Accurate Education: Cannabidiol (CBD) – Drug Actions & Interactions
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. When engaging the use of CBD for therapeutic benefits, one must be aware of potential drug interactions CBD may have with other medications.
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.
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Cannabidiol (CBD) Pharmacokinetics & Pharmacodynamics
Bioavailability and Tissue Distribution of CBD
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.
CBD and Piperine
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.
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.
Contraindications for use of lortab and cbd oil
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Volume 10, Number 4, August 2020, pages 132-135
Cannabidiol and Non-Steroidal Anti-Inflammatory Drug Interactions: A Case of Drug-Induced Aseptic Meningitis
Mallory Emig a, b , Jafar Kafaie a , Samantha Ong a , Xujia Li a
a Saint Louis University Hospital, Saint Louis, MO, USA
b Corresponding Author: Mallory Emig, Saint Louis University Hospital, Saint Louis, MO 63110, USA
Manuscript submitted May 8, 2020, accepted June 5, 2020, published online June 20, 2020
Short title: Cannabidiol and NSAIDs
Cannabidiol (CBD) and other marijuana derivatives are being more widely used in the medical community by people in an attempt to alleviate a variety of symptoms. While these products have shown promise in their analgesic properties, little is known about the potential pharmacological interactions of these and other drugs. We present a case of a 57-year-old Caucasian woman who presented with altered mental status, ataxia, left-sided numbness, and slurred speech. An extensive workup was completed and found to be largely unremarkable, though a thorough history revealed that her symptoms were likely caused by concurrent use of CBD and non-steroidal anti-inflammatory drugs (NSAIDs) resulting in drug-induced aseptic meningitis. The benign nature of CBD makes it a promising avenue for pain relief. Physicians and patients should be informed about the potential drug-drug interactions of CBD and other medications.
Keywords: Cannabidiol; NSAIDs; Drug-induced aseptic meningitis
Cannabidiol (CBD) is a phytocannabinoid that is derived from Cannabis sativa and Cannabis indica that has become more frequently used for its medicinal qualities. The consumer market of CBD-infused products is continuously growing, although its therapeutic benefits are still under question by the US Food and Drug Administration (FDA) [ 1 ]. Due to its low tetrahydrocannabinol (THC) concentration, CBD oils and other derivatives provide medicinal benefits without the psychoactive effects of recreational marijuana, one of the most commonly used illicit drugs in the USA [ 2 ]. CBD is generally used for the side effects of chemotherapy, pain, anxiety, and other neurological and psychiatric illnesses, including but not limited to post-traumatic stress disorder, seizures, and Tourette’s syndrome [ 3 ]. Generally, in the medical community, CBD is considered a low-risk drug and has been used for decades for its neuroprotective effects. However, CBD’s actions throughout the body are not fully understood and there are many side effects that should be considered before prescribing to patients.
CBD extracts usually contain no or very low amounts of THC, which is the component in marijuana that induces the euphoric psychoactive effect. However, CBD still has side effects including diarrhea, nausea, irritability, and weight/appetite changes that should not be ignored [ 4 ]. More importantly, because CBD interacts with common biological targets implicated in drug metabolism and excretion, it increases the likelihood of drug-drug interactions (DDIs) with commonly prescribed and over-the-counter medications such as non-steroidal anti-inflammatory drugs (NSAIDs), antimicrobials, and antiepileptics [ 5 ]. The mean half-life of CBD is 2 -5 days, so the drug can cause effects even if the patient stopped using before any symptoms of DDIs present [ 6 ]. As CBD is implicated as both a subject and a cause of DDIs, physicians and patients should be made aware of potential safety concerns with CBD use.
The adverse drug effects and DDIs of CBD are based on its pharmacologic targets and pharmacodynamic qualities related to metabolism, absorption, and elimination. Molecular targets of CBD include a wide variety of receptors and channels, and its metabolites can act on a multitude of cytochrome P450 (CYP) enzymes. In particular, CYP enzymes are responsible for the metabolism of NSAIDs, one of the most widely used drugs worldwide. In the USA alone, more than 30 billion doses of NSAIDs are consumed and more than 70 million prescriptions are written for NSAIDs [ 7 ]. These drugs (e.g. ibuprofen, diclofenac, ketoprofen, naproxen, flurbiprofen, meloxicam, piroxicam, and tenoxicam) are metabolized by two enzymes of the CYP superfamily, mainly the CYP2C8 and CYP2C9 [ 8 ]. CBD decreases the activity of both CYP2C8 and CYP2C9 in vitro [ 9 , 10 ]. Because the activity of CBD on the enzymes in vivo has not been established, clinical data is needed to fully understand the DDIs between CBD and NSAIDs. Physicians should strongly consider DDIs when the use of CBD is reported in concurrence with the use of commonly prescribed medications such as NSAIDs.
Although studies have shown the various adverse effects of CBD on different organ systems, clinical data demonstrating the negative consequences of CBD DDIs are minimal. One prior clinical study by Geffrey et al presented DDIs between CBD and clobazam, supporting the fact that concomitant use of CBD with other medications should be monitored carefully [ 11 ]. In fact, though CBD has shown promising results in treating a variety of symptoms, its effects on different processes throughout the body remain poorly understood and therefore should be treated/recommended with caution. The current case study offers further evidence that DDIs between CBD and common medications such as NSAIDs can lead to unforeseen and potentially severe nervous system pathology such as aseptic meningitis.
Our patient is a 57-year-old woman with a medical history significant for occasional headaches, thyroid nodules, a Warthin’s tumor of the left parotid gland resected in 2009, coronary artery disease, hypertension, thyroid nodules, rheumatoid arthritis and a 40-pack-year smoking history, who presented with altered mental status, ataxia, left sided numbness, and slurred speech.
She initially presented to an outside facility with the above symptoms for 9 days. She underwent routine testing including magnetic resonance imaging (MRI) of her brain without contrast which was unremarkable. She was discharged home after 2 days. Two days after being discharged, she returned to the facility with agitation, aggressive behavior, and staring spells along with ongoing altered mental status and ataxia. She was somnolent and complained of headaches. She had no fever and routine labs were again unremarkable. She underwent a lumbar puncture (LP) and extensive lab testing, the results of which were largely non-specific. Urinalysis and toxicology were negative. There were no metabolic or vitamin abnormalities. Thyroid studies were significant for a thyroid stimulating hormone (TSH) of 0.18. Inflammatory markers were not elevated. Autoimmune panels were within normal limits. Human immunodeficiency virus (HIV) and rapid plasma reagent (RPR) for syphilis were non-reactive. Cerebrospinal fluid (CSF) analysis revealed a white blood cell (WBC) count of 180, 96% lymphocytes, red blood cell (RBC) count of 5, glucose 62, protein 280, and cytology and flow cytometry were negative. Comprehensive cultures were sent and were all negative. MRI total spine was done and MRI brain with and without contrast was repeated, this time showing diffuse leptomeningeal enhancement. Routine electroencephalogram (EEG) was unremarkable. She was transferred to our hospital for further evaluation.
