at the beginning of the third millennium.
• CBD exerts a protective effect for testosterone [T] in the liver as a result of delaying the activity of certain subtypes of the CYP-450 enzyme that breaks down testosterone.
• CBD may seem to slow down T synthesis in Leydig cells, however it does not lower serum T levels. CBD simply seems to slow down the production process of T while it is in the bloodstream, but then T production returns to normal when the CBD disappears. No long-term damage was caused by CBD.
• CBD also lowers prolactin levels and lowers cortisol levels in the body. It’s a positive effect. We aim for lower prolactin and lower cortisol, since both are inversely correlated with levels of serum T. Oxidative stress causes a decrease in testosterone levels in the blood.

CBD and testosterone

In the cells of sperm, hypothalamus, pituitary gland, Leydig cells as well as testicle seroli cells, can be found in cannabinoid receptors that can affect testosterone production. There is evidence to suggest that CBD can play a role in balancing testosterone levels (T).

This is because CBD has the potential to slow down T production, while at the same time limiting its decomposition in the liver. Similarly, CBD does not lower testosterone levels in serum and bloodstream. Indeed, CBD can actually help stimulate testosterone production in other ways. This cannabis compound limits the production of the hormones prolactin and cortisol, two neurotransmitters that can slow down some testosterone production. This is because both of these hormones are produced in the human body in response to stress. After intense exercise, the body needs time to heal.

This is because cortisol is released after exercise. Training is a type of physical stress that triggers the same “fight or flight” response as emotional stress and stress. Increased levels of cortisol may affect human health over time. Tissues will begin to break down, proteins will not be synonymed at the same speed and the body will not properly convert protein into glucose. High cortisol in the blood also inhibits muscle development and leads to an increase in body fat. By limiting the amount of stress in life, it is possible to help our bodies naturally produce more T. From an emotional point of view, CBD is known for its anti-anxiety effects (22).

This means that some people may find that they feel more relaxed after using the CBD product. Many studies have found that CBD is an effective addition to general anxiety disorder treatment programs. By limiting the amount of emotional stress and stress, the body produces more T. A very important diet as well – a recent study found that subjects who increase the consumption of essential fatty acids (ESSENTIAL FAs), increased and improved testicular function, which apparently helped improve T production levels and improve fertility (23). Reporting the use of illegal drugs is not the most reliable method, especially in men seeking fertility treatments and depending on the decision of the authorities. On the contrary, it is possible that these men did not tell the truth about the use of cannabis to gain fertilization treatment.

Testosterone effect in the woman

When it comes to sex hormones, women are driven by oestrogen and men are driven by testosterone. However, they all have both – only women have more oestrogen while men have more testosterone. Testosterone is an androgen, which is a “male” sex hormone that plays a role in the proliferation, growth and maintenance of a healthy body. In men testosterone (T) is mainly produced in the testicles. In women’s bodies, testosterone is produced in the ovaries, adrenal glands, fat cells, and skin cells. In general, women’s bodies are about 1/10 to 1/20 of the amount of testosterone as men’s bodies. In men, testosterone and other androgens play a role in: body fat distribution, hair growth, bone density and facial and body shape, mood, muscle growth and strength, production of red blood cells, sperm production and sexual drive.

In women T affects bone health, breast health, fertility, sexual desire, menstrual cycles, and vaginal health. Women’s bodies easily convert testosterone and other underogens they produce into female sex hormones. Both females and men experience an initial surge of testosterone and oestrogen (hormonal) during adolescence, which lasts until young adulthood. This production of sex hormones contributes to the development of secondary sex characteristics. These include deep voices and facial hair in males and higher voices and breast development in women. Most females do not develop characteristics of men because testosterone and other androgens work differently in their bodies, quickly becoming oestrogen.

However, when female bodies produce an excess amount of testosterone or other androgens, their bodies cannot keep up with the conversion of T to oestrogen. As a result, they may experience a man, also known as virilization, and develop more male secondary sex characteristics, such as facial hair and male aculates. As men and women age, their bodies produce less T, but it continues to play a role in maintaining health and libido for both. Testosterone is an androgen found in both men and women. In the female body testosterone quickly becomes oestrogen, while in men it remains mainly as testosterone. In women, testosterone plays a role in reproduction, growth and overall health. Low levels of testosterone in women are best treated by treating any medical or mental health problems, rather than by taking testosterone supplements intended for men.

