Drug Interactions of CBD

Introduction

Humans have been using recreational drugs for centuries. There are pieces of evidence of the usage of cannabis since the second century AD, and the cultivation of the cannabis plant dates back even further. But, up till now, the use of these drugs was associated mainly with recreational purposes, and many of these drugs were considered to be detrimental to human health. It was thought that the use of these drugs triggered dangerous psychiatric symptoms in the people, and the drugs were declared illegal by many countries around the world. No doubt, illicit drugs such as cocaine and morphine surely do have excessive detrimental effects on the health of the user, but they’re certainly are some advantages along with the use of these natural herbs. For example, morphine (the active part of heroin, obtained from the poppy plant) carries a very important use in relieving the post-surgical pain in the patients. Similarly, many other drugs which were considered dangerous are now finding uses in the field of pharmaceutical therapy all over the world. 

Cannabis has been used for medical treatment for a long time now. The usefulness of using cannabis plant extracts to treat ailments related to the brain have particularly been so much highlighted in the past decade or so. Having found the sweet spot between the characteristic ‘high’ of the marijuana due to THC and the positive brain effects of marijuana due to the existence of cannabidiol (CBD), the therapeutic uses of marijuana are certainly increasing day by day.

Cannabis sativa, or more commonly known simply like cannabis, has been used for medical treatment for a long time now owing to some of its natural healing properties it grants to the body. Cannabis has several chemicals that exist naturally in it, the chemicals which have a potent effect on the natural healing system of the nervous structure of our body. Among these chemicals, tetrahydrocannabinol (THC) is the substance that gets you the characteristic ‘high’ when marijuana is consumed. However, cannabidiol (CBD) is a chemical that helps our body get rid of stress and anxiety along with some other medical benefits without giving the ‘high’ effect of marijuana. 

In recent years, Cannabis has found a drastic shift in its uses. Before modern research, it was considered that marijuana was no more than a street drug used for recreation by the street junkies. Almost no more than a decade ago, when modern research techniques coined the term ‘medical marijuana’, the concept of using the medical properties of marijuana as pharmaceutical drugs gained popularity. It was discovered that Cannabis contains two main agents that are responsible for the psychiatric effects of marijuana. These two main agents were tetrahydrocannabinol (THC) and cannabidiol (CBD). Among these two contents, the main agent responsible for the ‘high’ effect of marijuana is tetrahydrocannabinol (THC), which binds to and affects the cannabinoid receptors in the central nervous system, thereby manifesting psychiatric effects in the subject. For this reason, THC is considered to be a psychoactive substance. The other main constituent is cannabidiol (CBD). Cannabidiol (CBD) differs from other chemicals found in cannabis, as it has a different mechanism of action and a different effect on the body as compared to other chemicals such as the tetrahydrocannabinol (THC). 

CBD to Combat Drug Abuse

There is an increasing trend of using drugs in the whole of the North American continent, particularly by the elderly people ranging in the ages 50 and above. The increased use of drugs has largely caused negative symptoms in the users, along with withdrawal-related illnesses. The fast lifestyle of first-world countries such as the United States has taken people to an extent that they find entertainment in drug abuse. This killer trend is proving fatal for the large part of the population and is more prevalent in elderly people having ages above 50.

A study was conducted by some amateurs to investigate the prevalence of illicit substance abuse in older adults. The results were published in PubMed. Among all the drugs used by older adults to gain psychoactive signs, Cannabis use by older adults is considerably more common. The increased prevalence of Cannabis among the adults for recreational use can be estimated from the fact that the adults aged 50 years and older, 4.6 million reported using Cannabis for recreational purposes in the previous year, while less than 1 million of the drug-using adults reported dependence upon other illicit substances such as cocaine, hallucinogens, methamphetamine, and heroin use in the past year. The results gained from this study were confirmed by the later studies conducted by independent sources. Nowadays, there is an increasing trend of legalization of medically important drugs such as medical marijuana not only in the United States but throughout the world. According to statistics gathered the previous year, 47 states out of all the states in the US have legalized at least one form of medical marijuana. The fact that marijuana is being rapidly legalized and the relaxation in the terms for the possession of marijuana explains that the substance abuse rate among older adults may increase. This is because this particular group of the population uses illicit substances in order to cope with the illnesses that usually come with normal aging or the mental degradation caused due to diseases that affect older people such as Alzheimer’s disease or Parkinson’s disease. 