Upon arrival at our facility, she was awake and alert without agitation. A detailed history was taken, which noted worsening of her intermittent headaches starting in April 2019. At that time, she began to use CBD oil for her rheumatoid arthritis along with her prescribed NSAIDs. Around that time, her headaches became more frequent and more painful, leading her to increased NSAID use. Over the next few months, she experienced persistent headaches and developed gait difficulties. The memory issues and confusion were the newest symptoms she experienced, leading to her wandering the streets around the neighborhood lost and confused. Upon further questioning, she recalled having episodes of subjective fevers and night sweats as well as unintentional weight loss of 25 LBS. Review of systems was otherwise negative.
She reported a family history of thyroid disease as well as rheumatoid arthritis. She denied a recent history of travel, dietary changes, and knowledge of any exposure to toxins. Neurological exam was non-focal and was significant for decreased orientation (only oriented to self and place), fatigue, and mild weakness. Palpation of the thyroid revealed an enlarged goiter. She had diffuse bruising of her extremities. No rashes were noted.
Over the next 24 h, the patient’s headaches worsened and she again became aggressive and agitated. She was started on hydrocodone-acetaminophen for headaches. She underwent thyroid ultrasound which showed a large multinodular thyroid as well as a second LP. LP showed protein 182, WBC 238 w/93% lymphocyte, glucose 60, and flow cytometry and cytology were pending but eventually were unremarkable. Infectious labs were all negative. Encephalopathy, encephalitis, and paraneoplastic panels were sent out to Mayo clinic. The patient continued to have episodes of agitation and aggression, particularly at night, eventually requiring scheduled quetiapine. In the mornings, she had a poor recollection of the events that occurred overnight.
Due to high concern for an underlying malignancy, she underwent a whole-body positron emission tomography-computed tomography (PET-CT) which was significant for “intense fluorodeoxyglucose (FDG) uptake in the right parotid gland with subsegmental and tonsillar lymph nodes demonstrating increased FDG avidity concerning for malignancy”. Hematology was consulted for the significant PET findings. They recommended a biopsy of the parotid gland. Due to her negative infectious workup and lack of fever, the patient was not started on antibiotics. An ear, nose, and throat (ENT) specialist was consulted for fine needle aspiration (FNA) of the right parietal mass which showed recurrence of a Warthin’s tumor.
After discussion with the patient and family about the unclear etiology of her presentation, she denied leptomeningeal biopsy and the decision was made to trial a dose of intravenous (IV) steroids. She was started on IV methylprednisolone 500 mg twice a day (BID) for 3 days. She was given intravenous immunoglobulin (IVIG) 2 g/kg in 2 days after receiving solu-medrol for 3 days. The patient reported significant improvement in her headaches and cognition. She was able to be discharged home under the care of her family.
Encephalitis, encephalopathy, and paraneoplastic panels resulted in no abnormalities. She was seen in a follow-up clinic 1 month after being discharged and reported that she felt completely back to her baseline which was confirmed by family members. She underwent a follow-up MRI which showed no leptomeningeal enhancement or signal abnormality and no other findings.
The patient’s presentation and complicated medical history led to a concern for a wide range of etiologies. Malignancy was high on the differential given her smoking history and B symptoms. Metabolic disorders were also considered though it was difficult to pursue this differential with a lack of abnormal lab findings. Careful history taking helped support the possibility of medication-induced encephalitis given that her headaches worsened with an increase in the use of her NSAIDs and subsequent administration of topical CBD. Infection was considered, but the patient was never febrile while in the hospital and she did not improve with antibiotics. Extensive infectious labs were sent with no significant results, helping us rule out this possibility. Because of all the negative lab findings, a diagnosis of drug-induced aseptic meningitis was highly considered.
The current case study found that the concomitant use of CBD with meloxicam could have precipitated drug-induced aseptic meningitis (DIAM). DIAM is a rarer cause of meningitis that is associated with NSAID use [ 12 ]. The symptoms of DIAM are similar to those that are found in cases of meningoencephalitis, including fever, headache, altered mental status, arthralgia, and myalgia [ 13 ]. The diagnosis of DIAM is a diagnosis of exclusion and is made by ruling out other possible causes of meningitis. The fact that all the laboratory tests, in this case, were negative for malignancy, infections, and autoimmunity and she returned to her baseline with complete resolution of the brain MRI findings, supporting the likelihood that our patient’s aseptic meningitis was caused primarily by the use of medications. The pathogenesis of DIAM can be attributed to two proposed mechanisms, one being direct meningeal irritation by the drug and the other being a hypersensitivity reaction to the drug [ 14 ].
Although there are no published clinical cases about meloxicam specifically inducing aseptic meningitis, NSAIDs have been shown to be related to this pathology [ 12 ]. Therefore, it is possible that meloxicam can have similar effects as other NSAIDs that have been shown to cause DIAM. Meloxicam is primarily metabolized to a 5’-hydroxymethyl metabolite by CYP2C9 (major) and CYP3A4 (minor) [ 15 ]. As stated before, CBD decreases the activity of CYP2C9 in vitro. It is possible that the inhibitory effect of CBD on CYP2C9 led to a higher concentration of meloxicam, which led to the DIAM. Given the increasing popularity of CBD, it is important for both physicians and patients to be aware of possible DDIs of these substances and the symptoms that may result.
None to declare.
None to declare.
Conflict of Interest
None to declare.
Consent to write and publish the case was obtained from the patient.
ME provided the body of the case report and summarized the case as well as contributing to the discussion, revising the final draft, and submitting the final paper for review. JK revised the final draft and provided expertise on the clinical importance of the case. SO and XL drafted the Introduction and Discussion and compiled and reformatted the references section.
The authors declare that data supporting the findings of this study are available within the article.