Women with high testosterone may naturally reduce testosterone levels by incorporating foods and herbs into your diet. CBD – which lowers serum T levels in both sexes, can treat the aforementioned feminine disorders caused by too high levels of serum T. Only men during their reproductive period should reduce CBD doses while women are less sensitive in this respect (23). To naturally improve men’s testosterone levels, most experts recommend focusing on prioritizing sleep, fostering a healthy and balanced diet, shedding excess weight, regularly moderate physical training, and finding ways to drastically reduce stress.

There is no doubt that the use of marijuana for recreational purposes and medicines will increase and become even more common in the near future. In light of the deep involvement of the Endo-cannabinoid System (ECS) in the regulation of male reproduction and the direct effect of exogenous cannabinoids on the homeostasis of the ECS, it is certainly necessary to continue to examine the effects of marijuana smoking on the reproductive system in both sexes. Surprisingly, very few studies have examined the direct effect of marijuana on male infertility. This can be attributed mainly to legislation and ethic considerations that make research almost impossible to carry out as clinical studies in humans.

The current body of knowledge relating to this subject consists mainly of several previous human studies and more recently animal and test-on studies. Despite these limitations, it is clear that marijuana and its compounds can affect male fertility at multiple levels. Several studies have attributed de-regulation of the HPG axis, and a specific reduction in a key hormone such as the Luteinizing Hormone (LH) and Follicle Stimulating hormone (FSH), which, in turn, can affect testosterone [T] and sperm production. Other studies show the opposite effect – an increase in LH levels as a result of smoking cannabis (23).

It appears that marijuana can affect sperm parameters and sperm function by acting through the cannabinoid receptors (CB1R & CB2R) and the honyloid receptors [TRPV1-3]. Moreover, sexual health has also been linked to marijuana because it appears to have a positive effect on erection function in men. With the change in legislation and the de-criminalization of marijuana use and the fact that some studies report conflicting findings, it is of the utmost importance to carry out additional clinical studies to examine the effects of marijuana use in more detail.

Although human studies today are few and limited by the nature of their observation, the existing assumption underpins the argument that marijuana use has a detrimental effect on male reproductive potential. It will also be interesting to investigate the effects of marijuana use on tobacco smokers, since a recent study found that cigarette smokers also tend to misuse cannabis, while cigarette-smoking males in fertile pairs showed lower ejaculation volumes despite higher serum T levels (23).

An increase in acidity (pH) and Reactive Oxygen Species concentration (ROS) of seeds was found in men as a result of environmental exposure to toxins and poor diet. All of these findings highlight the fact that doctors should include questions about marijuana use while evaluating fertility in men.

Health professionals should also remember the relationship and potential impact of marijuana on male fertility when writing a prescription for medical marijuana. Social studies have found that cannabis is an effective aphrodisiac, suggesting that there is another link between cannabis and the bedroom (in vivo) than can be learned in the laboratory (in vitro). To date, cannabis and reproductive research remains preliminary, with conflicting results and no clear conclusions.

Claim 3. CBD and alcohol [EtOH]combined have a synergistic effect and can cause dangerous side effects.

Interaction of CBD and alcohol in humans

Six men and four healthy volunteers (total 10) received oral placebo (glucose capsule and orange juice), cannabidiol (capsule 200mg and orange juice), alcohol (1kg of orange juice), alcohol (1kg of orange juice and glucose capsule) and CBD (200mg capsule) plus alcohol (1g/kg of orange juice) in a random trial design, double-blind and cross-referenced. The treatments were conducted a week apart.

The parameters measured were finger-pressing test (motor performance), differential elimination and adjustment capacity tests (psychomotor performance), one-minute time production task, subjective effects (66 degree points semantic difference) and respiratory assessments of blood alcohol levels. Compared to placebo, alcohol and alcohol plus CBD, but not only CBD, significant impairments in motor and psycho motor functions, overestimations of time production and subjective reactions that indicate self-perception of intolerance and their disadvantages.