Therapeutic Uses of CBD and Drug Interactions

Owing to recent developments in medical research related to CBD, it has been found that cannabis has several chemicals that surely do have the potential to be used as a therapeutic measure in various pathologies. Most commonly, CBD is being used for the disorders related to the central nervous system, such as psychological disorders, anxiety, neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and fibromyalgia. Physicians have started prescribing CBD as a treatment for these impairing diseases. The major hindrance in the way of CBD being an effective drug for all these disorders is the interactions CBD can have with other drugs if administered along with medications being used to treat a disorder. 

Although there are many advantages of using CBD as a symptomatic reliever in many disorders, the dosage and the frequency at which CBD should be used remains a large concern to the physicians. There is a large probability that people start using CBD as a recreational drug to replace others such as heroin, marijuana, and cocaine. This brings along many dangers, the most particular of them being the psychiatric ones to the person who abuses this drug. Using CBD in excessive quantities brings along the danger of overdose, which severely affects the central nervous system and hampers it from carrying out the normal activities without the use of CBD as a fuel. The unchecked use of marijuana among the people who are already suffering from psychiatric symptoms prove to be a pitfall if the users are already suffering from cardiovascular symptoms or terminal stage disease in their old age. Although the checked use of medicinal marijuana comes with its advantages, marijuana abuse can lead to impairment of short-term memory due to its ability to affect the vital brain circuits that are involved in short term memory formation and its reconsolidation at a later stage. The primary site of action of marijuana constituents is the areas of the central brain such as the hippocampus, amygdala, and basal ganglia. These are the areas of the brain which are responsible for fine-tuning the various movements that are coordinated by the areas of the brain that control voluntary muscle movements. The fact that marijuana primarily acts in these areas is also of considerable importance because these areas of the brain also control the cognitive behavior of any person. The psychoactive marijuana constituents, primarily tetrahydrocannabinol serve to affect the functions in these areas, and that is why one experiences altered thoughts and deranged state of mind after consuming marijuana in large quantities.

The patients who are suffering from certain cardiovascular symptoms already before abusing marijuana can report a consistent increased heart rate along with hyperventilation and elevated blood pressure. The unchecked marijuana use in the older patients who are already suffering from neurodegenerative brain damage due to diseases like Alzheimer’s and Parkinson’s disease may lead to the aggravation of the symptoms caused by those diseases, which not only drastically reduces the quality of the lifestyle of the patient, but is also exhaustive to the caregiver. The increased marijuana use may also result in cognitive disabilities among the patients leading to the impairment in the judgment-making ability. The increased tobacco use among older adults is associated with greater mortality due to the lethal effects the use of tobacco has on the respiratory systems. The increased tobacco use elevates the risks of different cardiopulmonary events such as coronary events along with myocardial infarctions, and the danger of complete lung collapse due to the severe degradation of alveolar walls owing to prolonged smoking history. The risk from prolonged marijuana smoking in older adults may also manifest its results in the form of smoking-related cancers due to lung-related damage, along with chronic obstructive pulmonary disease (COPD) which then results in a large decline in pulmonary function. Moreover, continued smoking also inhibits the effective treatments used for the symptomatic treatment for these conditions.

The recent legalization of medical marijuana has brought about an increased danger of abusing marijuana, and the therapeutic properties of marijuana for which it can be effectively used might be overlooked by the people. Up to now, 47 of the states in the United States have legalized some form of marijuana in their territories. This not only has made the availability easier, but there also is no efficient mechanism to regulate the quantities people might get their hands on this drug. 

The Role of P450 System

The degradation of CBD in the body is attributed to the function of the liver enzyme p450 system. Any breakdown in the function of this system might lead to an accumulation of CBD in the body in dangerous quantities. 

