Cannabidiol - Indications, Uses, Dosage, Administration, Warnings, and Side Effects

Overview:

The Cannabis sativa plant contains around 80 chemicals which are known as Cannabinoids. Cannabidiol (CBD) is obtained from hemp, a form of Cannabis sativa plant.

Decarboxylation from a cannabidiolic acid precursor forms a 21-carbon terpenophenolic compound called Cannabidiol. The medicine can also be synthesized artificially.

A prescription form of CBD is used for the treatment of epilepsy. CBD is also used for the management of pain, anxiety, dystonia, Crohn's disease, and Parkinson's disease. However, not much scientific evidence is available to support the same. A law was passed in 2018 to sell hemp and hemp products in the United States. CBD is a prescription medicine that cannot be legally used in food and dietary supplements. However, it can be used as a part of cosmetic products.

A prescription product named Epidiolex manufactured by GW pharmaceuticals is legally approved by the United States FDA (Food and Drug Administration) for the treatment of seizures caused by Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex. Other than the prescription product Epidiolex, the effectiveness of other forms of Cannabidiol for the treatment of seizures is not established. Epidiolex has completed phase III trials and is under current review for approval for use in the United States. CBD is also a part of various products like gums, supplements, oils, and high-concentration extracts available for the treatment of various ailments; however, it is marked normally as unapproved for medical use. CBD is a well-tolerated medicine, with adverse effects reported only in patients using drugs for other conditions that lead to drug interactions. Also, there is no evidence regarding public health problems associated with using a pure form of CBD.

How Does Cannabidiol Work?

CBD works by reducing neuronal hyperexcitability and inflammation by modulating intracellular calcium via GPR55 and TRPV1 channels and modulation of adenosine-mediated signaling. Studies are in progress to know the way Cannabidiol works at the molecular level. It is believed to produce multiple effects through various molecular pathways. Though CBD has a less binding affinity for CB1 and CB2 cannabinoid receptors, Cannabinoid works through non-cannabinoid receptors and ion channels. It also acts through several receptor-independent pathways. Cannabinoid activates serotonin receptors, vanilloid receptors, GPR 55 (G-protein coupled receptor) orphan receptors, and PPARS - nuclear receptors. Three critical phase III randomized, placebo-controlled, double-blind, multi-center trials showed the efficacy and safety of CBD in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). There were changes from the baseline for drop seizure frequency in LGS and convulsive seizure frequency in DS patients.

Indications and Uses of Cannabidiol:

Besides its prominent use in the treatment of epileptic seizures, Cannabidiol is also effective in treating multiple sclerosis (MS), a disease affecting the central nervous system (CNS), causing inflammation and lesions around the nerve fibers. A prescription product consisting of a nasal spray under the trade name sativex, manufactured by GW pharmaceuticals, is a combination of 9-delta-tetrahydrocannabinol (THC) and Cannabidiol that has been found useful for reducing pain, muscle tightness, and frequency of urination in MS patients. However, there is insufficient evidence on the effectiveness of Cannabidiol use alone for treating MS symptoms. A Cannabidiol spray to be used under the tongue is found effective solely in decreasing pain and muscle tightness in MS patients; however, patients' overall quality of life was not found to improve.

For Patients:

What Is Lennox-Gastaut Syndrome?

Lennox-Gastaut syndrome is a rare and severe form of epilepsy that begins in early childhood. It affects children between the ages of two to six years. The condition is characterized by frequent seizures that can be of several types. Along with seizures, the children also develop learning disabilities, developmental delays, and behavioral problems that can range from mild to severe. The causes of Lennox-Gastaut syndrome can be a lack of oxygen at birth, brain injuries, brain infections, or genetic abnormalities. Treatment helps reduce the frequency of seizures using a combination of drugs. Also, a ketogenic diet incorporating lesser carbohydrates and more fats helps reduce the intensity of seizures in children.

What Is Dravet Syndrome?

