Drug Interactions between cannabis and tramadol
This report displays the potential drug interactions for the following 2 drugs:
Interactions between your drugs
cannabis (Schedule I substance)
Applies to: tramadol and cannabis
Using narcotic pain or cough medications together with other medications that also cause central nervous system depression can lead to serious side effects including respiratory distress, coma, and even death. Talk to your doctor if you have any questions or concerns. Your doctor may be able to prescribe alternatives that do not interact, or you may need a dose adjustment or more frequent monitoring to safely use both medications. Do not drink alcohol or self-medicate with these medications without your doctor’s approval, and do not exceed the doses or frequency and duration of use prescribed by your doctor. Also, because these medications may cause dizziness, drowsiness, difficulty concentrating, and impairment in judgment, reaction speed and motor coordination, you should avoid driving or operating hazardous machinery until you know how they affect you. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.
Drug and food interactions
Applies to: tramadol
Alcohol can increase the nervous system side effects of traMADol such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with traMADol. Do not use more than the recommended dose of traMADol, and avoid activities requiring mental alertness such as driving or operating hazardous machinery until you know how the medication affects you. Talk to your doctor or pharmacist if you have any questions or concerns.
cannabis (Schedule I substance)
Applies to: cannabis
Alcohol can increase the nervous system side effects of cannabis (Schedule I substance) such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with cannabis (Schedule I substance). Do not use more than the recommended dose of cannabis (Schedule I substance), and avoid activities requiring mental alertness such as driving or operating hazardous machinery until you know how the medication affects you. Talk to your doctor or pharmacist if you have any questions or concerns.
Therapeutic duplication warnings
No warnings were found for your selected drugs.
Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.
- Cannabis Drug Interactions
- Tramadol Drug Interactions
- Tramadol General Consumer Information
- Drug Interactions Checker
Drug Interaction Classification
|Major||Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.|
|Moderate||Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.|
|Minor||Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.|
|Unknown||No interaction information available.|
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
Some mixtures of medications can lead to serious and even fatal consequences.
A Major Drug Interaction exists between cannabis and tramadol. View detailed information regarding this drug interaction.
Accurate Education: Cannabidiol (CBD) – Drug Actions & Interactions
Cannabidiol (CBD) – Drug Actions & Interactions
Pharmacokinetics & Pharmacodynamics
The medical information on this site is provided as a resource for information only, and is not to be used or relied upon for any diagnostic or treatment purposes and is not intended to create any patient-physician relationship. Readers are advised to seek professional guidance regarding the diagnosis and treatment of their medical concerns.
Pharmacokinetics refers to what the body does to a drug: how the drug moves into, through, and out of the body; the time course of its absorption, bioavailability, distribution, metabolism, and excretion.
Understanding the pharmacokinetics of cannabis constituents allows for identifying the pros and cons of the different formulations of cannabis/cannabinoids available as well as avoiding unintended responses and adverse effects associated with taking cannabis/cannabinoid products.
Pharacodynamics refers to the effects a drug has on the body, including desired, therapeutic effects as well as side effects.
Cannabidiol (CBD) has promise for many medical applications although they are not yet well defined nor are the mechanisms by which it works well understood.
This page is still being updated for accuracy and completeness.
Over-the-Counter Cannabinoid Medications:
Prescription Cannabis-Based Medications:
Clinical Applications of Cannabis:
Cannabis – Anxiety (coming soon)
Cannabis – Headaches (coming soon)
Cannabis – Inflammatory Bowel Disease (coming soon)
Cannabis – Neuroinflammation (coming soon)
Cannabis – Sleep (coming soon)
The Medical Science of Cannabis:
Cannabinoids and Terpenes:
Cannabinoids & Terpenes – An Overview (coming soon)
“Entourage Effect” (coming soon)
THC (Delta-9 Tetrahydrocannabinol or ∆9 THC) (coming soon)
Terpenes – An Overview (coming soon)
Key to Links:
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Red text – another page on this website
Blue text – Journal publication
Cannabidiol – Pharmacokinetics & Pharmacodynamics
Pharmacokinetics & Pharmacodynamics
Bioavailability and Tissue Distribution of CBD
A 2018 systematic review of the pharmacokinetic of CBD analysed all available pharmacokinetic data on CBD in humans. Only a few publications were identified. Only 8 publications evaluated CBD pharmacokinetics alone, the other publications evaluated combination products with THC and CBD.
