Given the complex physicochemical processes that take place inside the human body, virtually all chemical compounds interact with one another – from prescription pharmaceuticals to illicit drugs such as cannabis. While medical marijuana is safe to take for the most part, especially when consumed in appropriate doses, caution must be taken when co-administrating it with prescription drugs. This is because it has the potential to interact with pharmaceuticals and alter how these are metabolized in the body. Understanding the drug interactions and knowing which medications should not be paired with cannabis could reduce the risk of adverse reactions.
The Dangers Of Drug Interactions
When consumed in conjunction with prescription medicines, cannabis may interact with it by exerting either antagonistic or synergistic effects. Depending on the extent of the impact, this interaction could reduce (antagonize) or increase (synergize) the efficacy of the drug which could result in unpredictable and life-threatening consequences.
Synergistic effects could be dangerous when the pharmacodynamic effect of the drugs is exaggerated way beyond the intended threshold. Some interactions could result in antagonistic effects when the interacting substances are both processed or metabolized by the same receptors in the body. Furthermore, the co-administered substance may chemically react with one another and potentially give off harmful byproducts during the metabolism process. Other serious clinical implications of drug interactions include altered drug response, reduced medication adherence, and increased costs for care.
If it is inevitable to take multiple drugs, it is crucial to be aware of the possible interactions between the substances and the amount of time it stays in the system. Knowing this will enable the patient to take both substances but at different times so that the effects will not overlap.
Cannabis And The CYP450 Pathway
The Cytochrome P450 system is an elaborate group of enzymes in the liver that metabolizes the drugs that enter the system. It breaks down substances for elimination and in some cases, it activates prodrug’’ beneficial effect. Without it, the ingested medications would linger in the body and make the patient more susceptible to side effects. Similarly, when prodrugs are not activated by the CYP450, it remains inactive and does not exert intended results.
Given CYP450’s significance in drug metabolism, any blockage or alteration of this system can make a significant impact on the uptake of many other substances. This is why cannabis should not be mixed with most prescription drugs as CBD inhibits the enzymes CYP3A4 and CYP2D6 in this system. In other words, it might increase or decrease the rate at which medications are metabolized by the liver – hence, reducing its overall efficacy.
On the other hand, CYP3A4 inhibitors slightly increase THC levels – thereby making the blood THC concentration higher than usual which leads to unpleasant effects and prolonged removal in the system. THC is also a CYP1A2 inducer. Thus, it can decrease serum concentrations of certain medications such as clozapine, duloxetine, naproxen, cyclobenzaprine, olanzapine, haloperidol, and chlorpromazine.
That being said, the following drugs metabolized by CYP450 enzymes could potentially interact with cannabis:
- HMG CoA reductase inhibitors
- Calcium channel blockers
- HIV antivirals
- Immune modulators
- Angiotensin II blockers
- Oral hypoglycemic agents
Possible Pharmacodynamic Cannabis Drug Interactions
Cannabis is known to interact with a total of 612 drugs. Out of these, 129 are major drug interactions whereas 483 are moderate. Interactions classified as major are highly clinically significant. Therefore, these combinations must be avoided at all cost as the risk of the interaction outweighs the benefits. On the other hand, moderate drug interactions are only moderately clinically significant. Generally, it is recommended to avoid such combinations, but it could be used in conjunction under special circumstances.
Disclaimer: It must be noted that the information provided below is meant for educational purposes only. These pieces of advice are not intended to replace expert diagnosis and recommendations from medical professionals. Moreover, just because some drugs are not mentioned in this article, it does not guarantee that it has no possible interaction with cannabis. Always seek the counsel of a licensed medical professional before co-administering marijuana with prescription drugs.
Benzonatate is the generic name of drugs classified under antitussives. These drugs are used to prevent or alleviate coughs caused by common colds or breathing problems such as pneumonia, bronchitis, emphysema, asthma. It works by suppressing the cough reflex in the lungs and air passages. The most well-known brands of this medication are Tessalon®, Tessalon Perles®, and Zonatuss®.
Using Benzonatate in conjunction with cannabis can result in moderate drug interaction and intense dizziness. Some other side effects are noted as follows:
- Drug abuse
- Urinary retention (the inability to completely or partially empty the bladder)
- Bladder dilatation
- Dyspnoea (difficult or labored respiration)
- Pneumothorax (the presence of air or gas in the cavity between the lungs and the chest wall, causing the collapse of the lung)
It is generally not recommended to take cannabis and benzonatate simultaneously. Since benzonatate stays in the system for 6 to 8 hours after ingestion, it is advised not to consume marijuana within this time frame.