Dravet syndrome is also a rare form of the epileptic disorder, also called myoclonic epilepsy of infancy that starts in early infancy. The first seizure occurs in the first year of life, that lasts for more than five minutes, and is triggered by a high fever. Along with variations in the seizure types and frequency, the seizures are also accompanied by developmental delays. Dravet syndrome is an autosomal dominant disorder due to the transmission of a mutated SCN1A gene. The genetic mutations can be mild, causing migraine headaches, moderate forms of epilepsy, and the most severe form of epilepsy, Dravet syndrome. Complications of Dravet syndrome can be status epilepticus (continuous seizures) or SUDEP (sudden unexplained death in epilepsy). Medications are used for the treatment of epileptic attacks. They work by reducing the frequency of attacks.

What Is Tuberous Sclerosis?

Tuberous sclerosis is a rare genetic disorder that causes the growth of benign tumors in different body parts. The signs and symptoms vary in type and severity based on the location of the growths. The condition usually starts in infancy or childhood. Tuberous sclerosis can involve the skin, eyes, heart, lungs, and brain. Also, the affected children experience cognitive impairment and learning disabilities. Growths in the brain can cause symptoms like seizures, which is one of the earliest signs of tuberous sclerosis. The treatment is usually symptomatic that involves managing and treating the symptoms to prevent them from developing into complications.

For Doctors:

Chemical Name:

2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1- yl]-5-pentylbenzene-1,3-diol.

Physical Appearance:

CBD is a crystalline solid.

Chemical Properties:

Melting point - 62 to 63 degrees Celsius.

Solubility - Approximately 23.6 mg/mL in dimethyl sulphoxide and ethanol.

Ease of Convertibility Into Controlled Substances:

A few studies indicate the convertibility of Cannabidiol (CBD) into tetrahydrocannabinol (THC). There are also pieces of evidence about spontaneous conversion in vivo; however, additional research has suggested the transformation occurs only in specific experimental conditions and is unlikely to occur upon oral administration of CBD in humans.

Routes of Administration:

Currently, there are several CBD medicinal products under development. In research studies and clinical trials, CBD was administered orally, either in the form of capsules or dissolved in an oil solution like olive oil or sesame oil. CBD can also be administered through intranasal or sublingual routes. The oral doses reported in the literature ranged from 100 to 800 mg/kg per day.

Dosage and Administration:

Cannabidiol is available in the form of oils, creams, and tablets. The medical use and exact dosage of the drug are as below:

The Recommended Dosage for Treatment of Seizures in Lennox-Gastaut Syndrome and Dravet Syndrome:

The initial dose of Cannabidiol is 2.5 mg/kg to be taken orally twice daily. After a week, the dosage can be increased to a 5 mg/kg oral dose twice a day if well tolerated by the patient. In patients who require further seizure reduction, the dose can be increased by 2.5 mg/kg per day. The maximum dose of Cannabidiol is 20 mg/kg/day. The maintenance dose is 10 to 20 mg/kg/day. A dosage of 20 mg/kg/day has shown an increased reduction in the rate of seizures; however, it was associated with a greater risk of adverse effects. In pediatric patients aged one year and older, the maintenance dose is 10 to 20 mg/kg/day in two divided doses. Standard dosing with meals is advised to reduce variability in the plasma exposure of Cannabidiol.

The Recommended Dosage for Treatment of Seizures in Tuberous Sclerosis Complex:

The initial dose of Cannabidiol is 2.5 mg/kg to be taken orally twice a day. A weekly increment of 2.5 mg/kg to a maximum dose of 12.5 mg/kg per day is recommended. In patients requiring a rapid titration, the dosage is increased not very frequently than every other day. The maximum dose is 25 mg/kg/day, and the maintenance dose is 12.5 mg/kg orally twice a day. The effectiveness of the drug, when used at doses lower than 25 mg/kg/day, is yet to be studied. Standard dosing with meals is advised to reduce variability in the plasma exposure of Cannabidiol.

Dose Adjustments:

Dose Adjustments in Renal Impairment Patients:

No dose adjustment is recommended in renal impairment patients.