The combination of alcohol plus CBD resulted in a significant decrease in blood alcohol levels compared to alcohol given alone, however, few differences were observed between the pharmacological effects of the two alcohol states. Thus, the inactivity of CBD, a major marijuana component, on motor and mental performance also affects the interaction with alcohol (24). Excessive alcohol consumption, which characterizes alcohol misuse disorders, causes neurodegenerative nervous system cells and behavioural and cognitive deficiencies that contribute to the chronic and repetitive nature of alcoholism.

In trial 1, CBD jelly of 1.0%, 2.5% and 5.0% were tested for neural protection tests. The CBD gel of 5.0% resulted in a 48.8% decrease in intrauterine cortical nervous degeneration evaluated by Fluoro-Jade B (FJB), which tended to be statistically distinct (p = 0.069). The treatment of the CBD gel of 5.0% resulted in plasma concentrations of CBD on day 3~~100.0 nanograms per ml and therefore this level was used as a target concentration for the development of a modified gel compound.

Experiment 2 tested CBD gel at a concentration of 2.5%, which was compared to CBD moderating by injecting peritorous facial into the perineum cavity of the abdomen (40.0mg per kg per day IP). In this experiment, a similar level of protection of nervous system cells was found following both ways of insertion; CBD on the skin reduced the FJB+ cells in the intrauterine cortex by 56.1% (p <0.05), while injectable CBD (IP) resulted in a 50.6% decrease (p <0.05) in FJB+cells. These results demonstrate the feasibility of using CBD transfer systems on the skin to treat alcohol-induced anaesthy  (25).

Claim 4. CBD can cause fatigue, sleepiness and falling asleep.

CBD operations were recently tested on the sleep wake cycle of male wistar rats. Systemic administration of CBD appears to increase overall sleep time, in addition to increasing sleep latency (the time that passes from turning off the light to the appearance of sleep) during the light period of the day of taking (26). During the trials, individual doses of 20mg/kg CBD reduced the delay time of slow sleep (SWS).

After 40mg/kg SWS time was significantly increased while comments decreased. REM sleep has not been significantly changed. Following one-time injections per day of 40mg/kg CBD for a period of 15 days, tolerance has developed for all of the above effects (27). Despite the stimulating effects caused by CBD in one trial, others reported conflicting findings. One possible explanation can lie in the differences described in the methodological procedures (through giving, carrier, doses, genetics of the subjects, etc.). For example, in some reports, CBD is given either i.c.v or leaked directly into a transverse hypothalamus).

Moreover, some authors reported doses of 40mg/kg while others used a maximum dose of 20 mg / mcg. More trials are needed to clarify the potential mechanism of action of CBD on sleep modus operandi  (28).

Endocannabinoid signaling regulates the stability of sleep

These results support the hypothesis that endocannabinoid signaling using the CB1R receptor is necessary to maintain NREM stability but no homaustsis is needed in sleep (29). The research on cannabis and sleep is in its infancy and has yielded mixed results.

Further controlled research is critical to further our understanding of the issue as a whole and its clinical implications, with currently the claim that CBD improves sleep quality and does not impair its quality and combination of cannabinol (CBN) with CBD or CBG relaxes and anesthesisiose (30).

Claim 5. CBD causes gastrointestinal problems such as diarrhoea, abdominal pain and Irritable Bowel Disease (IBD)

Many studies prove the varied effects of CBD due to its antioxidant properties and inflammation calms in various gastrointestinal disorders, such as Crohn’s disease, ulcerative colitis and IBD. Furthermore, the strong anti-inflammatory and antioxidant effects of CBD throughout the digestive system (including pancreas, liver and gallbladder) have recently been found to protect against gastrointestinal malignation. CBD also reduces nausea, vomiting and loss of appetite which are common symptoms of gastrointestinal disorders.

That is why we must carefully consider the many advantages and disadvantages that are few in relation to the effects of CBD on the digestive system in humans. It is worth noting that gastrointestinal problems occurred only in a negligible part of the millions of CBD users (31).

Claim 6. Safety of CBD during pregnancy and lactation

As a rule of thumb – a pregnant and lupating woman should not ingest Phyto-cannabinoids in any way. Instead of warning letters, the FDA should educate the public honestly and honestly. Reliable, eye-level theory will benefit the FDA much more than a blanket ban on CBD use for everyone.

