CBD is big news. CBD, or cannabidiol, is the second most common cannabinoid in the cannabis plant trailing second only after tetrahydrocannabinol (THC). Let’s be clear, CBD is not psychoactive like THC, so why all the fuss? More than likely the reason is CBD has shown unprecedented promise in treating conditions medicine has not yet effectively been able to treat.
History of CBD
Cannabinoids, all 113 of them, have been used medicinally in the form of cannabis dating back 5,000 years and was even a patented medicine in the nineteenth and twentieth centuries. Evidence has been found that THC was used in a medicinal fashion as early as 400 AD.
CBD was identified in 1942 earlier than its companion, THC, and originally was thought to be the active component in the psychoactive effects of the plant. The chemistry of CBD was not isolated until 1963 and that of THC in 1964 so researchers found it difficult to know which effects came from which cannabinoids.
Is CBD Legal to Use?
Prohibition was enacted under U.S. federal law in 1970 and cannabis became illegal to use. This act put a limit on research into cannabis and its various potential medicinal effects as it was not legal to procure it for study. In December of 2018, however, the Farm Act was passed and it legalized hemp as a source of CBD at < 3% THC. Hemp is legal in much of Europe with a THC content of <2%.
In the UK, CBD is allowed in foods as “novel foods” unlike in the grey areas of the US where edibles are not legally endorsed. Cold pressed CBD oil or flour is not allowed in the preparation of the edibles, however. Some examples of “novel foods” that fall under this regulation include:
- CBD supplement capsules, oils, or sprays
- CBD sweets, gummies, candies
- CBD infused beverages such as beer, tea, sodas
- CBD infused snacks and energy bars
Technically speaking, for a CBD edible to be legal it should contain no THC, the .2% regulation applies only to the cultivation of hemp and not extracted components.
Despite the legal grey areas and loopholes, CBD has become a 9 billion dollar industry with almost 7% of the U.S. population admitting to trying it. Recent news predicts the use of CBD in the UK to rise by 700% reaching a $2.1 billion dollar industry by the year 2020. It is estimated that 300,000 people in the UK use CBD.
Molecular Structure of CBD
It is interesting that both CBD and THC contain the same molecular formula, C21H30O2, or 21 atoms of carbon, 30 atoms of hydrogen and 2 atoms of oxygen. Their molecular mass is remarkably similar as well So, what makes up the difference between the two molecules? There is one exceedingly small difference between the two molecules. THC contains a cyclic ring in its molecular structure and CBD contains a hydroxyl group and this is enough to create a world of difference in their pharmacological attributes.
Figure 1. Cannabidiol1
Potential Benefits of Using CBD
While human studies are scarce thanks to the legal red tape that has tied the hands of researchers for years, animal studies and a few surviving clinical studies have shown stunning potential medical benefits for CBD as well as the entire line of cannabinoids identified to date. The primary areas of scrutiny for the use of CBD have focused on the alleviation of pain from inflammation, anti-anxiety effects, effects on the sleep-wake cycle, and antidepressant actions.
Benefits to lab animals are encouraging but cannot be directly extrapolated to the human population due to differing metabolisms, diets, lab conditions, bioavailability of the CBD and dose adjustments. Nevertheless, testimonials as to CBD’s effectiveness for these various conditions just mentioned abound and are not about to be silenced by a public hungry for medical answers to pressing problems.
Subjective anxiety in one study was reduced with 300 mg CBD but not 100 or 900 mg indicating a U curve of response to dose. The study compared 3 doses of CBD against 1 mg of Clonazepam. Clonazepam showed more of a sedative effect than CBD did.
Dose response curves vary with the type of product being used. While CBD isolate shows a U-shaped response curve, full spectrum CBD exhibits a linear dose response curve which may have greater clinical implications. Full spectrum CBD contains all the cannabinoids including THC while an isolate is just CBD.
Other conditions CBD is being researched for include the improvement of skin conditions, neurological conditions (Parkinson’s, Autism, ALS), schizophrenia, seizures, pain, mood in general, cannabis withdrawal, nicotine withdrawal, PTSD, sleep disorders, cancer, Alzheimer’s Disease and gastrointestinal disorders.
Benefits of CBD compounded by the endocannabinoid system interactions
However, because the endocannabinoid system affects so many physiological functions in the body and CBD interacts with our endocannabinoid system in an indirect fashion, it only stands to reason that CBD has the potential to impact those same areas the endocannabinoid system regulates such as the functions of appetite, immune system, reproduction, pain management, neurological functions, oxidation reactions and the sleep cycle.
Mechanisms of Action of CBD
CBD and CB1 receptors
CBD acts on multiple systems and interacts with a wide array of neurotransmitters. CBD interacts with both the CB1 and CB2 receptors although not directly. CBD is a negative allosteric modulator of the receptor CB1. What this means is that it changes the shape of the receptor so that THC cannot bind to it and create the psychotropic effects that it is so well known for. It also accomplishes other actions by this modulating effect on the CB1 receptor.
The CB1 receptors are in the brain, central nervous system, cardiovascular system, reproductive system, liver, and others.
CBD and CB2 receptors
The CB2 receptors are in the peripheral tissues, lymph, and immune system. Activation of these receptors do not initiate any psychotropic effects. CBD has little binding affinity to these receptors but may affect them indirectly.
CBD and Serotonin or 5-HT Receptors
CBD directly activates the serotonin receptor, thus conveying an anti-anxiety effect. This G-coupled protein receptor is implicated in a range of biological and neurological processes, including (but not limited to) anxiety, addiction, appetite, sleep, pain perception, nausea, and vomiting.