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Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability
Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals. Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability. This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability. Healthy cannabis smokers (N = 18) were administered oxycodone (0, 2.5, and 5.0 mg, PO) with smoked cannabis (0.0, 5.6% Δ 9 tetrahydrocannabinol [THC]) and analgesia was assessed using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4 °C); times to report pain (pain threshold) and withdraw the hand from the water (pain tolerance) were recorded. Abuse-related effects were measured and effects of oxycodone on cannabis self-administration were determined. Alone, 5.0 mg oxycodone increased pain threshold and tolerance (p ≤ 0.05). Although active cannabis and 2.5 mg oxycodone alone failed to elicit analgesia, combined they increased pain threshold and tolerance (p ≤ 0.05). Oxycodone did not increase subjective ratings associated with cannabis abuse, nor did it increase cannabis self-administration. However, the combination of 2.5 mg oxycodone and active cannabis produced small, yet significant, increases in oxycodone abuse liability (p ≤ 0.05). Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis’s abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.
In the United States, an estimated 11.2% of the adult population suffers from chronic pain  and nearly 20% of patients presenting with acute and chronic non-cancer pain are prescribed opioids . Between 1999 and 2015, opioid prescribing tripled  along with the number of deaths attributed to opioid analgesics, with an estimated 17,500 fatalities in 2015 relative to 6160 reported in 1999 . With recent recognition of the significant health risks associated with high doses of opioids including opioid use disorder  and overdose [6, 7] physicians are asked to limit the number of prescriptions written, shorten the duration of opioid therapy, and decrease the total daily doses prescribed . As awareness of the risks of prescription opioid use grows, medical cannabis use is also garnering widespread acceptance, with over half of the United States passing medical cannabis laws . Pain is the primary indication for use by patients who are prescribed cannabis , and chronic pain is one indication for which strong evidence exists supporting the use of cannabinoids (National Academies of Sciences, Engineering, and Medicine [62, 11]). Yet recent systematic reviews concluded that there is limited or inconclusive evidence supporting the use specifically of cannabis-based products for neuropathic pain and insufficient evidence supporting its use for other types of chronic pain [12, 13]. These findings exemplify the need for more rigorously controlled clinical trials in this area.
With increased access to cannabis and more conservative opioid prescribing, evidence suggests that patients are substituting cannabis for opioids. For example, opioid analgesic prescriptions filled by Medicare Part D enrollees fell significantly in states with medical cannabis laws , and patients with chronic pain report over 60% reduction in their opioid use in these states . In lieu of full substitution, some pain patients report that cannabis increases the analgesic effects of their opioids  or decreases the opioid dose needed for therapeutic effect . Moreover, some randomized controlled studies have demonstrated analgesic effects of cannabinoids in patients taking opioids for chronic and cancer pain [18–20]. These data suggest that cannabis may (1)increase the pain-relieving properties of opioids and consequently decrease the total dose used, or (2) provide adequate analgesia on its own thus acting as a substitute. However, there are no data from placebo-controlled studies directly addressing whether cannabis can decrease the effective analgesic doses of opioids. Furthermore, to date, no studies have investigated the impact of opioid-cannabinoid drug combinations on abuse liability, a critical aspect when considering the therapeutic utility of two drugs that have significant abuse liability when administered alone.
Based on animal studies, combining opioids and cannabinoids for pain relief is hypothesized to provide superior clinical therapeutic effectiveness than opioid administration alone by increasing the analgesic potency of the opioid and therefore decreasing its effective analgesic dose (termed opioid-sparing effects). Although this effect has yet to be confirmed in humans, preclinical evidence regarding the pro-analgesic effects of co-administration of mu-opioid agonists and cannabinoids abounds, predominantly with Δ 9 tetrahydrocannabinol (THC), a partial CB1 and CB2 receptor agonist  and the main psychoactive component of cannabis . Combining THC and mu-opioid agonists has been reported to have additive or synergistic effects across a range of routes of administration in rodents (i.e., [23–28]) and non-human primates, depending on the efficacy of the opioid agonist (i.e., [29–31]). Achieving analgesia with lower opioid doses may also decrease adverse effects related to opioid use that diminish their therapeutic utility, including constipation, respiratory depression, and the development of opioid tolerance and dependence . For instance, although chronic administration of a CB1 or mu-opioid receptor agonist alone produces antinociceptive tolerance and physiological dependence, co-administration of the drugs prevents these effects in rodents [33, 34]. In addition to reducing the development of tolerance and dependence, CB1 receptor agonists also reduce the discriminative stimulus and reinforcing effects of opioid agonists in non-human primates [30, 35]. This potential for cannabinoids to decrease the abuse liability of opioids has profound implications for the most significant adverse effects of opioids; that is, the risk of opioid use disorders and associated fatalities [4, 36]. Based on the preclinical literature, co-administration of cannabinoids, specifically CB1 receptor agonists like THC, would potentially decrease the risk of developing an opioid use disorder.
Few controlled clinical studies have sought to identify the opioid-sparing effects of cannabinoids; one assessed the impact of vaporized cannabis on opioid analgesia and pharmacokinetics, however this was under non-placebo controlled conditions. In addition, that study was not designed to assess if cannabis could decrease the effective opioid analgesic dose . Other studies have used various cannabinoid preparations and routes of administration (i.e., oral THC or THC:CBD oromucosal spray) and have either lacked an opioid control (i.e., opioid placebo) or failed to include more than one opioid dose, again making it difficult to conclude whether cannabinoids can decrease the effective opioid dose for analgesia [18–20, 38, 39]. Furthermore, while one study assessed the effects of cannabis and opioid co-administration on subjective intoxication , no studies to date have assessed the abuse liability of the drug combination, a critical endpoint when determining if the combination can mitigate risks of abuse associated with opioid administration.
This within-subject, randomized, placebo-controlled, double-blind study sought to determine the opioid-sparing effects of cannabis by assessing analgesia and abuse liability of sub-threshold and lowest-effective doses of oxycodone (2.5 and 5.0 mg, respectively) when administered alone or in combination with smoked cannabis over six experimental sessions in a healthy, cannabis-smoking population. The sub-threshold dose was chosen specifically to assess potential synergistic effects of the drug combination that may not have been apparent with higher doses. Analgesia was assessed using the Cold Pressor Test (CPT) an experimental test of pain that has predictive validity for medications used for chronic pain (opioids [40–42], gabapentin , and lamotrigine ). Assessing analgesic effects using this elicited pain test in a non-pain population afforded robust experimental control by excluding significant confounding variables that occur when studying a pain population including (1) current use of analgesics and (2) fluctuations in baseline pain across session days.