Dose Adjustments in Hepatic Impairment Patients:

There is no dosage adjustment recommended in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the initial dose is 1.25 mg/kg to be taken orally twice a day, followed by 2.5 to 5 mg/kg orally twice a day (for Lennox-Gastaut syndrome and Dravet syndrome). A maintenance dose of 6.25 mg/kg is to be administered twice a day (for tuberous sclerosis). In patients with severe hepatic impairment, the initial dose is 0.5 mg/kg to be taken orally twice a day, with a maintenance dose of 1 to 2 mg/kg orally twice a day (for Lennox-Gastaut syndrome and Dravet syndrome), and 2.5 mg/kg orally twice a day (for tuberous sclerosis). Slower dose titration is recommended for patients with moderate to severe hepatic impairment. Also, it is advised to stop the therapy in patients whose transaminase levels are three times the upper limit of normal and bilirubin two times the upper limit of normal.

Dose Adjustments in Elderly Patients:

The selection of dosage has to be done cautiously in elderly patients, usually starting with the lower end of the dosage range. During discontinuation of the therapy, a gradual reduction of the dose is recommended to reduce the risk of status epilepticus and increased seizure frequency.

Warnings and Precautions:

The use of the drug is contraindicated in the following conditions:

• The patient has a hypersensitivity to any active substance or product excipients.

• In patients younger than one year, the safety and efficacy of the drug are yet to be studied.

• The use of Cannabidiol is contraindicated in pregnant and breastfeeding women as the drug can be contaminated with other ingredients causing harmful effects on the fetus or the infant.

• Research suggests that taking high doses of Cannabidiol can worsen the tremors and muscle movements in patients with Parkinson's disease.

Administration Advice:

• The drug is recommended for oral administration only.

• It has to be taken consistently, either with or without food, to reduce the variability in plasma exposure.

• A calibrated measuring device must be used to ensure accuracy in dosage.

• Enteral feeding tubes like nasogastric tubes can be used for liquid forms of the drug. However, the use of tubes made up of PVC (polyvinyl chloride) is contraindicated.

Drug Interactions:

Cannabinoids THC (delta-9-tetrahydrocannabinol) and CBD (Cannabidiol) are metabolized by the CYP-450 (cytochrome P450) enzyme system. Studies conducted in animal models have shown that CBD inhibits the enzymes CYP3, CYP2D6, CYP2C9, and CYP2C19 and induces the drugs metabolized by the CYP2B enzyme. In addition, it has been found that CBD was an inhibitor of a few transporter systems.

The following drug interactions were noted when specific drugs were used with CBD for certain medical conditions.

1. Cilostazol: CYP2C19 is the enzyme that metabolizes the substrate Cilostazol. CBD is a CYP2C19 inhibitor, which increases the serum concentration of Cilostazol. It is recommended to consider therapy modification.

2. Citalopram: CYP2C19 inhibitors moderately increase the serum concentration of the substrate Citalopram. Therefore, a therapy modification is recommended.

3. Clobazam: Studies have shown that CBD interacts with 2C19 substrate, leading to increased Clobazam levels. It is studied that CBD increases the serum levels of the active metabolites of Clobazam. It is recommended to monitor the therapy as the interactions are common only during oral administration of CBD.

4. Clopidogrel: CYP2C19 inhibitors are found to moderately decrease the serum concentrations of the active metabolites of Clopidogrel.

5. CNS depressants: CBD is found to enhance the CNS depressant effects of CNS depressants. It is recommended to monitor the therapy.

6. CYP2C19 Inducers: Strong CYP2C19 inducers can decrease the serum concentration of CBD.

7. CYP2C19 Inhibitors: Moderate inhibitors of CYP2C19 can increase the serum concentration of CBD. It is recommended to monitor the therapy.

8. CYP2C19 Inhibitors: Strong CYP2C19 inhibitors increase the serum concentration of CBD.

9. CYP2C19 Substrates: Moderate inhibitors of CYP2C19 are found to decrease the metabolism of CYP2C19 substrates.

10. CYP3A4 Inducers: Strong inducers of CYP3A4 decrease the serum concentration of CBD.

11. CYP3A4 Inhibitors: Moderate and strong inhibitors of CYP3A4 can increase the serum concentration of CBD.

Monitoring of therapy is advised to increase or decrease the serum concentrations of CBD due to drug interactions.

