Accurate Education – Marijuana (Cannabis): Pharmacokinetics

Marijuana (Cannabis)

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.

 

Marijuana (Cannabis): Pharmacokinetics

Pharmacokinetics entails 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.

 

See:

Marijuana – Legislative Update

Marijuana – Medical Use Overview

Marijuana – Prescription Cannabinoids

Marijuana – Cannabidiol (CBD)

Marijuana – Edibles (coming soon)

Marijuana – Inhaled (Smoked and Vaporized)

Marijuana – Cannabinoids and Opioids (coming soon)

Marijuana – Pharmacokinetics

Marijuana – The Endocannabinoid System (coming soon)

    

See also:

Marijuana – Discontinuing Use

Marijuana Addiction – Cannabis Use Disorder (CUD)

 

 

 

 

Key to Links:

Grey text – handout

Red text – another page on this website

Blue text – Journal publication

cannabis-caduceus

Marijuana (Cannabis) – Pharmacokinetics

Introduction

Medical marijuana (Cannabis), while largely available for less than a decade, has experienced an explosive development of different products in different forms, with different potencies and constituent combinations. Medical cannabis use is directed at a wide range of clinical applications associated with an equally wide range of therapeutic benefits and potentials for adverse effects and toxicity. Thus, it is important to understand cannabinoid pharmacokinetics and the disposition of cannabinoids into biological fluids and tissues. Understanding the pharmacokinetics of cannabinoids is essential to understanding the onset, magnitude, and duration of its pharmacologic effects in order to maximize benefit and minimize side effects.

 

Cannabinoid pharmacokinetics includes how cannabinoids are absorbed into the body with different routes of administration and from different drug formulations, how cannabinoids are distributed throughout the body, metabolized by the liver and other tissues, and eliminated in feces, urine and sweat. Pharmacokinetic processes can change over time and under different conditions, and may be affected by the frequency and magnitude of cannabinoid exposure.

 

Bioavailability

The “bioavailability” of a medication is the measure of how effectively administration of that medicine achieves blood levels. As a standard, the bioavailability of a medication given directly intravenously is generally 100%. Other forms of administration, smoking, eating, application to skin, will be associated with less bioavailability. Bioavailability is generally described in terms of maximum time in the blood (Cmax) and maximum overall absorption into the blood (AUC).

 

The Major Constituents

The clinical benefits from marijuana are derived from the many constituents found  in the plant, including more than 142 or more potentially pharmacologically active cannabinoids. In addition to the  cannabinoids, there are eighteen different classes of chemicals, including nitrogenous compounds, amino acids, hydrocarbons, carbohydrates, terpenes, and fatty acids, that contribute to the known pharmacological and toxicological properties of cannabis.

 

The two best understood and most common of these cannabinoids are THC (tetrahydrocannabinol) and CBD (cannabadiol). THC has mind-altering effects (euphoria), analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties, while CBD is non-euphoric but has anti-anxiety, anti-depressant, anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD is a versatile anti-inflammatory analgesic through numerous distinct mechanisms.

 

Cannabinol is the nonenzymatic oxidative breakdown product of tetrahydrocannabinol (THC), found in aged Cannabis, and is about 25% of the potency of THC. It likely plays a role in the pharmacologic effects of plant based cannabis products but it is not available commercially as an isolated compound.

 

Botanical cannabis is highly variable in its chemical composition. In actuality, CBD is not the natural form in plants, it is cannabidiolic acid (CBDA) which, when exposed to light, heat, or aging is decarboxylated into CBD. In the same manner, Delta 9-tetrahydrocannabinol (THC) is formed from the corresponding THCA.

 

THC and CBD concentrations depend on the species, strain, cultivation, and storage of the plant. The average concentrations in more than 30,000 cannabis preparations confiscated in the U.S. between 1980 and 1997 were 3.1% THC and only 0.3% CBD. Various strains and marijuana-based products are now available that contain substantially higher contents of these constituents, especially THC.

 

The amounts and ratios of THC and CBD play a large role in the clinical effects of marijuana. A synergy exists between these two components in which their combination produces effects that are uniquely determined by the amount and ratios of these two constituents. In addition to cannabinoids there are other pharmacologically active chemical constituents believed to impact clinic effects of marijuana.

 

Distribution in the Body

THC and its metabolites are predominantly found in the plasma fraction of blood, where 95−99% are bound to lipoproteins. Because only about 10% of these cannabinoids are found in erythrocytes (red blood cells), whole-blood cannabinoid concentrations are approximately one-half the concentrations found in plasma specimens.

 

THC plasma concentrations decrease rapidly due to rapid distribution into tissues and metabolism in the liver. THC is highly lipophilic and is initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver with what is considered a large volume of distribution of THC alog with slow elimination from body stores. Studies of the distribution of THC into brain are especially important for understanding the relationships between THC dose and behavioral effects. After single intra-muscular injection of THC, maximal levels are reached in brain after 2−4 hours while after smoking THC, maximal brain levels are reached even sooner. Importantly, THC concentrates in fat cells, especially with prolonged drug exposure. The ratio of fat to brain THC concentration is approximately 21 : 1 after 7 days of daily exposure, and 64 : 1 after 27 days. These fat stores are responsible for the prolonged finding of THC metabolite THC-COOH in the urine for up to 3 months after chronic use of THC.