Methods and materials
Volunteers, 21–45 years of age, who met basic inclusion/exclusion criteria after an initial telephone screen came to the laboratory for further screening, received a psychiatric and medical evaluation, and provided a drug use and medical history. Eligible participants currently smoked ≥ three cannabis cigarettes at least three times a week for the four weeks before screening, as determined by urine toxicology and self-report (one ‘blunt’ = two cannabis cigarettes ) and were physically healthy, as determined by a physical examination, electrocardiogram, and urine and blood chemistries. Participants also had to have experience with opioids without adverse effects. Volunteers were excluded if they endorsed current pain, used over-the-counter or prescription medications each day, with the exception of oral contraceptives, used illicit drugs other than cannabis, as determined by urine toxicology and self-report, or had problematic alcohol consumption. Those meeting Diagnostic and Statistical Manual (of Mental Disorders), fourth edition revised criteria for Axis I psychopathology were excluded. Pregnant or nursing females were also excluded. Volunteers were told that the study aimed to determine the effects of smoked cannabis and a Food and Drug Administration (FDA)-approved medication on pain and that during each session they would take a capsule and smoke a portion of a cannabis cigarette. Participants were admitted into the study after providing informed consent. Procedures were approved by the Institutional Review Board of the New York State Psychiatric Institute and were in accord with the Declaration of Helsinki.
Design and procedures
The study included six 8-hour outpatient sessions over the course of 4–8 weeks at the New York State Psychiatric Institute. Sessions were separated by >72 h to prevent medication carryover effects and began around 9 AM. Volunteers also participated in two additional sessions assessing the effects of naltrexone (25 mg) on cannabis analgesia; findings will be reported separately. Before study onset, participants were familiarized with computerized tasks, the CPT, and study procedures during a medication-free training. During each session, one capsule containing placebo or oxycodone (2.5 or 5.0 mg) was administered 45 min before cannabis was smoked (0.0 or 5.6% THC). Each combination of cannabis (0.0 and 5.6% THC) and oxycodone strength (0.0, 2.5, and 5.0 mg) was tested. A within-subject design was used in which all participants received all six dose conditions in randomized order.
Participants were instructed not to eat breakfast before sessions as they would be served the same standard breakfast before each session in the laboratory to control for any possible effects of the meal or macronutrients on mood or drug absorption. Participants were also asked not to smoke cannabis or nicotine cigarettes after midnight the night before each session to ensure low carbon monoxide levels in the morning and provide a way to assess any recent cannabis smoking. Upon arrival at the laboratory, carbon monoxide levels were measured to confirm no recent smoking, breath alcohol levels were assessed, urine toxicology screens confirmed no recent use of illicit drugs other than cannabis, and a standardized breakfast was provided.
Before capsule administration, participants completed a baseline pain assessment (CPT and pain ratings). Heart rate and blood pressure were measured using a Sentry II vital signs monitor (Model 6100: NBS Medical Services, Costa Mesa CA). Pupil photographs were taken using a digital pupillometer (VIP-200 Pupillometer, Neuroptics, Inc., San Clemente, CA) under ambient lighting conditions. Participants smoked 70% of an 800 mg cannabis cigarette 45 min after capsule administration, following a cued-smoking procedure . Heart rate, blood pressure, pain assessments (CPT and pain ratings), subjective drug effect ratings, and pupil diameter were assessed at set times throughout the session after capsule administration and cannabis smoking (refer to Table 1 ). Cannabis’s reinforcing effects were assessed 195 min after smoking (see below for details). During each session, nicotine cigarette smokers were permitted to smoke after carbon monoxide levels were measured (before any assessments) and at predetermined intervals to minimize nicotine withdrawal. At the end of each session participants were given subway fare and left the laboratory after passing field sobriety tasks and verbally agreeing not to drive for the remainder of the day. Table 1 provides details related to timing of assessments relative to capsule administration and cannabis smoking.
|−75||Urine toxicology, breathalyzer, carbon monoxide, breakfast|
|−60||Pain assessments, BP/HR, pupil measurement, SE-VAS|
|(0.0, 2.5 or 5.0 mg oxycodone, oral)|
|−20||Pain assessments, BP/HR, pupil measurement, capsule-RF, SE-VAS|
|(0 or 5.6%, smoked)|
|15||BP/HR, pupil measurement, capsule-RF, cannabis-RF, SE-VAS|
|30||Pain assessments, BP/HR, capsule-RF, cannabis-RF, SE-VAS,|
|60||Pain assessments, BP/HR, pupil, capsule-RF, cannabis-RF, SE-VAS,|
|90||Pain assessments, BP/HR, pupil, capsule-RF, cannabis-RF, SE-VAS,|
|120||Pain assessments, BP/HR, capsule-RF, cannabis-RF, SE-VAS|
|180||Pain assessments, BP/HR, pupil, capsule-RF, cannabis-RF, SE-VAS|
|195||Choice to purchase 1-3 puffs of marijuana followed by smoking|
|300||BP/HR, Field Sobriety Test, participant discharge|
Timing of session events relative to cannabis smoking. Session began at approximately 9 AM
Pain assessments Cold Pressor Test, McGill Pain Questionnaire, and Painful and Bothersome Rating Forms, BP/HR blood pressure and heart rate readings, SE-VAS Subjective Effects -Visual Analog Scale, Capsule-RF Capsule Rating Form, Cannabis-RFC Cannabis Rating Form
Pain responses were measured before and repeatedly after drug administration (Table 1 ). Based on earlier reports of smoked cannabis and oral THC’s effects in the CPT , these were the primary outcomes for the current study.
Cold pressor test
The cold pressor apparatus consisted of two water coolers, each fitted with a wire cradle and an aquarium pump for water circulation. One cooler was filled with warm water (37 °C) and the other was filled with cold water (4 °C) . Briefly, each CPT began with an immersion of the left hand into the warm-water bath for 3 min. The left hand was then immersed into the cold-water bath, and participants were instructed to report the first painful sensation after immersion and asked to tolerate the stimulus as long as possible before withdrawing their hand (up to 3 min). Pain threshold, defined as latency to first feel pain, and pain tolerance, latency to withdraw the hand from the cold water, were recorded. Staff administering the CPT was the same sex as the volunteer.
Pain Intensity and Bothersomeness Scales (PIB)
Immediately after removing the hand from the cold water, participants rated pain intensity and bothersomeness of the cold water stimulus on a scale from 0 to 10, 0 being “not painful/bothersome at all” and 10 being “most painful/bothersome feeling imaginable.”