The drug interactions between CBD and various other drugs include:

Sedative Medications and CBD:

Both Cannabidiol and sedatives (CNS depressants) can cause drowsiness and slow breathing. Therefore, a combination of drugs has to be avoided.

Clobazam and CBD:

The liver metabolizes Clobazam. CBD decreases the speed of metabolization of Clobazam which can increase the actions and side effects.

Eslicarbazepine and CBD:

CBD affects how quickly the body breaks down Eslicarbazepine. This increases the serum concentration of Eslicarbazepine in the body in small amounts.

Rufinamide and CBD:

CBD can increase the levels of Rufinamide in the body by affecting the way how quickly it is metabolized in the body.

Topiramate and CBD:

Topiramate levels are also found to increase by small amounts when administered along with CBD.

Valproate and CBD:

Valproic acid can damage the liver. When Valproate and CBD are prescribed together, it can increase the chances of liver injury. Either of the drugs has to be stopped, or the dosages have to be reduced.

Zonisamide and CBD:

The serum levels of Zonisamide have also been found to increase in small quantities when prescribed, along with CBD.

Lithium and CBD:

Higher doses of CBD can increase the levels of lithium, thereby increasing lithium toxicity.

Warfarin and CBD:

CBD increases the levels of Warfarin in the body, which can increase the risk of bleeding.

The other drugs whose levels can increase in the body when administered along with CBD include:

• Brivaracetam.

• Everolimus.

• Tacrolimus.

• Methadone.

• Carbamazepine.

• Sirolimus.

• Stiripentol.

• Tamoxifen.

• Caffeine.

• Citalopram.

Description:

Each packet of CBD oral capsules contains 15000 mg of decarboxylated Cannabis sativa and 300 mg of the active ingredient Cannabidiol (CBD). Each capsule of CBD delivers 10 mg of Cannabidiol. The medicine is prescribed for oral use. It is recommended to swallow the capsule and not chew. For best results, a CBD capsule has to be taken with or after food.

Pharmacokinetics:

The oral route of an oil-based capsule of CBD has been studied in humans. Due to its poor aqueous solubility, CBD absorption from the gut is difficult, resulting in a variable pharmacokinetic profile. The bioavailability of CBD was found to be six percent because of a significant first-pass metabolism. Aerosolized CBD was reported to reach peak plasma concentrations within five to ten minutes and have higher bioavailability compared to oral administration routes. CBD was found to get rapidly distributed into the tissues with a high volume of distribution around 32 L/kg. Also, the drug accumulation was mostly in the adipose tissue due to its lipophilic nature. CBD is greatly metabolized in the liver. A study on the human liver microsomes suggested that pooled HLMs metabolized CBD into eight monohydroxylated metabolites.

The seven recombinant enzymes that are capable of metabolizing CBD include:

• CYP1A1.

• CYP1A2.

• CYP2C9.

• CYP2C19.

• CYP2D6.

• CYP3A4.

• CYP2C19.

Studies have shown CBD inhibits CYP isoenzymes invitro; however, it is unclear whether this occurs at concentrations achieved by the use of clinical doses.

Mechanism of Action: Cannabidiol reduces the hyperexcitability and inflammation of neurons through modulation of intracellular calcium via GRP55 and TRPV1 channels and modulation of adenosine-mediated signaling.

Absorption: Cannabidiol exposure up to a dose of 6000 mg under fasting conditions has exhibited a nonlinear increase. The median time of peak plasma concentration (T max) for CBD ranges from two hours 30 minutes to five hours. The absolute bioavailability of the drug is yet to be determined. When taken with a high-fat meal, C max (peak concentration of the drug in a specific compartment of the body after the administration of the first dose and before the administration of the second dose) and AUC (area under the curve) of CBD is five-fold and four-fold respectively.

