How CBD interacts with other medications, contraindications & side effects
The safety profile of cannabidiol (CBD) has been extensively researched. Data from studies, laboratory experiments and clinical trials all show that CBD is well tolerated in both animals and humans, even at extremely high dosages. In fact, to date, not a single report of a CBD overdose or death has been reported.
This favourable safety profile of CBD, along with its purported ability to relieve a wide variety of health conditions and symptoms effectively, is probably what accounts for it becoming one of the most popular, and widely used, health and wellness supplement in recent years.
As our understanding of the effects of CBD increases, scientists are also finding that it is a powerful pharmacological agent - one that interacts with a wide range of neurobiological and physiological systems in the body.
CBD is a Multipurpose Molecule
Research has highlighted CBD’s potential as a treatment for a wide range of conditions. To name a few, scientists have found that CBD shows to help relieve the symptoms of:
- Autoimmune diseases like rheumatoid arthritis
- Neurodegenerative diseases including Alzheimer’s disease, Multiple Sclerosis andepilepsy
- Neuropsychiatric illnesses such as autism, ADHD and schizophrenia
- Mood disorders including depression and anxiety
- Digestive issues such as Crohn’s disease and irritable bowel syndrome (IBS)
Researchers theorise that the reason why CBD has such wide ranging pharmacological and pharmacological interactions is because of the way in which it can modulate and interact with almost every receptor and system in the body.
However, it is also this ability of CBD to affect a wide range of functions that can lead it to interact negatively with certain medications, or cause some mild side effects.
Metabolism, CBD & Medications
Most people have heard of metabolism in relation to nutrition, weight loss and exercise, often in terms of someone having a “fast” or “slow” metabolism. However, this is actually what is known as basal metabolic rate, or simply the amount of energy a person needs to sustain normal body functions when they’re not engaged in physical activity.
When scientists speak of metabolism, they are really referring to the process of the chemical reactions involved in maintaining the living state of the cells and the organism. In other words, although metabolism is related to nutrition, it goes far beyond just that and encompasses the way in which all substances are broken down and used in the body - including medications and cannabinoids.
The Drug Metabolic Process
When a substance is ingested by mouth, most of the metabolic process happens in the intestines and liver. This is because the liver performs various vital functions in the body, some of which are to:
- Metabolise, or break down, substances like medications into their individual components for use by the body
- Produce bile, which helps carry away waste, toxins and other unwanted byproducts
- Detoxify the blood of and excrete potentially harmful compounds such drugs and other toxic substances
In the context of CBD and medication or drug interactions, metabolism, detoxification and excretion are of most relevance to our discussion, so let us take a look.
When food is eaten, a medication is swallowed, or a supplement is taken orally, it travels from the mouth, through the oesophagus, through the digestive system and to the liver. Once a substance reaches the liver, using various relevant enzymes, the liver breaks it down and transforms the individual compounds into their individual metabolites for use by the body. (As a side note, it is also these metabolites that drug tests use for detection).
The same process occurs with pharmacologicals such as medications and CBD supplements in what is called drug metabolism. More specifically, drug metabolism is the term used to define the rate at which pharmacologically active compounds are broken down into its individual metabolites by the liver, as well as how long these metabolites stay in the body.
Ultimately, drug metabolism determines the fate of foreign drugs (called xenobiotics) when they enter the body - controlling whether that compound has pharmacological or toxic effects. Similarly, it also determines whether these xenobiotics are degraded to harmless, water-soluble metabolites which are easily excreted via the urine or bile, or whether they hang around.
Detoxification & Excretion
As mentioned, another vital function of the liver is the detoxification and excretion of xenobiotics and other types of toxic substances. This happens primarily via a system known as the cytochrome P450 system (CYP system)
The CYP system is primarily made up of a special group of enzymes called cytochromes P450 (CYPs), a superfamily of enzymes containing heme as a cofactor. Their main function is to convert fat-soluble compounds into water-soluble compounds in order to aid and increase their bioavailability (i.e., absorption rates and usability) for use by the body.
In fact, it is estimated that the CYP system is responsible for over 60% of the metabolism of any pharmacological agent consumed, which is why scientists can also use changes in cytochrome P450 (CYP) activity as well as interactions between metabolites and CYPs to predict pharmacokinetic drug-drug interactions (DDIs).
CBD & The Cytochrome P450 System
Because CBD also has the ability to interact directly with the CYP system in the liver, CBD can have profound DDIs with other types of prescription medications. And, just like DDIs can be predicted between different xenobiotics, so too can scientists make predictions about the potential interactions between them, and cannabinoids like CBD.