McGill Pain Questionnaire (MPQ)
A 15-item shortened, computerized form of the MPQ was used to assess the sensory and affective dimensions of the pain experience immediately following the CPT. Participants were ask to describe the pain by choosing among a series of possible answers (None [score = 1] to Severe [score = 4]) when prompted by a descriptor (“Throbbing,” “Shooting,” “Stabbing,” etc.). Scores were added across all 15 items to generate a sum score, ranging between 15 and 60. This questionnaire was completed immediately after the PIB.
Subjective drug effects
Ratings of subjective drug effects were measured repeatedly on a scale of 0 mm = no effect to 100 mm = maximum possible effect (Table 1 ).
Subjective Effect-Visual Analog Scale (SE-VAS)
Participants were asked to rate their mood and physical symptoms on a modified 44-item, computerized VAS that measures affective and physical subjective drug effects (see [47, 48]).
Cannabis Rating Form (Cannabis-RF) and Capsule Rating Form (Capsule-RF)
Subjective cannabis-and capsule-related effects were assessed using two 5-item VASs asking participants to rate the strength of the drug effect, good effect, bad effect, drug liking, and willingness to take the drug again .
Cannabis reinforcing effects
Cannabis self-administration was assessed by providing the participants an opportunity to purchase up to 3 puffs ($1/puff, taken from study earnings) of the cannabis that was smoked 3 h earlier. Self-administered cannabis was smoked immediately after the choice according to the puffed-paced procedure.
Capsules (size 00 opaque capsules with lactose filler) containing placebo or oxycodone (2.5 or 5.0 mg) were prepared by the New York State Psychiatric Institute Research Pharmacy. Cannabis cigarettes (0.0 or 5.6% THC; ca. 800 mg) were provided by the National Institute on Drug Abuse. Cigarettes were stored frozen in an airtight container and humidified at room temperature for 24 h prior to the session.
Repeated measures analysis of variance (ANOVA) with planned comparisons were used to assess the analgesic and subjective effects of cannabis and oxycodone administered alone and in combination. For each drug condition, pain threshold and tolerance were calculated for each participant as the percent of the baseline pre-drug administration CPT response. Pain ratings were also measured as a function of change from the baseline response. For each dependent measure, seven planned comparisons between dosing conditions were completed. Active cannabis and the two oxycodone strengths were compared to the placebo (three comparisons), and the two drug combinations (active cannabis + 2.5 mg oxycdone and active cannabis + 5.0 mg oxycodone combination) were compared to the placebo (2 comparisons). Lastly, the two drug combinations were compared to active cannabis alone (2 comparisons). Results were considered statistically significant when p values were equal to or less than 0.05 using Huynh-Feldt corrections. One participant held his hand in the cold water for the full 3 min during all CPTs; his data were excluded from analyses.
Table 2 portrays the demographic characteristics of the participants who completed the study. An additional 12 volunteers enrolled, but did not complete the study; nine discontinued for personal reasons, one had a positive toxicology screen for amphetamine, one reported unwanted effects of study medication (nausea), and one provided false information regarding psychiatric and legal history during screening. All participants had experience with prescription opioids with no adverse effects; 14 participants had histories of prescription opioid use for pain only, one participant used prescription opioids for pain and for recreational purposes on one occasion, and three participants had a history of using prescription opioids only for recreational purposes. Recreational use spanned 1–3 occasions. Participants did not have a history of heroin use. Average times since last use prior to study participation was 3.4 ± 4.4 years for therapeutic purposes and 2.6 ± 3.7 years for recreational use.
Demographic characteristics of study participants
|Demographics (N = 18)|
|Age (years)||29.9 ± 1.6|
|Years regular use||12.1 ± 8.5|
|Days/Wk||6.6 ± 0.9|
|$/Wk||153.8 ± 193.1|
|Cannabis cigarettes/day||7.9 ± 5.3|
|Daily nicotine smokers||44%|
|Tobacco cigarettes/day||4.9 ± 2.9|
|Drinks/occasion||3.3 ± 2.4|
|Past use for pain only||78%|
|Occasions of recreational use||2.0 ± 1.2|
Note: Data are presented as means (±SD) or as percent
Race is indicated as Black (B), White (W), and Mixed (M)
CPT: pain sensitivity and tolerance
Figure 1 portrays the time course of pain threshold (latency to first report pain, top panels) and pain tolerance (latency to withdraw the hand from cold water, bottom panels) as a function of cannabis strength and oxycodone dose (left column, 2.5 mg oxycodone; right column, 5.0 mg oxycodone). Baseline and post-capsule pain threshold and tolerance did not differ across dosing conditions. Administered alone, only 5.0 mg oxycodone increased pain threshold (F [1, 17] = 7.5, p ≤ 0.01) and tolerance (F [1, 17] = 5.4, p ≤ 0.05) compared to placebo (inactive cannabis and 0.0 mg oxycodone). When administered with active cannabis, 5.0 mg oxycodone also increased pain tolerance compared to the placebo condition and active cannabis alone (F [1, 17] = 5.5, p ≤ 0.05). The combination of active cannabis and 2.5 mg oxycodone increased pain threshold and tolerance relative to the placebo condition (F [1, 17] = 5.9, p ≤ 0.05 and F [1, 17] = 6.5, p ≤ 0.05, respectively) and active cannabis alone (F [1, 17] = 5.2, p ≤ 0.05 and F [1, 17] = 5.5, p ≤ 0.05, respectively).
Cold Pressor Task pain threshold (top panels) and tolerance (bottom panels) as calculated by percent baseline latency (seconds) to report pain and withdraw the hand from cold water. Data are presented as mean values +/- SEM according to cannabis strength, oxycodone dose (2.5 mg, left panels; 5.0 mg, right panels), and time. Placebo oxycodone + inactive cannabis condition = PBO; placebo oxycodone + active cannabis condition = CAN; 2.5 mg oxycodone + inactive cannabis condition = 2.5 Oxy; 2.5 mg oxycodone + active cannabis condition = 2.5 O + C; 5.0 mg oxycodone + inactive cannabis condition = 5.0 Oxy; 5.0 mg oxycodone + active cannabis condition = 5.0 O + C. Baseline response is shown as BSL on the x-axis; response after oxycodone is indicated by C on the x-axis. Significant differences from placebo are indicated by *p ≤ 0.05 and **p ≤ 0.01; significant differences from active cannabis alone are indicated with # p ≤ 0.05
Pain ratings including MPQ and PIB ratings did not differ between active cannabis or oxycodone, either administered alone or in combination, as compared to placebo (Table 3 ). Baseline and post-capsule ratings for these measures also did not differ across sessions (average baseline MPQ ratings = 20.0 ± 0.3; average ‘Painfulness’ ratings = 5.9 ± 0.2; average ‘Bothersomeness’ ratings = 5.7 ± 0.2). MPQ ratings increased throughout the sessions for all drug conditions. Lower ratings were observed under active drug conditions compared to placebo, but differences were not statistically significant. Similarly, ‘Painfulness’ and ‘Bothersomeness’ ratings also increased across the session with no significant differences between dose conditions.