 

Metabolism – THC & CBD

THC Metabolism – Liver

Most of the THC that enters the body is metabolized in the liver into over 100 metabolites, with 11-OH- THC and THC-COOH being the major metabolites. The primary metabolite, 11-OH-THC, is psychoactive, contributing to the effects of THC on thought processing, mood and euphoria. 11-OH-THC diffuses into the brain more readily than THC does and its effects are perceived more rapidly than with THC. 11-OH-THC is subsequently metabolized into THC-COOH, which is inactive, and ultimately excreted into feces (65%) and urine (20%). THC is significantly metabolized with just one pass through the liver, the “first pass effect,” which is why formulations that are ingested orally and must pass through the liver before entering the blood have less bioavailability than other formulations.

 

Liver enzyme CYP 450 2C9 is thought to be primarily responsible for the transformation of 11-OH-THC into THC-COOH, whereas CYP 450 3A breaks down the other minor metabolites. After smoking cannabis, THC-COOH concentrations gradually increase, and are greater than THC concentrations within 30−45 min.  This compares with ingestion of a single oral dose of Marinol® (10 mg THC), when plasma THC- COOH concentrations are higher than those of THC and 11-OH-THC  1 hour or more after dosing. Unlike after smoking, THC and 11-OH-THC concentrations are similar after oral THC administration. Much lower plasma 11-OH- THC concentrations (about 10% of THC concentrations) are found after cannabis smoking than after oral administration.

 

THC Metabolism – Outside the Liver

Other tissues, including brain, intestine, and lung, also metabolize THC. THC is metabolized in the brain with 11-OH-THC being the primary metabolite. Levels of 11-OH-THC  can persist in the brain contributing to prolonged effects after administration of THC.

 

CBD Metabolism

CBD metabolism is similar to that of THC, with primary oxidation in the liver to the inactive metabolite, THC-COOH. Like THC, CBD has a significant first-pass effect in the liver although, unlike THC, a large proportion of the dose is excreted unchanged in the feces. It has been reported that CBD  inhibits THC metabolism but it is believed that the pharmacokinetics of THC are not meaningfully affected by CBD, except for a slight slowing of the metabolism of 11-OH- THC to THC-COOH. Co-administration of CBD does not significantly affect the total clearance, volume of distribution, or terminal elimination half-lives of THC or its metabolites. 

 

Elimination of THC and Metabolites

The slow release of THC from fat storage compartments and significant enterohepatic circulation contribute to a long terminal half-life of THC in plasma, and even longer in urine. Up to 10−15% of a THC dose can be enterohepatically circulated (excreted into the feces, then reabsorbed into the blood again). Urinary THC-COOH concentrations drop rapidly until reaching about 20−50 ng/ml, where they may intermittently slightly increase or decrease depending on inconsistent release of stored cannabinoids in brain and fat tissues until the stores are finally completely depleted.

 

It has been suggested that measuring THC and/or 11-OH-THC in the urine might provide a reliable marker of recent cannabis use, but it has been found that 11-OH-THC may be excreted in the urine of chronic cannabis users for a long period of time, beyond the period of pharmacologic effects and performance impairment. Additional research is necessary to determine the validity of estimating time of cannabis use from THC and 11-OH- THC concentrations in urine.

 

Interpretation of Cannabinoid Concentrations in Biological Fluids

Blood and Serum Levels

Compared to many other drugs, analysis of cannabinoids is difficult because THC and 11-OH-THC are highly lipophilic, and are present in very low concentrations in body fluids. Complex specimen matrices, i.e., blood, sweat, or hair, may require multi-steps to separate out the cannabinoids. THC and THC-COOH are predominantly found in the plasma fraction of blood and 95−99% are bound to lipoproteins. Only about 10% of either compound is found in blood cells so whole-blood cannabinoid concentrations are approximately one-half the concentrations found in plasma.

 

Interpreting drug effect, whether therapeutic effect or physical or mental impairment is particularly difficult due to a lack of correlation between drug effect and biologic levels as well as there being a wide variability from person to person, even with the same person at different times.

 

Prediction models have been proposed for estimation of cannabis exposure but there is controversy in the interpretation of cannabinoid results from blood analysis. THC effects appear rapidly after initiation of smoking. A dose-response relationship has been established for smoked THC and THC plasma concentrations and it is well-established that plasma THC concentrations begin to decline prior to the time of its peak effects.