It is reported that the bioavailability of CBD is 31% following smoking – in other words, only 31% of the CBD inhaled while smoking will make it into the blood. Oral bioavailability of CBD is estimated to be only 6-19% due to significant first-pass metabolism of CBD in the liver.
Peak CBD blood concentrations and total amounts of CBD entering the blood (area under the curve or AUC) are dose-dependent. Maximum blood levels (Cmax) are increased and reached faster with smoking or vaping CBD compared with oral or sublingual/buccal administrtion. Additionally, Cmax is increased and reached faster after oral administration when taken on a full stomach or with eating, especially fatty foods. The time it takes to reach maximal blood levels (Tmax) does not appear to be dose-dependent and is between 1 and 4 hours.
The time it takes for blood levels to go down to half of a maximum level (half-life) depends on dose and route of administration. The half-life is shorter for smoked/vaped administration and longer for oral and buccal use. The half-life of CBD is reported between 1.4 and 10.9 hours after oromucosal spray, 2–5 days after chronic oral administration, 24 hours after intravenous use, and 31 hours after smoking. Overall, however, there is considerable variation of these parameters in different individuals. Like THC, CBD is rapidly distributed into tissues with a high volume of distribution CBD and preferentially accumulates in adipose (fat) tissues due to its high lipophilicity.
Cmax and Tmax may be increased if CBD is accompanied by ingestion of piperine found in black pepper. Piperine has been found to reduce metabolic breakdown of CBD in the intestines and the liver. Furthermore, piperine may suppress the elimination of CBD (and THC) from the brain by inhibiting the transporter mechanism involved, leading to prolonged effects of CBD and THC.
Additionally, formulations of CBD and other medications are being developed that envelop the drug molecules with layers of fats called nanolipospheres which leads to enhanced absorption.
Tissue Distribution of CBD
Little or no published data exists on the tissue distribution of CBD in humans. Although plasma levels of CBD do not show accumulation with repeated dosing, it is possible that there may be tissue accumulation. One small 2018 study was conducted in children (4–10 years old) with Dravet syndrome who were administered an oral solution of CBD. It is important to emphasize that children are not small adults, and there are many differences in their pharmacokinetic and pharmacodynamic profiles. Absorption, excretion, metabolism, and plasma protein binding are generally reduced in children compared to adults, and apparent volume of distribution is generally increased. These parameters need to be explored fully for CBD in order to understand and advise dose adjustments in children.
Metabolism of CBD
CBD is extensively metabolised in the liver, primarily to 7-OH-CBD which is then metabolised further into as many as 100 metabolites that are excreted in feces and urine. Seven CYP enzymes have been identified as metabolising CBD: CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5, but the two main ones are CYP3A4 and CYP2C19.
Although research is lacking, the metabolites formed from CBD are believed to be present in the body at pharmacologically significant concentrations. Pharmacological studies of CBD metabolites are scarce but suggest biological activities not directly related to CB receptors. The pharmacological effects observed with CBD may be attributed at least in part to its metabolites.
CBD: Drug Interactions
Cannabinoids and Opioids
There appears to be a synergistic analgesic (pain-relieving) benefit when cannabinoids are added to opioid treatment for pain in which there is a greater-than-additive benefical effect with the addition of cannabinoids. Studies indicate a trend towards reduced use of opioids when patients taking opioids add cannabinoids to their regimen. It is not uncommon for patients started on cannabinoids to be able to taper down or off opioids.
Interestingly, animal studies suggest that cannabinoids may reduce the development of tolerance to the analgesic benefits of opioids, resulting in less need for opioid dose escalation.