|Drug condition||Oxycodone||0.0 mg||0.0 mg||2.5 mg||2.5 mg||5.0 mg||5.0 mg|
|Cannabis||0.0 %||5.6 %||0.0 %||5.6 %||0.0 %||5.6 %|
|Subjective effect||MPQ||2.2 ± 0.5||1.5 ± 0.5||2.0 ± 0.5||0.7 ± 0.6||1.7 ± 0.4||1.2 ± 0.4|
|Painfulness||0.4 ± 0.1||0.6 ± 0.1||0.6 ± 0.1||0.3 ± 0.2||0.3 ± 0.1||0.2 ± 0.1|
|Bothersomeness||0.6 ± 0.1||0.6 ± 0.2||0.8 ± 0.2||0.6 ± 0.2||0.5 ± 0.2||0.0 ± 0.2|
Mean reductions from baseline in pain ratings ± standard error of the mean (SEM) for the McGill Pain Questionnaire (MPQ), and Painfulness and Bothersomeness scales after administration of placebo (inactive cannabis + 0 mg oxycodone), oxycodone (2.5 and 5.0 mg) and active cannabis (0.0 and 5.6% THC) administered alone or together
Subjective drug effects
Figure 2 illustrates representative subjective cannabis effects as measured by the Cannabis RF and ratings of ‘High’ measured with the SE-VAS. Ratings of cannabis ‘Strength,’ ‘Liking,’ and ‘High,’ were significantly higher after active cannabis administration relative to placebo (Strength, F [1, 17] = 83.6, p ≤ 0.0001; Liking, F [1, 17] = 53.6, p ≤ 0.0001; High, F [1, 17] = 51.1, p ≤ 0.0001). Oxycodone alone did not increase these ratings. While the combination of 2.5 and 5.0 mg oxycodone and active cannabis increased these ratings relative to placebo (2.5 mg oxycodone in combination with active cannabis, Strength, F [1, 17] = 82.3, p ≤ 0.0001; Liking, F [1, 17] = 51.7, p ≤ 0.0001; High, F [1, 17] = 64.4, p ≤ 0.0001, 5.0 mg oxycodone in combination with active cannabis, Strength, F [1, 17] = 73.7, p ≤ 0.0001; Liking, F [1, 17] = 59.4, p ≤ 0.0001; High, F [1, 17] = 51.9, p ≤ 0.0001), ratings were not higher than those engendered by active cannabis alone. The same effects were observed for other positive subjective effects including ratings of ‘Good’ and ‘Take Again’ (active cannabis alone, Good, F [1, 17] = 57.4, p ≤ 0.0001; Take Again, F [1, 17] = 53.7, p ≤ 0.0001; 2.5 mg oxycodone in combination with active cannabis, Good, F [1, 17] = 52.4 p ≤ 0.0001; Take Again, F [1, 17] = 51.7, p ≤ 0.0001; 5.0 mg oxycodone in combination with active cannabis, Good, F [1, 17] = 67.2, p ≤ 0.0001; Take Again, F [1, 17] = 62.2, p ≤ 0.0001) However, 5.0 mg oxycodone increased ratings of ‘Take Again’ when administered with inactive cannabis relative to placebo (F [1, 17] = 4.8, p ≤ 0.05).
Subjective ratings of representative abuse-related subjective effects (‘Strength,’ ‘Liking’) as measured by the Cannabis Rating Form and intoxication (‘High’) as a function of time, cannabis strength, and oxycodone dose. Data are presented as mean ratings +/- SEM. Significant differences from placebo are indicated by ***p ≤ 0.0001
Subjective drug effects related to oxycodone as measure by the Capsule RF are shown in Table 4 . Neither active cannabis nor either oxycodone dose alone affected ratings of capsule ‘Strength,’ ‘Good (Drug Quality),’ ‘Liking,’ or ‘Take Again’ compared to placebo. However, the combination of 2.5 mg oxycodone and active cannabis increased these ratings relative to placebo (Strength, F [1, 17] = 4.1, p ≤ 0.05; Good, F [1, 17] = 12.9, p ≤ 0.001; Liking, F [1, 17] = 20.7, p ≤ 0.0001; Take Again F [1, 17] = 20.4, p ≤ 0.001). The combination also increased ratings of ‘Strength,’ ‘Good,’ Liking,’ and ‘Take Again’ relative to cannabis alone (Strength, F [1, 17] = 10.5, p ≤ 0.01; Good, F [1, 17] = 11.8, p ≤ 0.01; Liking, F [1, 17] = 12.2, p ≤ 0.01; Take Again F [1, 17] = 12.2, p ≤ 0.01). The combination of 5.0 mg oxycodone and active cannabis increased ratings of ‘Good’ and ‘Take Again’ relative to placebo (Good, F [1, 17] = 4.4, p ≤ 0.05; Take Again, F [1, 17] = 5.7, p ≤ 0.05).
Abuse-liability ratings of oxycodone
|Drug condition||Oxycodone||0.0 mg||0.0 mg||2.5 mg||2.5 mg||5.0 mg||5.0 mg|
|Subjective effect||Strength||10.1 ± 1.5||16.5 ± 1.9||12.6 ± 1.8||27.2 ± 2.4 **, #||16.18 ± 1.9||20.5 ± 2.1|
|Good drug||10.8 ± 1.6||11.7 ± 1.7||11.1 ± 1.8||31.1 ± 2.9 ***, ##||11.7 ± 1.7||22.6 ± 2.5 *|
|Liking||11.1 ± 1.7||16.7 ± 1.9||17.9 ± 2.0||39.0 ± 2.7 ***, #||18.4 ± 2.1||20.6 ± 2.3|
|Take again||6.9 ± 1.3||12.1 ± 1.7||12.9 ± 2.0||39.3 ± 2.8 ***, ##||15.9 ± 2.1||18.7 ± 2.3 *|
Mean subjective ratings ± standard error of the mean (SEM) for the Capsule Rating Form under placebo conditions (inactive cannabis + 0 mg oxycodone), and oxycodone (2.5 and 5.0 mg) and active cannabis administered alone or together. Significant differences from placebo are indicated by **, p ≤ 0.01, and ***, p ≤ 0.001; significant differences from active cannabis alone are indicated with #, p ≤ 0.05, ##, p ≤ 0.01, and ###, p ≤ 0.001.