Cytochrome P450 enzymes are a group of enzymes found deep within the liver and are essential for the metabolism of many drugs and medications that affect the functioning of the liver. The function of this system is crucial for the normal functioning of the body, as this system not only metabolizes drugs but also has a role in many important functions of the liver including detoxification of many toxins. This enzyme class has more than 50 enzymes distributed throughout the liver. Of all the 50 enzymes, six of them carry the main role in drug metabolism and are responsible for metabolizing 90 percent of drugs that are taken through oral and various other routes, with the two most significant enzymes being CYP3A4 and CYP2D6. Minor differences in the translation of these enzymes may influence the metabolism of commonly prescribed drugs. The most prominent examples include beta-blockers and antidepressants. 

There is scientific evidence of Cytochrome P450 enzymes being inhibited or induced by certain medications so that the rate of removal of a drug from the body is also influenced. Uncalculated changes can result in clinically significant drug-drug interactions that can cause adverse reactions within the body of the patient consuming those drug classes. Interactions with certain commonly prescribed drugs such as warfarin, antidepressants, antiepileptic drugs, and cholesterol-inhibiting drugs such as statins often involve the cytochrome P450 enzymes. So, anything that affects the activity of the cytochrome P450 enzyme system may affect the concentration of these drugs in the body. Knowing the route of degradation of the most important drugs metabolized by cytochrome P450 enzymes can help minimize the possibility of adverse drug reactions, thereby averting potentially fatal life situations. 

The drug interactions that CBD might have in patients who are using CBD for the symptomatic treatment of certain disorders such as Alzheimer’s disease, Parkinson’s disease, fibromyalgia, and multiple sclerosis, also come through the fact that CBD has pronounced effects on some components of the P450 system in the body. Through research, it has been found that CBD serves to inhibit certain enzymes of the P450 system. These enzymes are found to metabolize certain drugs in the body. So, if any person who is taking these drugs and also is using CBD at the same time, he or she is at the risk of an overdose, because CBD inhibits the vital systems of his or her body that is responsible for the degradation of the drugs. It is particularly important for the physicians treating the patients having these disorders to have a comprehensive history of the drugs taken by the patients before prescribing them CBD for their symptomatic treatment. 

CBD certainly does have some drug interactions when it is used for some of the disorders. They are explained comprehensively below:

CBD and Epilepsy

Epilepsy, most commonly characterized by photo-sensitive seizures, is a mental disorder that involves abnormal brain activity in the central nervous system. The most common signs are seizures and periods of abnormal behavior and loss of awareness. The epileptic seizures are prone to hit anytime in the affected persons and are the major cause of insomnia in epileptic patients. 

Currently, a large percentage of people are affected by epilepsy, around 40 to 51 percent of the patients are suffering from insomnia due to epileptic symptoms. The sleep deprivation due to these symptoms triggers more seizures, which further aggravates the condition. Moreover, there are certain seizures called ‘sleep seizures’ that are triggered due to brain activity during sleeping and waking. These periodic seizures are the major reason for sleep deprivation in epileptic patients.

There is a form of epilepsy known as treatment-resistant epilepsy, which is not affected by conventional anti-epileptic drugs. The result is, severely increased seizures and even death in aggravated cases of treatment-resistant epilepsy. Under these conditions, recommendations were generated to use cannabidiol alongside anti-epileptic drugs to relieve the seizures due to treatment-resistant epilepsy.

A research paper published on PubMed Central reports a study that was conducted to examine whether the addition of cannabidiol in the list of existing anti-epileptic drugs would be safe. The subjects were administered 2-5 milligrams of cannabidiol per kilogram of body weight, increased to a maximum of 25 mg per kilogram of body weight. The clinical trial, which lasted for a year between 2014 and 2015, reported that there was a median reduction of 36.5 percent in monthly motor seizures in the treatment of resistant epileptic patients. These findings openly stated that cannabidiol, when employed to treat motor seizures in treatment-resistant epilepsy, might decrease seizure frequency to a considerable extent and might have an adequately safe to use in children and young adults suffering from treatment-resistant epilepsy.