There is no enhancement of cardiorespiratory suppression from opioids with the addition of cannabinoids due to the very low density of cannabinoid (CB) receptors in brainstem cardiorespiratory centers. There does not appear to be any significant interactions with opioids regarding a cannabinoid effect on the metabolism of most opioids. However, there is research showing that CBD may inhibit CYP2D6, one of the liver enzymes responsible for metabolizing tramadol and codeine. Because the analgesic benefits from tramadol and codeine come from their active metabolites resulting from CYP2D6 metabolism, these two opioids may be less effective if taken with CBD.
Another way in which medications may interact with one another is through their effect on drug transport systems, especially the P-glycoprotein (P- gp) system. The P-gp transporters transport medications and metabolites out of the central nervous system and brain through the blood-brain barrier into the blood. The activity of P-gp transporters can significantly impact the effect of drugs such as morphine, oxycodone and methaone on the brain by reducing their levels in the brain. Early findings indicate that CBD significantly inhibits P-gp-mediated drug transport, suggesting CBD could potentially increase brain levels of morphine and other opioids that are P-gp substrates thus enhancing their impact. CBD may also influence the absorption and disposition of other coadministered compounds that are P-gp substrates.
Smoking – Tobacco and Marijuana
Smoking marijuana and tobacco both induce CYP 1A2 through activation of the aromatic hydrocarbon receptors, and this effect between the two products is additive. Of note: this effect is based on the smoke associated with the smoking of marijuana or tobacco, not the drugs in the smoke. As a result of this CYP 1A2 enzyme being induced, in other words more CYP 1A2 enzyme is manufactured, medications that are metabolized by CYP 1A2 will be broken down faster, blood levels will be decreased and the therapeutic effects of the drug will be reduced. CYP 1A2 is the enzyme responsible for metabolizing such drugs as caffeine, tizanidine (Zanaflex), duloxetine (Cymbalta), methadone, olanzapine (Zyprexa) and melatonin.
When one suddenly stops smoking either tobacco, marijuana or both, the induction effect is quickly reversed and the levels of CYP 1A2 enzyme rapidly return to previous levels (downregulation) over a few days. When this occurs in an individual chronically taking one of the medications metabolized by CYP 1A2, the blood levels of this medication may quickly rise leading to the potential for increased side effects and toxicity from the medication.
This is especially significant in medications that have a narrow therapeutic index such as tizanidine (Zanaflex), in which even small increases in blood levels may be associated with increased side effects. It is therefore important to reduce doses of these medications in the first few days after suddenly stopping smoking either tobacco, marijuana or both to avoid possible toxicity from the medication. Due to body size and gender-related variables, this reduction is especially warranted in small females.
While the CYP 1A2 enzyme is not a major enzyme in the metabolism of methadone, it has been reported that methadone levels can dangerously increase with smoking cessation. As a rule of thumb, it has been recommended that a stepwise daily methadone dose reduction of approximately 10% be engaged until the fourth day after smoking cessation.
Alcohol and Benzodiazepines
The combination of cannabinoids with alcohol and benzodiazepines may increase sedation and cognitive impairment.
NSAIDS (Non-Steroid Anti-inflammatory Drugs)
It has been reported that NSAIDs such as ibuprofen and naproxen, particularly indomethacin, can partially antagonize the effects of THC, although the mechanism responsible is not fully understood.
Anticholinergic drugs (Tricyclic antidepressants (TCAs) and some muslce relatxers)
Medications with anticholinergic activity such as amitriptyline (Elavil) and doxepin, and muscle relaxers such as cyclobenzaprine (Flexeril) may increase the psychoactive side effccts of cannabinoids.
CBD: Drug-Metabolic Interactions
The major cannabanoids, THC and CBD are both metabolized in the liver by the CYP450 enzymes 2C9, 2C19 and 3A4. Drugs that inhibit these enzymes may enhance or prolong the effects of THC and CBD. Whether people with genetic variants of these enzymes may experience altered effects from cannabinoids is not known. In one study, potential drug–drug interactions of THC/CBD oro-mucosal spray (Sativex, nabiximols) in combination with CYP450 inducers and inhibitors were assessed using various dose regimens. The antibiotic rifampicin, an inducer of CYP3A4, significantly reduced the peak plasma concentration of CBD, while the antifungal ketoconazole, a CYP3A4 inhibitor, nearly doubled the peak plasma concentration of CBD. However, the moderate CYP2C19 inhibitor omeprazole (Prilosec), a proton-pump inhibitor used to treat gastroesophageal reflux disease (GERD), did not significantly alter the pharmacokinetics of CBD.