Distribution: Studies have shown a high plasma binding of greater than 94 percent for Cannabidiol and its metabolites. (6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD). The estimated volume of distribution was 20963 L to 42849 L when observed in healthy volunteers.

Metabolism: CBD is metabolized extensively in the liver and gut. The enzymes CYP2C19, CYP3A4 and UGTIA7, UGTIA9, and UGT2B7 are primarily involved in the metabolism. 7-COOH-CBD (7-carboxy-cannabidiol) and 7-OH-CBD are the major circulating metabolites of CBD, whereas 6-OH-CBD (6-hydroxy-cannabidiol) is the minor circulating metabolite. Non-clinical animal models of epilepsy have shown CBD and 7-OH-CBD to be the most abundant and active metabolites and 7-COOH-CBD to be the inactive metabolite.

Elimination: The mean elimination half-life was between 56 to 61 hours in healthy volunteers who were administered doses of CBD twice daily for seven days. After administering a single dose of 5 mg/kg, the total radioactivity recovered after 168 hours was 94 percent, with the fecal route being 84 percent and small proportions recovered through urine being eight percent.

Pharmacodynamics: CB1 and CB2 are the two important cannabinoid receptors. CB1 receptors are primarily located in CNS (central nervous system), with a few of them in the peripheral tissues. CB2 receptors are found on the cell peripheries of the immune system, GI (gastrointestinal tract), and at lower densities of the CNS. CBD has a low affinity for both CB1 and CB2 receptors with a low binding affinity.

CBD was also found to interact with endocannabinoid systems through indirect mechanisms leading to an improved action of endogenous cannabinoid ligand anandamide. CBD was also studied to regulate non-endocannabinoid signaling systems.

Toxicology: The potential toxic effects of CBD have been studied extensively during in vitro studies and animal studies. CBD was proven to have lower toxic effects comparatively; however, all the effects are yet to be explored.

The below findings have been noted based on studies:

• CBD affects the growth of tumor cells; however, there are no significant effects on the growth of other cells, except for a pro-apoptotic effect on the lymphocytes.

• Limited research suggests no effect of CBD on embryonic development.

• Effects on hormonal changes have a mixed result, with some studies pointing towards possible effects and others pointing to no effects. The result also depends on the hormone that is involved.

• There are no significant effects on various physiological and biochemical parameters.

• Effects on the immune system are unclear. However, there is evidence of stimulation of the immune system at lower concentrations of CBD and suppression of the immune system at higher concentrations of the drug.

• CBD can cause certain drug interactions by inhibiting cytochrome P450 enzymes. However, it is not clear whether these interactions occur at physiological concentrations.

Adverse Reactions in Humans:

CBD does not produce any pronounced adverse effects, as noted with cannabinoids like THC. A number of clinical trials have shown that CBD is a well-tolerated drug with a good safety profile.

Dependence Potential in Humans:

Physical dependence effects like withdrawal and tolerance of CBD are yet to be reported in human studies.

Abuse Potential in Humans:

Though there is limited evidence, well-controlled clinical studies have shown that CBD does not pose a risk of abuse potential.

Effects on Pregnancy and Lactation:

There is limited evidence on the safe use and efficacy of CBD in pregnant and lactating females. As the endocannabinoid system plays a role in regulating fertility, the use of cannabis and disruption of the endocannabinoid system has shown a negative impact on reproduction.

Effect of Food Intake on the Bioavailability of the Drug:

A diet high in fat, when consumed after taking oral Cannabidiol has shown increased absorption of the drug compared to taking it on an empty stomach. An oral capsule of CBD rather than a liquid form was found to have a precise determination of pharmacokinetic parameters. A university study was conducted in which the subjects were administered a single dose of 99 percent pure form of CBD under fasting and having a high-fat meal, whose blood samples were collected and assessed over a period of zero to 72 hours have shown a Cmax value of 14 times and AUC of four times higher in people who were fed a high-fat meal when compared to those who took the dose post fasting.

Drug Exposure at a Steady-State Following Therapeutic Dosing Regimen:

The mean overall exposure at a steady state of Cannabidiol at 10 mg/kg/day was 966 ng.hr/mL and at 20 mg/kg/day was 2000 ng.hr/mL in patients between the age groups of 18 and 55 years.