Figure 3 depicts the number of cannabis puffs self-administered and money spent during each session as a function of cannabis strength and oxycodone dose. Active cannabis was self-administered significantly more than inactive cannabis (F [1, 17] = 7.5, p ≤ 0.01). The combination of active cannabis and 2.5 or 5.0 mg oxycodone was also self-administered more than placebo (2.5 mg oxycodone in combination with active cannabis, F [1, 17] = 20.3, p ≤ 0.0001; 5.0 mg oxycodone in combination with active cannabis, F [1, 17] = 20.3, p ≤ 0.0001); however, no significant differences were observed between the combination of active cannabis and oxycodone compared to active cannabis alone.
Puffs of cannabis self-administered and money ($) spent as a function of cannabis strength (inactive cannabis, left side; active cannabis, right side) and oxycodone dose (white bars = placebo oxycodone, grey bars = 2.5 mg oxycodone, black bars = 5.0 mg oxycodone). Each puff cost $1. Significant differences from the placebo oxycodone + inactive cannabis condition are indicated by **p ≤ 0.01 and ***p ≤ 0.0001
Figure 4 portrays the effects of cannabis and oxycodone on miosis and heart rate (Fig. 4 ). Both doses of oxycodone administered alone decreased pupil diameter relative to the placebo (2.5 mg oxycodone, F [1, 17] = 7.4, p ≤ 0.01; 5.0 mg oxycodone, F [1, 17] = 8.3, p ≤ 0.01) and compared to active cannabis administered alone (2.5 mg oxycodone, F [1, 17] = 7.5, p ≤ 0.01; 5.0 mg oxycodone, F [1, 17] = 17.1, p ≤ 0.0001). Under active cannabis, 5.0 mg oxycodone significantly decreased pupil diameter relative to placebo (F [1, 17] = 9.6, p ≤ 0.01).
Pupillary (top panel; diameter measured in cm) and cardiovascular (bottom panel; beats per minute) effects as a function of cannabis strength (inactive cannabis, left side; active cannabis, right side) and oxycodone dose (white bars = placebo oxycodone, grey bars = 2.5 mg oxycodone, black bars = 5.0 mg oxycodone). Values represent means across post-smoking time points. Significant differences from the placebo oxycodone + inactive cannabis condition are indicated by *p ≤ 0.05 and **p ≤ 0.01; significant differences from active cannabis alone are indicated with ## p ≤ 0.01
Active cannabis increased heart rate compared to the placebo (F [1, 17] = 7.7, p ≤ 0.05), an effect that was retained when co-administered with 2.5 and 5.0 mg oxycodone (2.5 mg oxycodone in combination with active cannabis, F [1, 17] = 8.6, p ≤ 0.05; 5.0 mg oxycodone in combination with active cannabis, F [1, 17] = 7.4, p ≤ 0.05). Compared to active cannabis alone, the combination of active cannabis and oxycodone did not significantly affect heart rate.
Preclinical studies and population findings provide a strong signal for the potential opioid-sparing effects of cannabinoids . This study sought to determine how active cannabis affected the analgesic dose of a frequently prescribed opioid analgesic, oxycodone, while also assessing the impact of the opioid-cannabis combination on another clinically relevant endpoint, abuse liability. Both active cannabis and a low dose of oxycodone (2.5 mg) were sub-therapeutic, failing to elicit analgesia on their own; however, when administered together, pain responses as measured by the CPT were significantly reduced, pointing to the opioid-sparing effects of cannabis. Oxycodone did not significantly increase cannabis self-administration. However, the combination of 2.5 mg oxycodone and active cannabis produced modest increases in positive subjective ratings related to oxycodone. These are important data to consider in light of findings from observational studies that prescription opioid use is associated with greater likelihood of CUD , and that certain features of problematic prescription opioid use (i.e., high doses, non-adherence with medication dosing regimens) were greatest among chronic pain patients who also used cannabis . No consistent changes in oxycodone-induced or cannabis-induced physiological effects were observed when the two drugs were co-administered. Overall, these findings demonstrate opioid-sparing effects of cannabis for analgesia that is accompanied by increases in some measures of abuse liability.
The current findings correspond to preclinical literature demonstrating the additive and synergistic effects of opioids and cannabinoids on antinociception . These results are also similar to previous human laboratory studies and clinical trials demonstrating that the addition of a THC-based cannabinoid (i.e., dronabinol, THC:CBD oral preparation, or vaporized active cannabis) enhances the analgesic effects of an opioid [18–20, 37–39]. This study extends those findings in a number of important areas in that it (1) assessed the effects of smoked cannabis on opioid analgesia and used a placebo comparison, (2) determined cannabis’s effects on multiple doses of oxycodone, and (3) assessed the impact of the combination on markers of abuse liability. Previous controlled laboratory and clinical studies have not been explicitly designed to measure whether THC-based therapies decrease the effective analgesic dose of an opioid, with the exception of one study that assessed the impact of dronabinol and a single, sub-therapeutic dose of morphine on responses to experimental thermal pain in healthy volunteers . They found that ineffective analgesic doses of dronabinol and morphine produced an affective analgesic response (i.e., reduced the negative valence of the nociceptive stimulus) when administered together. However, the combination did not produce sensory analgesia, a different dimension of pain measured by ratings of sensation intensity. The mixed results may have been due to the timing of the experimental pain test. Analgesia was assessed at a single time-point, 105 min after dronabinol (5 mg) administration and 15 min after intravenous morphine (1.4 mg/70 kg) administration. With peak analgesia of dronabinol previously reported to occur 180 min after administration , it is possible that peak effects of the dronabinol/morphine combination weren’t captured in that study. Another controlled laboratory study that found potentiation of opioid analgesia with a cannabinoid for one endpoint, failed to find an effect for others; 20 mg dronabinol and 30 mg morphine had an additive analgesic effect in an electrical stimulation pain test, but did not elicit an additive effect in thermal, pressure, or cold experimental pain tests .