CBD has been identified as a potent inhibitor of CYP2D6 which may have significant impact on the metabolism of medications that are broken down by CYP2D6, including hydrocodone (Norco, Vicodin, Zohydro, Hysingla). As such, use of CBD especially at high doses with tramadol, codeine or hydrocodone may significantly reduce the analgesic effectiveness of these opioids.
Limited evidence also suggests that CBD may significantly inhibit CYP2C19, the enzyme responsible for metabolizing many medications including:
- Anticoagulants such as clopidogrel (Plavix),
- Tricyclic antidepressants such as amitriptyline (Elavil)
- SSRI antidepressants including citalopram Celexa) and e scitalopram (Lexapro)
- Proton pump inhibitors such as omeprazole (Prilosec) and pantoprazole (Protonix)
- Other drugs including indomethacin (Indocin), diazepam (Valium) and propranolol (Inderal).
As a result this may lead to elevated blood levels of these medications and their associated side effects.
CBD: Mechanism of Action
Scientific evidence shows that CBD has analgesic benefits for inflammatory and neuropathic pain but the explanation of how is not yet clear, although it may in part be attributed to the anxiolytic properties of CBD which may influence the impact of pain. CBD is an allosteric modulator of the mu- and delta-opioid receptors and has been noted to potentially enhance the analgesic effects of both endogenous and exogenous opioids. An allosteric modulator is an agent that modulates, or changes, the shape of a receptor. A “negative” modulator changes the shape in such a way as to weaken or reduce the ability of the receptor to interact with another molecule, whereas a “positive” modulator changes the shape in such a way as to enhance the ability of the receptor to interact with another molecule.
CBD also behaves as an agonist of the TRPV1 (transient potential vanilloid receptor, type 1), the receptor associated with the analgesic benefit of capsaicin in neuropathic pain, suggesting another mechanism for its action against nerve pain.
Clinical studies have revealed definitive anxiolytic effects of CBD. CBD reverses anxiety brought on by THC and by a public-speaking simulation in patients with social phobia. Neuroimaging studies also show that CBD decreases activation of brain regions associated with anxiety, fear, and emotional processing, including the amygdala and the anterior and posterior cingulate cortex.
While the mechanism by which CBD may reduce anxiety is not clear, there is strong evidence that the serotonergic system is involved in the anxiolytic action of CBD. 5-HT1A is a member of the family of 5-HT receptors, which are activated by the neurotransmitter serotonin. Found in both the central and peripheral nervous systems, 5-HT receptors trigger various intracellular cascades of chemical messages to produce either an excitatory or inhibitory response, depending on the chemical context of the message. At high concentrations, CBD directly activates the 5-HT1A (hydroxytryptamine) serotonin receptor, which confers an anti-anxiety effect. This G-coupled protein receptor is implicated in a range of biological and neurological processes, including anxiety, addiction, appetite, sleep, pain perception, nausea and vomiting.
The serotonergic system in the brain is the site of action of the prominent classes of anxiolytic medications, the Selective Serotonin Reuptake Inhibitors (SSRIs – Prozac, Paxil, Zoloft, Celexa etc.) and the Serotonin Norepinephrine Reuptake Inhibitors (SNRIs – Cymbalta and Effexor). It is likely that CBD also acts on the endocannabinoid system by direct or indirect stimulation of cannabinoid receptors in ways that effect emotion and emotional memory.
CBD also acts as a “positive allosteric modulator” of the GABA-A receptor and as such it changes the receptor shape in such a way as to enhance the ability of the receptor to interact with another molecule. In other words, CBD interacts with the GABA-A receptor in a way that enhances the receptor’s binding affinity for its principal endogenous agonist, gamma-Aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the central nervous system. The sedating effects of Valium, Xanax and other benzodiazepines are mediated by GABA receptor transmission. CBD reduces anxiety by changing the shape of the GABA-A receptor in a way that amplifies the natural calming effect of GABA.