Dose Proportionality: The pharmacokinetics of CBD was nonlinear over a dose range of 750 to 6000 mg in healthy subjects and 5 to 20 mg/kg/day in epilepsy patients.

Accumulation: A mean accumulation ratio noted at a steady-state was between 1.79 and 2.0.

Variability: Intra-subject variability is yet to be studied. Inter subject variability ranges from 35.1 percent to 112.8 percent for Cannabidiol Cmax and 32.3 percent to 104.1 percent for Cannabidiol AUC. The central volume of distribution is 28 to 72 percent, and the peripheral volume of distribution is 91 percent.

Patient Information:

Warnings:

Cannabidiol can harm the liver. Therefore it is advised to undergo liver function tests before starting and during the use of the drug. A doctor must be consulted when symptoms like nausea and vomiting, appetite loss, fatigue, right-sided upper abdominal pain, itching, dark-colored urine, or yellowish discoloration of the eyes and skin are noted. It is advisable to avoid driving or any hazardous activity before knowing the drug's actions on the body. Some patients may experience suicidal thoughts. They are advised to stay alert to their feelings and emotions and report any symptoms that worsen with time to the doctor.

Things to Remember Before Taking Cannabidiol:

• The medicine is to be avoided in people who are allergic to Cannabidiol or sesame seed oil.

• It is not approved for use in patients less than two years of age.

• Inform the doctor in case of pregnancy or breastfeeding.

• People experiencing suicidal thoughts should inform the doctor right away. Also, the family and caregivers must be alert to notice the changes in the patient.

• A history of liver disease or drug or alcohol addiction must be informed to the doctor.

How Is Cannabidiol Taken?

1. The medicine has to be taken as per the prescribed dosage. It is advised to follow all the instructions given on the prescription label.

2. CBD has to be taken twice daily. Also, it is recommended to take medicine at the same time of the day.

3. CBD can be taken either with food or without food. However, the same pattern has to be followed every day.

4. CBD must be stored at room temperature, away from moisture and heat.

5. The medicine must not be frozen or refrigerated.

6. The laboratory staff must be informed about the use of Cannabidiol before a drug screening test, as the results may come positive for cannabis (Marijuana).

7. Cannabidiol should not be stopped suddenly as it can cause an increase in seizures. A doctor's advice is mandatory for tapering the dose of the drug.

What Happens When a Dose Is Missed?

The medicine must be taken as soon as possible when a dose is missed. However, if it is the time for the next dose, then two doses at close intervals should be avoided.

What Are the Things to Avoid When Taking Cannabidiol?

It is recommended to avoid drinking alcohol when taking CBD as it can increase drowsiness.

What Are the Side Effects of Cannabidiol?

Along with the necessary effects, CBD can also cause some side effects. Not all the listed side effects can occur at once; however, when they occur, they require immediate medical attention.

Side Effects That Require Immediate Medical Attention:

More Common:

• Agitation.

• Chills.

• Pain in the chest.

• Cough.

• Fever.

• Dark urine.

• Irritability.

• Hoarseness of voice.

• Lack of appetite.

• Lower back pain.

• Nausea and vomiting.

• Painful urination.

• Pale stools.

• Sore throat.

• Difficulty breathing.

• Unusual fatigue.

• Yellowing of eyes and skin.

Less Common:

• Aggression.

• Anger.

• Confusion.

• Dizziness.

• Diarrhea.

• Rapid heartbeat.

• Blue lips, nails, and skin.

• Irregular, shallow breathing.

• Abdominal pain.

Side Effects That Do Not Require Immediate Medical Attention Include:

Some side effects that occur when using the drug may not require medical attention as they occur as the body gets adjusted to the medicine and can subside on its own. However, if they continue to persist, a doctor's consultation is necessary.

More Common:

• Rashes.

• Difficulty sleeping.

• Lack of strength.

Less Common:

• Increase in saliva.

• Drooling.

• Decrease in weight.

• Unstable walking.