Scientists have found that the way in which CBD causes DDIs is because of how it interacts with the receptors at the site where enzyme activity occurs, acting as a type of “competitive inhibitor”. What this means is that CBD basically overrides and supplants the competition, preventing the CYP system from metabolising other xenobiotics. In effect, this means that CBD prevents the metabolism of all the other pharmacological compounds that pass through the CYP system.
The degree to which CBD displaces other CYP binding proteins is dependent on different factors, including:
- The amount of CBD ingested (dosage)
- The method of administration and type of the CBD product used (bioavailability)
- The physiology and metabolism of the individual (uniqueness)
- The presence of other cannabinoids and compounds (entourage effect)
The reason for this is that these factors will determine the concentration of CBD to reach the bloodstream as well as the degree with which CBD molecules are able to interact with and modulate the activity of the metabolic enzymes at receptor sites.
In other words, if CBD blood levels are low, it will have little to no noticeable effect on CYP system activity, and the majority of the pharmacological agent will be metabolised. However, if the CBD concentration in the blood is high, it will “out compete” the medicine, leaving it largely unmetabolised.
CBD & Drug Interactions: Contraindications
The CBD’s competitive inhibitor effects not only changes the way in which other pharmacological compounds are metabolised, but also determines how much of it is metabolised, causing higher levels of that compound to remain in the body. In turn, this can lead to elevated concentrations, ultimately producing unwanted side effects or even result in an overdose.
It is therefore important to understand that the metabolism of any medication that interacts with the CYP system, whether over-the-counter or prescription, has the potential of being influenced, altered or modified by CBD. An easy rule-of-thumb (although by no means a solid test) to know whether this is the case is if your pharmacist or doctor contraindicated the consumption of grapefruit, watercress, St. John’s Wort or goldenseal supplements.
The Indiana University Department of Medicine put together a list of pharmaceutical drugs and medications which could be contraindicated for use with CBD:
- Anaesthetics including but are not limited to barbiturates, amobarbital, methohexital, thiamylal, etomidate., ketamine and propofol
- Angiotension II Blockers including but are not limited to azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan
- Antiarrhythmics including but are not limited to amiodarone, flecainide, procainamide, propafenone, quinidine and tocainide
- Antibiotics including but are not limited to amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole-trimethoprim, amoxicillin-clavulanate and levofloxacin
- Anticonvulsants / Anti-Seizure Medications including but are not limited to acetazolamide, carbamazepine, clobazam, clonazepam, ethosuximide, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, methsuximide, nitrazepam, oxcarbazepine, paraldehyde, phenobarbital, phenytoin, primidone, topiramate, valproic acid, vigabatrin, felbamate, tiagabine hydrochloride and zonisamide
- Antidepressants including but are not limited to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine and vilazodone
- Antihistamines including but are not limited to brompheniramine. cetirizine, chlorpheniramine, clemastine, diphenhydramine, fexofenadine and loratadine
- Antipsychotics including but are not limited to aripiprazole, asenapine, cariprazine, clozapine, lurasidone, olanzapine, quetiapine, risperidone and ziprasidone
- Benzodiazepines including but are not limited to alprazolam, clobazam, clonazepam, clorazepate, chlordiazepoxide, diazepam, estazolam and lorazepam
- Beta blockers including but are not limited to acebutolol, atenolol, betaxolol, betaxolol, bisoprolol fumarate, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, propranolol, sotalol and timolol
- Calcium channel blockers including but are not limited to amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil
- HIV antivirals including but are not limited to e abacavir, didanosine, emtricitabine, stavudine, tenofovir alafenamide and disoproxil fumarate
- HMG CoA reductase inhibitors (statins) including but are not limited to atorvastatin, fluvastatin, pravastatin, pitavastatin, simvastatin and rosuvastatin
- Immune modulators including but are not limited to immune globulins, immunosuppressive agents and immunostimulants for example bacterial and viral vaccines
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including but are not limited to aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin
- Oral Hypoglycaemic Agents including but are not limited to sulfonylureas, meglitinides, biguanides, thiazolidinediones, α-Glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors and cycloset
- Prokinetics (motility drugs) including but are not limited to domperidone, metoclopromide, levosulpiride, renzapride and pruclopride
- Proton-Pump Inhibitors(PPIs) including but are not limited to omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole
- Steroids and corticosteroids including but are not limited to hydrocortisone, cortisone, prednisone, triamcinolone and dexamethasone
- Sulfonylureas including but are not limited to glynase, micronase, amaryl, diabinese, glucotrol, tolinase and tolbutamide
There are also other types of medications known as “prodrugs”. Unlike most medications that are pharmacological compounds in and of themselves, prodrugs are inactive precursors (or forerunners) when ingested, that first need to be broken down into its individual pharmacologically constituents before it can be metabolised into its therapeutically active components.