Benzodiazepines are CNS depressant primarily used to treat patients with anxiety disorders. However, it can also remedy conditions such as panic attacks, seizures, and insomnia. Benzodiazepines induce profound relaxation and sedation by reducing the activity of overactivity of nerves in the brain. This is done by enhancing the effects of Gamma-aminobutyric acid – a major inhibitory neurotransmitter that suppresses the activity of nerves.
The major brands classified under benzodiazepines that are approved in the US are as follows:
- Diazepam (Valium®)
- Clorazepate (Tranxene®)
- Oxazepam (Serax®)
- Lorazepam (Ativan®)
- Alprazolam (Xanax®)
- Clonazepam (Klonopin®)
- Midazolam (Versed®)
- Triazolam (Halcion®)
- Estazolam (Prosom®)
- Temazepam (Restoril®)
- Chlordiazepoxide (Librium®)
- Flurazepam (Dalmane®)
- Quazepam (Doral®)
Taking these medications along with products infused with cannabis must be avoided at all cost because it causes major drug interaction. This is because cannabis products – especially those high in CBD content – have the potential to further increase sedation induced by benzodiazepines. On the other hand, THC could paradoxically worsen the anxiety instead of alleviating it. Potential interactions also include the build-up of benzodiazepines in the system due to inhibition of the CYP450 system.
The interaction of benzodiazepines and cannabis may result in a combination of the following symptoms:
- Intense sedation, sleepiness, and drowsiness
- Increased risk of severe breathing problems
- May induce a coma
- Confusion and lack of concentration
- Impairment in thinking and judgment
- Impaired motor coordination
- Slurred speech
The rate of onset exhibited by different medications classified under benzodiazepines widely vary. Hence, it is best to consult with a physician with regards to medication intake scheduling to avoid adverse interactions.
Antidepressants are drugs that reduce the symptoms of depressive disorders. It works by rectifying the chemical imbalances in the brain which causes alterations in mood and behavior.
Serotonin, dopamine, and norepinephrine are the primary neurotransmitters that patients with depression lack. A newer class of antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective and Norepinephrine Reuptake Inhibitors (SNRIs) work by inhibiting the reuptake of certain neurotransmitters to increase its levels around the synapses and receptors of the brain. On the other hand, antidepressants that are rather obsolete and have fallen out of favor for treatment due to its severe side effects include Monoamine oxidase inhibitors (MAOIs) and Tricyclic antidepressants (TCAs).
Brands classified under SSRIs:
- Citalopram (Celexa®)
- Escitalopram (Lexapro®)
- Fluoxetine (Prozac® and Sarafem®)
- Fluvoxamine (Luvox®)
- Paroxetine (Paxil®)
- Sertraline (Zoloft ®)
- Duloxetine (Cymbalta®)
- Venlafaxine (Effexor®)
- Desvenlafaxine (Pristiq®)
- Tranylcypromine (Parnate®)
- Phenelzine (Nardil®)
- Isocarboxazid (Marplan®)
- Imipramine (Tofranil®)
- Amitriptyline (Elavil®)
- Doxepin (Sinequan ® and Adapin®)
- Trimipramine (Surmontil®)
While only low to moderate drug interactions were noted for mixing cannabis and SSRIs/SNRIs, research reveals that SSRIs inhibit the CYP450 system enzymes. Hence, these agents may impair the metabolism of a wide variety of medications, akin to the effects of cannabis. It can also result in a major central nervous system depression.
On the other hand, the older class of antidepressants – MAOIs and TCAs – exhibit major drug interactions with cannabis due to its high-risk profile and the propensity of inducing adverse side effects. Case reports of patients highlighted the manifestation of transient cognitive changes, delirium, and tachycardia after smoking marijuana while on TCAs.