In the present study pain threshold and tolerance were affected by the combination of oxycodone and cannabis, while pain ratings (MPQ and PIB) assessed after termination of the painful stimulus were not. These discrepant findings point to potential limitations related to the quality of the pain relief associated with opioid-cannabis combinations. Findings from controlled clinical trials with chronic pain populations administered a THC-based cannabinoid as an adjunct to currently prescribed opioid analgesics have also varied. Dronabinol (10 and 20 mg) provided additional analgesia relative to placebo in patients taking opioids for chronic non-cancer pain . In a clinical population with intractable cancer-related pain, THC:CBD oromucosal spray increased analgesia as measured by mean pain severity rating score (NRS), and THC oromucosal spray significantly decreased pain as measured by the Brief Pain Inventory–Short Form (BPI-SF) compared to placebo . A later study in chronic cancer-related pain patients treated with opioids demonstrated the dose-dependent nature of a THC:CBD oromucosal preparation on pain and clinical outcomes; improvement in pain endpoints were observed in the low and medium dose groups, but not in the high-dose group . The lack of consistent additivity or synergy across and within laboratory and clinical studies highlights the importance of dose (both opioid and cannabinoid), route of administration (oral, oromucosal, intrapulmonary), time-course, endpoint, and modality of experimental pain for laboratory studies.
Abuse-related and reinforcing effects of active cannabis were not significantly altered with the administration of oxycodone. However, subjective ratings related to oxycodone abuse liability showed small, but reliable, increases after active cannabis administration warrants consideration. Future studies should assess the impact of cannabis administration on oxycodone’s reinforcing effects, the primary public health concern related to abuse liability of opioid-cannabinoid combinations. Additionally, employing a more sensitive cannabis self-administration procedure may help to detect potentially subtle changes in reinforcement as a function of opioid co-administration. A pharmacotherapeutic strategy that capitalizes on THC’s opioid sparing effects while also minimizing its positive subjective effects should be prioritized. For example, to decrease the intoxication observed with active cannabis while maintaining opioid-sparing effects, the impact of oral THC on low-dose oxycodone analgesia should be assessed; oral THC produces analgesic effects that are longer lasting than smoked cannabis while eliciting lower ratings of intoxication and positive subjective effects . Although oral THC administered with a single dose of morphine failed to elicit synergistic sensory analgesia in experimental pain , this may have been due to the time when the drug combination was tested as discussed above. Another possibility is that opioid-sparing effects in volunteers may be most prominent with higher efficacy opioid agonists, like oxycodone, relative to lower efficacy opioids .
The current findings provide evidence of the opioid-sparing effects of smoked cannabis; however, these results should be interpreted within the context of experimental and therapeutic limitations. Analgesia was assessed using an experimental pain model in a group of young, healthy, cannabis-experienced participants. Enrolling participants without pain and assessing analgesia using an experimental test that has predictive validity for analgesics (i.e., [40–42]) affords a degree of control that cannot be achieved with a patient population. Baseline pain sensitivity did not differ across sessions, and the influence of concomitant medications on outcomes was avoided, two outstanding factors that would have impacted experimental control had a pain population been utilized. Further, that the participants were current cannabis smokers assured that cannabis would be well-tolerated. These factors limit the generalizability of the current findings supporting opioid-sparing effects of cannabis and cannabinoids to patient populations, many of which are not current cannabis users. Understanding the safety and tolerability of cannabis or cannabinoids in non-cannabis as well as cannabis-exposed patients is an important consideration given that tolerability of cannabinoid products is contingent upon experience [20, 50, 51]. Another significant consideration is that the current study used smoked cannabis because this is the most common method of medical cannabis use . However, the therapeutic utility of smoked cannabis may be limited by respiratory risks including chronic bronchitis , the presence of combustion by-products [54, 55], a lack of regulation regarding medical cannabis strength (i.e., THC concentration) and other cannabinoid content , and subjective effects related to abuse liability which are not as apparent with other methods of administration (i.e., ). Adverse respiratory effects and combustion by-products would be avoided by vaporizing cannabis [61, 63, 64], while the superior bioavailability of THC afforded by the intrapulmonary route relative to oral administration would be preserved . However, other risks associated with smoked administration including intoxication and lack of dose regulation would still be a concern [57, 58] for intrapulmonary cannabis. Other routes of THC administration should be explored that would retain analgesic and opioid-sparing effects, while reducing unwanted subjective effects and other risks. An additional limitation to the study design was that cannabis effects on opioid respiratory depression, a significant risk associated with their use , was not assessed.
Cannabinoids may provide a therapeutic strategy to enhance the analgesic effects of opioids while mitigating their serious adverse effects. Smoked cannabis combined with an ineffective analgesic dose of oxycodone produced analgesia comparable to an effective opioid analgesic dose without significantly increasing cannabis’s abuse liability. Yet the combination did increase opioid-related positive subjective ratings. These findings warrant future well-controlled, double-blind, placebo-controlled studies designed to assess the opioid-sparing effects of cannabinoids across therapeutically viable routes of administration, employing multiple nociceptive stimuli, patient populations, and importantly, addressing the impact of the drug combination on other critical endpoints including opioid self-administration, tolerance, and dependence. Such studies will determine the generalizability of these findings and the clinical benefit of combined cannabinoid-opioid therapy to treat chronic pain.
The authors acknowledge and appreciate the exceptional assistance of Olivia Derella and Bennett Wechsler in data collection and Dr. Richard Foltin for his assistance with regulatory and computer programming aspects of the study.
This research was supported by US National Institute on Drug Abuse Grant DA19239, DA009236, and DA027755. ZDC, GB, DR, RB, SDC, and MH have no competing interests in relation to the work described. ZDC and MH have received research funds and partial salary support from Insys Therapuetics. Over the past 3 years, SDC received compensation (in the form of partial salary support) from studies supported by Braeburn Pharmaceuticals, Cerecor, Indivior, MediciNova, and Reckitt-Benckiser Pharmaceuticals. In addition, SDC has served as a consultant to the following companies over the past 3 years: Advances in Pain Management, AstraZeneca, Clinilabs, Collegium Pharmaceutical, Daiichi Sankyo, Depomed, Egalet, Endo, Guidepoint Global, Heptares Therapeutics Limited, Inspirion Delivery Sciences, IntelliPharmaCeutics, Janssen, KemPharm, Mallinckrodt, Neuromed, Opiant, Orexo, Pfizer, and Shire.