More often than not, this is a CYP system-dependent process that, in the presence of CBD can cause an insufficient amount of the active therapeutics of a prodrug to be available in the body, rendering its therapeutic effects ineffective.
Examples of prodrugs include but are not limited to:
- ACE inhibitors such as captopril and lisinopril
- ADHD medications such as lisdexamfetamine
- Anti-asthmatic medications such as bambuterol
- Analgesics & anti-inflammatories such as codeine, aspirin, sulfasalazine, ketoprofen, diclofenac
- Antibiotics such as bacampicillin, chloramphenicol, erythromycin, erythromycin-stearate and anderythromycin-estolate
- Anti-cancer medications such as irinotecan
- Antiglaucoma medications such as dipivefrin
- Anti-lipemic medications such as mevastatin, lovastatin and sinvastatin
- Anti-Parkinsonian medications such as levodopa and L-dopa
- Antipsychotics such as Fluphenazine decanoate and haloperidol decanoate
- Anti-ulcerous medications such as esomeprazole (S-omeprazole), lansoprazole, pantoprazole and rabeprazole
- Anti-neoplasic medications such as cyclophosphamide and ifosfamide
- Cardiovascular medications such as enalapril, benazepril, quinapril, ramipril and fosinopril
- HIV Antivirals such as valacyclovir, fosamprenavir, tenofovir disoproxil, oseltamivir, acyclovir, gancyclovir, pencyclovir, zidovudine, estavudine, didanosine, lamivudine, zalcitabine, entricitabine,
- Steroid hormones such as medroxyprogesterone acetate, hydroxyprogesterone caproate, algestone acetophenide (long-acting progestogens), estradiol valerate, and estradiol enanthate
These lists are by no means complete. Likewise, just because a medication category is listed, it does not mean all medications in that category will necessarily interact with CBD. That is why, when using other medications, it is of the utmost importance to consult a treating physician or pharmacists regarding possible CBD-drug interactions before supplementing with CBD.
They can, for instance, prescribe an alternative medication, or recommend changes in your dosing and schedules to minimise IDDs. Similarly, they can monitor the pharmacological as well as side effects of both the CBD and the medications you are on, to ensure efficacy and safety.
CBD Side Effects
As mentioned, CBD’s safety profile is very good, even at high dosages. Similarly, with a good quality, organic and third-party lab tested CBD product side effects tend to be few and far between. However, because everyone’s physiologies are unique, some people do experience some side effects, although these tend to be mild. These can include:
- Tiredness, drowsiness or feeling sleepy: This usually happens at very high doses of 300 mg or more, however, for some people even smaller dosages can lead to drowsiness. Cut back on dosage, or try a product with a different cannabinoid profile as other plant compounds can mitigate the effects of CBD.
- Dry Mouth: CBD interacts with the cannabinoid receptors in the salivary glands that can inhibit the secretion of saliva, causing a “cotton mouth” feeling. Keeping hydrated with water and herbal teas should remedy the situation.
- Dizziness or lightheadedness: CBD can lower their blood pressure, that in rare cases, can cause some people to feel dizzy or lightheaded. Drinking coffee can help increase blood pressure. Also try micro-dosing or changing to a slow release CBD product to avoid drops in blood pressure.
- Changes in Appetite & Weight: CBD has been shown to regulate glucose levels that can lead feeling either more or less hungry. Over time, this can affect weight, either causing weight gain or weight loss. Use a slow release CBD product, and take it with, or directly after a meal to buffer the effects of CBD on blood sugar.
- Digestive Changes & Diarrhoea: This is a relatively common side effect in patients using Epidiolex. Although less common in over-the-counter, full- or broad spectrum CBD products, if and when these side effects are experienced, reduce dosage and stay hydrated. If this does not help, see a doctor as they can advise with regard to dosage or other changes that need to be made.
The safety profile of CBD is well established with both human and animal studies showing it is well tolerated and safe to use. CBD is also a powerful therapeutic agent with very real pharmacological, physiological and neurobiological effects in the body. This is what gives its many benefits and why it is gaining in popularity as a natural option to help relieve a wider variety of symptoms. However, it is these same qualities that could also make CBD potentially hazardous when taken in conjunction with other pharmacologically active compounds like certain medications and prodrugs. CBD can cause potentially dangerous drug interactions and should always be consumed with care and respect. And in the event of using it in conjunction with other medications, preferably also under the supervision of a treating physician or other trusted medical professional.