Some of the other side effects of pharmacodynamic interaction between antidepressants and cannabis may include but are not limited to:
- Hypomania (Irritability, nervousness, jittery, and excited state)
- Intensified dizziness and drowsiness
- Difficulty concentrating
- Impairment in thinking, judgment, and motor coordination
- Agitation and anxiety
- Excessive paranoia
- Severe headache
- Gastrointestinal distress
- Mood swings
Furthermore, since cannabis works synergistically with SSRIs/SNRIs to increase the levels of serotonin in the brain, the excessive serotonin stimulation may potentially result in Serotonin Syndrome. This condition is manifested by the following symptoms:
- Agitation or restlessness
- Dilated pupils
- Nausea and/or vomiting
- Rapid heart rate
- Impaired muscle coordination or twitching muscles
- Shivering and goosebumps
- Heavy sweating
In severe cases, high fever, seizures, arrhythmias, and unconsciousness may be present. Seek medical help immediately upon experiencing these symptoms as it tends to be life-threatening.
4. Antipsychotic Medication
Antipsychotics are psychiatric drugs that are used to treat schizophrenia, schizoaffective disorder, some forms of bipolar disorder, severe depression, and other psychotic disorders. It effectively reduces psychotic symptoms such as delusions, hallucinations, disruptive behavior, and paranoia among others by blocking the action of dopamine. Antipsychotics are classified into two: typical (the older class of drugs) and atypical (the newer forms). Recent large-scale studies revealed that the two drugs do not really have a significant difference, although, in some situations, atypical antipsychotics are easier to use.
- Chlorpromazine (Largactil® and Thorazine®)
- Haloperidol (Haldol®)
- Pimozide (Orap®)
- Trifluoperazine (Stelazine®)
- Sulpiride (Dolmatil®)
- Amisulpride (Solian®)
- Aripiprazole (Abilify®)
- Clozapine (Clozaril®)
- Quetiapine (Seroquel®)
- Olanzapine (Zyprexa®)
- Risperidone (Risperdal®)
Taking the listed antipsychotic medications concomitantly with cannabis is generally inadvisable because antipsychotics medications, in itself, are already riddled with severe side effects. Although research regarding its interaction with marijuana is mostly lacking, any attempt to do so may result in unpredictable and possibly adverse consequences.
Furthermore, antipsychotic medications are heavy tranquilizers. And since cannabis – particularly pure indica strains – can also be sedating, the tranquilizing effects may be too much for the patient to handle. Additionally, there is some evidence suggesting that cannabis may heighten the impact of antipsychotics such as Seroquel® and Abilify®. This may be due to the inhibitory effects of marijuana on inhibits CYP2D6 which subsequently increases the serum concentrations of antipsychotics and reduce the clearance this medication from the body.
Some symptoms that may arise from concomitant use of antipsychotics and cannabis include:
- Excessive sedation
- Slow motor skills
- Decreased cognitive function
- Impaired driving
Also known as anti-epileptics, anticonvulsant drugs are used for the treatment of epileptic seizures and sometimes, neuropathic pain. It could also be used as a mood stabilizer in patients with bipolar disorder. These pharmacological agents suppress the excessive and rapid firing of neurons during seizures and prevent the further spreading of seizures within the brain through the modulation of different neurotransmitters.
Conventional anticonvulsants enhance the function of GABA. On the other hand, new generation drugs work by reducing the release of the excitatory glutamate in which high levels are associated with higher susceptibility of having seizure attacks.
Among the medications classified as anticonvulsants are:
- Gabapentin (Neurontin®)
- Brivaracetam (Briviact®)
- Clobazam (Onfi®)
- Topiramate (Topamax®)
- Zonisamide (Zonegran®)
- Eslicarbazepine (Aptiom®)
- Ezogabine (Potiga®)
- Lacosamide (Vimpat®)
- Perampanel (Fycompa®)
- Rufinamide (Banzel®)
- Valproate (Convulex®, Depakote®, Epilim®, Stavzor®)
- Vigabatrin (Sabril®)
Clinical studies show that taking CBD with topiramate, rufinamide, and N‐desmethylclobazam significantly increased the serum levels of the drug. Meanwhile, the opposite effect was observed in clobazam with the addition of heavy sedation. However, the change in drug levels was well within the acceptable range.
On the other hand, taking Valproate exhibited higher ALT and AST ratios compared to other subjects not taking this particular drug. The high levels are indicative of abnormal liver function. Hence, caution must be taken as the drug interaction between CBD and Valproate can result in liver problems.
6. Opioid Pain Killers
An opioid is a type of narcotic pain medication prescribed for the treatment of severe pain. These drugs work by binding to opioid receptors in the brain, spinal cord, and other areas of the body. It then blocks pain pathways to modulate pain perception. However, these drugs pose equally severe side effects when taken in large doses over prolonged periods which make it less appealing as a form of treatment. Interactions with other drugs are also known to induce adverse effects such as overdose, coma, respiratory failure, and even death.