CBD at high concentrations has been shown to interact with the 5-HT receptors directly activating this serotonin producing process thus encouraging a wide range of biological and neurological processes surrounding these interactions.
CBD affects Fatty Acid Amide Hydrolase
CBD influences the CB2 receptor via inhibition of one of the key enzymes, Fatty Acid Amide Hydrolase (FAAH), that breaks down the body’s own endogenous cannabinoid, anandamide. Thus, this endocannabinoid remains active in the body’s system to exert its harmonizing effects throughout the body for a longer period. Anandamide has been coined with the term “blissful molecule” due to its generation of motivation and pleasure.
CBD and TRPV1
CBD also interacts with a number of other important physiological receptors, TRPV1, which mediates pain perception, inflammation and body temperature. CBD is considered a stimulant of this receptor.
TRPV1 is one of several receptor variants that mediate the effect of medicinal herbs. Capsaicin, found in hot chili peppers, also activates the TRVP-1 receptor.
CBD and adenosine receptors
Other receptors CBD interacts with include the adenosine receptors most commonly known for their anti-anxiety effects as well as playing significant roles in heart oxygenation and coronary blood flow. The adenosine receptors have wide anti-inflammatory effects throughout the body.
CBD and GPR55 receptors
Further is CBD’s interaction with the GPR55 receptor where it functions as an antagonist that deactivates several associated metabolic processes. GPR55 is involved in cell proliferation and bone density regulation. By blocking this receptor abnormal cell proliferation may be affected as well as the attenuation of bone resorption. This speaks to a possible role in osteoporosis management. It is interesting to note that in earlier times the GPR55 receptor was called the CB3 receptor.
It is interesting to note that when GPR55 is activated the cancer process is stimulated. Blocking this receptor may stop bone resorption and the cancer process.
CBD as a reuptake inhibitor
CBD competes with our endocannabinoids which are fatty acids for the same transport chemicals. For example, once inside the cell the body’s own endocannabinoid, anandamide is broken down by enzymes. CBD blocks this effect keeping anandamide active within the body’s system. Enhancing reuptake inhibition and thus, endocannabinoid tone, may be one mechanism for CBD’s anti-epileptic action in the body.
CBD as an allosteric modulator
What this means is that CBD can change the shape of a receptor and alter the way chemicals interact with it by either enhancing or inhibiting the signal the cell receives. Scientists in Australia report that CBD is a positive allosteric modulator of the GABA-A receptor meaning that it enhances the receptor’s activity with GABA, an inhibitory transmitter involved in the feelings of anxiety thus reducing anxiety in a similar fashion as benzodiazepines.
CBD and PPARs (Nuclear Receptors)
CBD exerts an anti-cancer effect by activating peroxisome proliferator activated receptors (PPARs) that are located on the surface of the cell’s nucleus. Activation of the receptor called PPAR-gamma degrades amyloid plaque found in Alzheimer’s disease. PPAR receptors may also regulate genes involved in energy metabolism, lipid uptake, insulin sensitivity and other metabolic functions. When activated, they help restore normal glucose levels making CBD a potential target for diabetic treatment.
This receptor, when activated, determines which genes get expressed. They are located mostly in fat tissue and immune cells.
Delivery of CBD
It takes between 2.5 and 5 hours to reach maximum concentrations in the blood when taken by the oral route. Its half life is between 56-61 hours and taking it on a full stomach results in higher blood levels more quickly. Existing data suggests that vaped CBD makes it into the blood stream in about 3 minutes. Sublingual CBD is thought to be more effective than oral since it bypasses the digestive track and enters the blood stream from the blood flow under the tongue.
The Entourage Effects
We have discussed the basics of how CBD interacts with various receptors but have yet to mention what is called the entourage effect. Essentially, CBD has a synergistic effect with other cannabinoids including THC, terpenes and other molecules that can enhance the systemic effects it exerts on the body. Thus, the various 113 some odd cannabinoids present in the cannabis plant can all work together to create an additive effect on the system that cannot be isolated by studying CBD alone.
Is CBD Safe?
According to the World Health Organization CBD is safe with a favorable safety profile and few, if any side-effects. Any side-effects noted are often the result of drug-drug interactions which need to be studied much more closely since CBD is involved in many drug detoxification pathways where in some cases it may cause a drug to be more or less potent than intended. The WHO has also commented that there is no evidence of a public health abuse problem or health related side-effects associated with pure CBD.
CBD reportedly increases warfarin levels and increases serum concentrations of many antidepressants, antipsychotics, beta blockers, statins, calcium channel blockers, benzodiazepines, and opioids, among others. While these drug interactions do not necessarily represent a contraindication to the use of CBD, but closer monitoring is warranted so drug dosages can be adjusted when needed.
A good rule of thumb is to avoid all drugs with an “Avoid Grapefruit” warning as these drugs all use the Cytochrome p-450 Oxidase System, the same enzyme system used by CBD. Taking drugs that use this enzyme system in conjunction with CBD may lead to drug overdoses or an excessive accumulation of the drug in the bloodstream.
Chronic use and high doses of up to 1500-2000 mg/day of CBD are well tolerated. CBD is non-toxic when metabolized in cells and does not alter food intake, induce catalepsy, affect heart rate, blood pressure or body temperature and does not affect gastrointestinal transit.
Despite this, the most reported side-effects include tiredness, diarrhea and changes of appetite and weight.
Conclusion
A national survey of over 4,000 respondents show that 22% of those surveyed use CBD to replace their pharmaceutical drugs completely referring mostly to pain medications, Tylenol, opioids, sleep aids and anti-anxiety medications.
If CBD can help people get off more dangerous medications, create favorable physiological changes and give the user a sense of well-being, well, we can see why it has become such a global overnight phenomenon.
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