Inflammatory Bowel Disease
The reduction of intestinal inflammation through the control of neuroimmune axis exerted by CBD suggests this CBD may be a promising drug for the therapy of inflammatory bowel disease, especially Crohn’s disease. CBD modulates inflammatory agents IL-12 and IL-10 and reduces activity of TNF-α, another inflammatory agent. CBD inhibits recruitment of inflammation-inducing mast cells and macrophages in the intestine, reducing intestinal damage principally mediated by peroxisome proliferator activated receptor-γ (PPAR-γ) receptor pathway. These findings may explain the significant reduction in disease activity for Crohn’s disease noted in a retrospective observational study of 30 patients treated with Δ9-THC and CBD. Lymphocytes are another key target of the immunomodulatory action of CBD. Specifically, CBD exhibits a generalized suppressive effect on T- cell functional activities in the gut.
CBD has a role in inflammatory neurodegenerative diseases. CBD strongly inhibits the production of inflammatory cytokines, including IL-1β, IL-6, and interferon-β (IFN-β), in microglial cells. Microglia act as primary responding cells for infection and injury, but prolonged or excessive activation may result in pathological forms of inflammations that contribute to the progression of neurodegenerative disease including Parkinson’s and Alzheimer’s diseases, multiple sclerosis and HIV-associated dementia and brain trauma-related chronic traumatic encephelopathy. In this case the effects are not mediated via CB1 or CB2 receptors.
CBD is also thought to be neuroprotective by reducing oxidative stress, mitochondrial dysfunction and inflammatory changes. One mechanism of the neuroprotection provided by CBD is the up-regulation of the mRNA levels for Cu–Zn superoxide dismutase, resulting in increased activity of an important enzyme in endogenous defenses against oxidative stress and mitochondrial dysfunction.
Reward Deficiency Syndrome – Addiction
As an allosteric modulator of the dopamine D2 receptor, an essential element in the reward system of the brain, evidence suggests CBD offers benefit in addiction treatment. In preclinical studies, CBD reduces drug-motivated behavior, suppresses withdrawal symptoms and limits cravings.
Opioid Addiction – The majority of the addiction treatment effects of CBD have been investigated in the context of opiate drugs. CBD normalizes opioid-induced impairments in the reward center (the nucleus accumbens – NAc), including AMPA and CB1 receptor levels. In a human clinical study it was demonstrated that CBD does not alter the subjective effects of fentanyl but reduces heroin cue-induced drug craving and anxiety. These results suggest that CBD reduces opioid-paired cue reactivity but has little effect on the acute reinforcing properties of opioids.
However, other research shows that the reward-facilitating effects of morphine are decreased by CBD, and these effects are associated with the 5-HT1A receptor. CBD is an agonist of the 5-HT1A receptor and evidence suggests that 5-HT1A agonists reduce baseline serotonin and dopamine release in the NAc, suggesting a mechanism whereby CBD may reduce the acute reinforcing effects of morphine. The 5-HT1A receptor is also localized in dopamine terminal regions elsewhere in the brain reward circuitry such as the prefrontal cortex, amygdala, and hippocampus as well as the NAc.
Nicotine Addiction – Preliminary findings indicate that CBD reduces cigarette smoking in smokers trying to quit. Although the mechanism for this effect has not been definitely identified, CBD may modulate nicotine reward through its ability to increase endocannabinoid levels by inhibiting FAAH, the enzyme that breaks down the endogenous endoccannabinoids (see belpw). It has been demonstrated that inhibiting FAAH blocks nicotine seeking and nicotine-induced dopamine release in the NAc reward center. It also reduces anxiety during nicotine withdrawal in animals.
Psychostimulant Addiction – In contrast to its effects on opioid-motivated behaviors, CBD has less impact on psychostimulant reward and reinforcement. Administration of CBD fails to reduce cocaine-mediated decreases in self-stimulation thresholds or disrupt cocaine- and amphetamine-conditioned place preference.
Accurate Education: Cannabidiol (CBD) – Drug Actions & Interactions Cannabidiol (CBD) – Drug Actions & Interactions Pharmacokinetics & Pharmacodynamics The medical information on