Claim 7. Interaction of CBD and pharmaceuticals 

Previously about the effect of CBD on the liver, the interactions between common drugs and high doses of CBD are described in detail. Doctors and pharmacists should have a list of medications not to be taken along with CBD. A clear warning should be written on the packaging and containers of CBD products in this regard.

How do I know if a prescription drug you are taking conflicts with CBD?

Our use is given a warning that accompanies the taking of certain medications – not to eat or drink grapefruit for the entire duration of use of the drug. *

The doctor who registers the drug should warn the consumer before using the drug that a collision between the drug and grapefruit may have bad results. Pharmaceutical companies are also obliged to warn consumers about not using grapefruit and the warning can be searched in a newsletter to the customer or on the drug’s website.

Why grapefruit?

Grapefruit contains plant chemicals called furanocoumarinsthat inhibit one of the enzymes responsible for the breakdown of drugs in the body (the enzyme CYP3A4 is found in the liver and in the walls of the small intestine).

The result of inhibiting the enzyme is a significant increase in the level of drugs in the blood and a worsening of their side effects. It should be noted that this effect of inhibiting enzymes from pharmaceutical joints is probably also responsible for plant chemicals called flavonoids that are also found in grapefruits.

External links:

• Plant Chemicals and Furanocoumarins 
• CyP3A4 enzyme
• Flavonoids

Claim 8. CBD toxicity to the vascular system.

Numerous studies have shown protective effects of CBD (at very low doses) on the heart and vascular system (33). CBD has been found to reduce high blood pressure [HBP] in rats and humans (34). CBD also reduces the risk of ischemic stroke (a blood clot that blockes blood flow to the brain) by increasing blood flow in the brain (35). CBD has been found to cure heart muscle ischemia by protecting the heart muscle from degeneration (36).

CBD also protects endothelial cells that cover blood vessels, reducing atherosclerosis (37). CBD has been found to strengthen the heart muscle and improve its oxygen consumption (36). The anti-inflammatory effect of CBD in myocardial tissue is the result of inhibiting the enzyme [MPO]- Myelo PerOxidase. MPO is involved in many inflammatory processes in many organs and tissues (38).

Furthermore, CBD inhibits the release of cytokines (TNF & IL-6) and mockins (MCP1 &2) from immune cells in inflated heart muscle tissue. CBD also blocks the migration of neutrophils to the inflammatory tissue. All these therapeutic effects of CBD improve the recovery of heart muscles. CBD toxicity to the vascular and heart system is only marginal (39).

Unspoilt CBD Products [OTC – over the counter]

Over-the-counter CBD products are not regulated or currently supervised by the FDA or any other party. It is recommended to buy CBD from a reliable source and prefer non-GMO, organic, GMP-standard and reliable third-party tests that ensure the product is accurately labelled. It is also recommended to start with a small dose of CBD and increase the dose gradually. If unwanted adverse side effects occur, discontinue CBD treatment and consult your physician.

Summary

Since 1994 I have been studying CBD and researching in detail the pros and cons and many modus operandi of Phyto-cannabinoids. The molecule helps alleviate the symptoms of many diseases and cures people around the world. CBD can protect against many physical and mental disorders and diseases.

For more than two decades, the concept of “medicinal cannabis” has become common in almost every home in the Western world and many countries have passed legislation regulating its use while refuting myths about “leakage” or cannabis-related crime. Now, thanks to new technologies and hemp growth, instead of marijuana, CBD has become an alternative product to a growing audience. The FDA’s warning letter does not correspond to the accumulated information in research and reality, and mentions the chazal article: “Suspecting kosher, lacking in his body” – an innocent person should not be suspected.

A year after the warning letter, in early December 2020, the United Nations decided that cannabis was not a dangerous drug that lacked medical value because its medicinal value had been proven. All the more so with regard to the psychoactively influential CBD, for which the EU Supreme Court recently rejected the claim that CBD is narcotic and allowed to sell and market CBD as a food additive. Today, more than ever, the FDA has a duty to create a binding and uniform standard for testing CBD products and to act to inform and educate the public for sensible consumption and to prevent drug collisions. With the FDA’s unwavering international authority comes tremendous responsibility.