Drug interactions of CBD in epilepsy are due to the property of CBD that causes the inhibition of various enzymes of the p450 system. Epidiolex is the only approved drug containing CBD from the FDA. This medication is used to treat rare forms of epilepsy, which is uncurable by using standard medications for epilepsy. Research has been carried out to investigate the role of Epidiolex in affecting the metabolism of various drugs in the body. The most pronounced effect that this drug had was on the metabolism of warfarin. Epidiolex was found to increase the levels of warfarin in the blood by inhibiting the enzyme class that is responsible for the degradation of warfarin. The increase was found to be more than 30 percent as compared to the persons who were not using CBD. This is particularly of great concern because warfarin can make the blood thin. The thinner is the blood, the greater is the chance of bleeding through a wound. So, CBD was found to increase the risk of bleeding in patients who were using Epidiolex to treat their epilepsy.

CBD and Inflammatory Diseases

Inflammation is defined as the response of the body towards an outside source that may be harmful to the tissues. This is an immune response that tends to cut a specific area off the whole body to clear it from debris. Inflammation is likely to be triggered in two ways normally, one of them is necrosis in the body tissues due to some form of toxins, the other one is due to the invasion of an outside antigen. The immune response in inflammation is carried out by lymphocytes and neutrophils. 

Normally, the response of the body (inflammation) is tightly regulated, but there might be some disorders in which the immune system abnormally starts attacking the body tissue, mistaking it for an inflammatory response. Examples of such diseases include multiple sclerosis and arthritis. In these disorders, the patient needs an effective anti-inflammatory drug that is capable of reducing inflammation right after the administration. The conventional drugs that are used are known as Non-Steroidal Anti-Inflammatory Drugs or NSAIDs. NSAIDs serve to reduce inflammation by interacting with the prostaglandin metabolism and reducing the factors that cause inflammation in the particular areas of the body, also known as ‘mediators of inflammation’. But, the effectiveness of these drugs varies widely from person to person.

In recent years, CBD has emerged to be an effective anti-inflammatory drug that can be used for various inflammatory disorders such as arthritis and multiple sclerosis. research has been carried out to investigate the role of CBD in averting inflammation, thereby providing symptomatic treatment to the people suffering from these chronic disorders. The primary mechanism due to which CBD can be used to avert brain damage due to the traumatic brain injury lies in the vast anti-inflammatory properties of the CBD. CBD averts inflammation due to various ways. One of the factors through which CBD can avoid inflammation is the dysfunction of the cytokines (chemical substances in the body which serve to mediate inflammation through promoting it). Endocannabinoids, particularly nonpsychoactive agents such as CBD, affect the cytokine structure and biology of various cell systems. Antiproliferative effects of endocannabinoids on cancer cells have been studied well, and their effect on stopping the inflammation is large. As inflammation particularly spreads vastly after a tissue injury due to contusion or other contact causes, so the rate of inflammation surrounding the brain injury can be particularly dangerous, as it causes necrotic cell death in the tissue on a large scale. This cell death proves fatal to certain brain areas that are hit directly by the injury. So, in the case, if traumatic brain injury, stopping the inflammation gains prime importance, as it reduces the chance of the damage spread. The microglia, or the macrophages that exist in the brain tissue, have a very important role in inflammation. Moreover, there are cells in the brain tissue called astrocytes. The astrocytes serve to nourish the brain tissue under normal circumstances, providing vital nutrients to the neurons thus playing an important role in tissue growth. However, under traumatic brain injury where the brain tissue becomes necrotic, the astrocytes have been found secreting certain cytokines along with other chemicals such as nitric oxide that mediate inflammation. 

Interestingly, these astrocytes are found to express both the CB1 and CB2 receptors on their surfaces. The effect of the endocannabinoid neurotransmitters on these receptors has been well explained earlier. Various cannabinoids, such as no psychoactive CBD, can serve to have an inhibitory effect on the activity of the astrocytes spreading inflammation.

The drug interactions that CBD might have with the medications being used for arthritis have not yet been studied well. Although CBD has been found to not affect the arthritis medications such as methotrexate and much of the NSAIDs. However, one NSAID diclofenac has been shown to have adverse reactions when taken along CBD in arthritis treatment. With the use of anti-inflammatory medications such as NSAIDs in the treatment of inflammatory diseases such as arthritis, physicians are always looking for the effects on the liver because of the interference in the drug metabolism.