Fortunately, upon the discovery of cannabis’s potent analgesic effects, the possibility of lessening opioid prescription came to light. On its own, low doses of both marijuana and opioids do not relieve pain. But when taken concomitantly, the improvement was drastic as both are known to interact with the CB1 receptors. Thus, the side effects of opioids can be reduced with the aid of cannabis.
However, it must be noted that certain opioid painkillers react negatively with cannabis when co-administered.
Drugs containing propoxyphene exhibit major drug interaction when mixed with cannabis. An increase in side effects such as dizziness, drowsiness, confusion, and difficulty concentrating was observed after coadministration of the two drugs.
Hence, the following propoxyphene-containing medications must never be used with cannabis:
- Darvon® (Compound 32, Compound 65, N)
- Darvoset® (N 100, A500, N 50)
- Propacet® 100
- Propoxyphene® Compound 65
Otherwise, the following symptoms will become apparent:
- Difficulty concentrating
- Impaired judgment and thinking
- Impaired motor skills
Levomethadyl Acetate Hydrochloride
The synthetic opioid painkiller levomethadyl acetate sold under the brand name Orlaam® is notorious for its serious and potentially life-threatening proarrhythmic effects. Hence, it is used as a last resort when the patient fails to show significant improvements to other treatments.
Due to its already potent sedative and heart rate increasing effects, combining Orlaam® with cannabis is not advisable as the cannabinoids can further amplify these effects and lead to symptoms such as:
- Extreme drowsiness
- Syncope or fainting
- Torsades de pointes or arrhythmia
- Poor motor coordination
- Impaired thinking
- Impaired judgment
Opioid pain medications containing buprenorphine are high-risk treatment options as it exhibits severe side effects such as respiratory distress, coma, and death, especially when taken in large doses. When co-administered with cannabis, these risks are further heightened because both substances depress the Central Nervous System. Heavy sedation is also frequently observed.
The following brands must not be taken simultaneously with cannabis to prevent adverse drug interaction effects:
Co-administration of the said substances results to the following adverse effects:
- Heavy sedation
- Breathing difficulties
- Inability to stay awake
- Impairment in motor function
- Slurred speech
- Decline in cognitive abilities
- Bradycardia or arrhythmia
Tips To Avoid Harmful Drug Interactions
Being knowledgeable about the possible detrimental effects of drug interactions is the first step in preventing such adverse impacts. But aside from this, other precautionary measures could also be employed.
- Always read drug labels and guidelines carefully before ingesting any drug. Comprehend the warnings, contraindications, drug interaction precautions, and any other pertinent information relating to the drug(s).
- If drug interactions between two substances are identified, consult a physician if the two drugs could be scheduled at different times to prevent interaction.
- Keep the medication in its original container so that it would be easy to identify it when needed.
- When prescribed with new medications, make it a habit to ask the doctor on what food, beverages, dietary supplements, and other drugs need to be avoided to avoid complications.
- Consult with a physician or pharmacist before taking an over-the-counter drug if it would have to be taken with any previously prescribed medications for other conditions.
- If possible, purchase all drug needs from one pharmacy only. This way, the attending pharmacist will have a record of all the obtained prescription drugs and can provide sound advice about possible drug interactions and side effects.
- Keep a record of all prescription drugs, OTC drugs, and dietary supplements (including herbs) that are being consumed at present. Bring this list when attending any medical appointment.
- Inform all health care professionals about every drug being taken to avoid being prescribed with drugs that have potential pharmacodynamic interactions with one another.
- It is generally recommended not to take any illicit drugs simultaneously with prescription drugs, but it is inevitable:
- Only use one drug type at a time
- Inform a friend who can respond in case of an emergency about what drugs will be taken
- Visit credible websites with information on what to do during a crisis or overdose.
Caution With Mixing Prescription Drugs With Cannabis
Cannabis is renowned for its vast array of potential therapeutic benefits. However, co-administering it with prescription medications in the hopes of enhancing its effects may not work as intended due to pharmacodynamic interactions. Taking different drugs concomitantly may bring upon either antagonistic or synergistic effects that can potentially impact biological processes negatively. Hence, it should not be done without the expert opinion of medical professionals. Keep in mind that it is best to err on the safe side than take a risk and suffer the consequences later.