CBD Interactions with Anxiolytic Medications

CBD is a component of marijuana, the widely used drug all over the world for the treatment of anxiety. Anxiety can be defined as the natural response of the body towards any type of stress, whether it be physical or psychological. Anxiety is found to impair the focusing abilities of the body towards a specific task. Anxiety is not always a medical condition requiring immediate attention, it is completely normal to have anxious feelings about something daily. It is very important to judge the situation when will a person having anxious feelings require medical attention before experiencing aggravated symptoms such as panic attacks due to increased anxiety. The anxiety is medically linked to the brain, or more specifically to the amygdala which controls the fear, thoughts, and emotions and serves as the hub of anxiety. The anti-anxiety drugs usually work by modifying the levels of certain chemicals in the central nervous system called neurotransmitters. These neurotransmitters are the chemicals which dictate our day to day mood and emotions. One of the most effective neurotransmitter systems in our body is the endocannabinoid system. The endocannabinoid system, consisting of some particular receptors called cannabinoid receptors, affect the overall mood, stress, anxiety, and metabolism of our bodies.    

The ability of CBD to affect the endocannabinoid system, which in turn has supernumerary effects on mood, stress, anxiety, and state of mind of a person, has enabled it to become an effective drug to cure long term stress and anxiety that might reduce the quality of lifestyle of any person. Moreover, the quality of CBD oil that does not affect the psychological state of mind of the person who is using it, has granted it the ultimate sweet spot for having all the perks of marijuana without getting the ‘high’ sensation which is the characteristic of marijuana. Humans have been using Cannabis to get rid of anxiety for centuries. Recently, the advances in the research field have pointed out the usefulness of CBD to get rid of anxiety and nervous symptoms in patients of insomnia and chronic pain. CBD is not psychoactive, which means that it can serve the purpose of getting rid of anxiety without the ‘high’ effects one gets by smoking marijuana. The main culprit behind that ‘high’ is tetrahydrocannabinol. CBD differs from THC in the way that it can grant equally good anxiety-relieving effects, without impairing thoughts which is true in the case of THC by smoking raw marijuana.

The anxiolytic properties on CBD oil have also been studied extensively through research. Particularly, the results of using CBD to relieve Social Anxiety Disorder (SAD) are fascinating. In 2011, a study examined the effect of CBD given to patients with a control group which was given a placebo. The administration involved giving 400 milligrams (mg) of CBD or placebo to the subjects. The results of the study were largely in favor of CBD treating anxiety. The subjects who were given CBD reported a considerable decrease in their anxiety levels. This study reports that administering CBD to patients reduces anxiety in SAD, particularly due to the effects of CBD on activity in limbic and paralimbic brain areas and related circuits involving the amygdala that control mood and emotions.

Anxiolytic medications are usually sedatives that are administered to a patient of anxiety to calm the mind and thoughts of that patient. However, owing to the potential of abuse, anxiolytic drugs need to be administered with great caution. If the person who is using anxiolytic sedatives such as barbiturates also uses CBD to treat the symptoms of anxiety, he or she needs to be of extra caution because CBD serves to increase the effect of the sedatives that the person is already taking. Administering a carefully calculated dose is of vital importance because the risk of adverse effects and overdose is greatly increased in the patient who is already using anti-depressants and sedatives for their anxiety management. 

Conclusion

The positive impacts of CBD on the patients suffering from debilitating brain disorders is surely gaining much attention from the physicians. There has been a marked increase in the CBD prescriptions by the physicians in the last decade or so, but the potential side effects that CBD might have on the patients suffering from compromised immune systems or liver disorders need to be considered carefully before therapy is started in such individuals. 

REFERENCES

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  3. Ince, Susan, and Susan Ince. “Does CBD Interfere With Medication? What Arthritis Patients Must Know Now”. Creakyjoints, 2020, https://creakyjoints.org/alternative-medicine/cbd-drug-interactions/.
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