 

Individual drug concentrations and ratios of cannabinoid metabolite to parent drug concentration have been suggested as potentially useful indicators of recent use. 45 min after smoking cannabis, the ratio (THC-COOH)/(THC) in the plasma has reported to be >1. It has been reported also that peak effects occur when THC and THC-COOH concentrations reach equivalency, within 30−45 min after initiation of smoking. Recent exposure (6−8 hours) and possible impairment have been linked to plasma THC concentrations in excess of 2−3 ng/ml.

 

However, interpretation is  complicated by residual THC and THC-COOH concentrations found in blood of frequent cannabis users who may have residual plasma THC concentrations of 2 ng/ml some 12 h after smoking cannabis and significantly higher residual concentrations of THC-COOH may be found. These findings also likely apply to chronic use of all forms of cannabinoids.

 

Furthermore, studies of drug effect and level of impairment do not correlate well with plasma levels due to differences in acute vs chronic exposure and other individual variables.

 

Urine Levels

Detection of cannabinoids in urine is indicative of prior cannabis exposure, but the long excretion half-life of THC-COOH in the body, especially in chronic cannabis users, makes it difficult to predict the timing of past drug use. In extreme cases, an individual’s urine may be positive for THC-COOH at concentrations >20 ng/ml up to 2 months or longer after last exposure.  As such, a positive urine test for cannabinoids indicates only that THC exposure has occurred. The result does not provide information on the route of administration, the amount of drug exposure, when drug exposure occurred, or the degree of impairment.

 

Urinary THC-COOH concentrations drop rapidly until reaching about 20−50 ng/ml, where they may intermittently slightly increase or decrease depending on inconsistent release of stored cannabinoids in brain and fat tissues until the stores are finally completely depleted.

 

Oral-Fluid Testing

Oral fluid can be used for monitoring cannabinoid exposure and is being evaluated for the assessment of driving under the influence and for workplace drug testing. Adequate sensitivity is best achieved by testing for THC, rather than of 11-OH-THC or THC-COOH. The oral mucosa is exposed to high concentrations of THC during smoking which serves as the source of THC found in oral fluid. THC may be detected at low concentrations by radioimmunoassay for up to 24 h after use and longer by GC/MS analysis. In general, only minor amounts of drug and metabolites diffuse from the plasma into oral fluid and no measurable 11-OH-THC or THC-COOH are found in oral fluid for up to 7 days following cannabis smoking. Even following intravenous THC, no THC can be found in oral fluid.

 

Detection times of THC in oral fluid are shorter than in urine, and more indicative of recent cannabis use. Oral-fluid THC concentrations temporally correlate with plasma cannabinoid concentrations and behavioral and physiological effects, but wide intra- and inter-individual variation precludes the use of oral-fluid concentrations as indicators of drug impairment. THC may be detected at low concentrations by radioimmunoassay for up to 24 h after use and somewhat longer by GC/MS analysis.

 

THC Pharmacokinetics

Absorption – THC

Inhalation (Smoking & Vaping) of THC

Smoking provides a very rapid and efficient means of delivery of cannabanoids from the lungs to the brain which can be intensely pleasurable and strongly reinforcing due to almost immediate drug exposure to the brain and central nervous system (CNS). Bioavailability with smoking ranges widely from 2−56%, due to intra- and inter-subject variability in smoking dynamics, including the number, duration, and spacing of puffs, hold time, and inhalation volume.

 

Peak THC plasma concentrations are reached about 9 minutes after smoking, dropping to about 60% and 20% of peak levels in 15 and 3o minutes, respectively. Depending on the potency of the inhaled product, mean plasma peak THC concentrations have been measured at 94.3, 107.4, and 155.1 ng/ml after smoking single cigarettes of 1.32, 1.97, or 2.54% THC potencies, respectively. These potencies are low and higher THC concentrations are found with higher potency cigarettes.

 

The clinical impact of THC is dose-dependent and may be related to plasma levels, but there is a great range of variability from one person to the next depending on the individual’s experience and frequency of use. Furthermore, the clinical effects of THC continue even after plasma levels drop to very low levels. Efforts to establish plasma levels of THC and/or its metabolites that correlate with physical and mental impairment how they have been established with alcohol have failed to be determined with marijuana.

 

Oral Ingestion of THC

There are fewer studies on the disposition of THC and its metabolites after oral use of cannabis/cannabinoids as compared to the smoked route. THC is readily absorbed when ingested but absorption is slower compared with smoking, with lower and more-delayed peak THC concentrations. Oral THC bioavailability is reported to be 10−20% due to variable absorption, degradation of drug in the stomach, and significant first-pass metabolism to active 11-OH-THC and inactive metabolites in the liver. In one study, patients dosed with either 15 mg (women) or 20 mg (men) of THC dissolved in sesame oil and contained in gelatin capsules reached peak THC plasma concentrations in 4−6 hours. In another study peak THC concentrations ranged from 4.4 to 11 ng/ml, occurring 1−5 hours following ingestion of 20 mg of THC in a chocolate cookie; the oral bioavailability was estimated to be 6%.

 

THC Metabolites (11-OH-THC & THC-COOH) with Ingestion

While the THC and other cannabinoids and pharmacologically active cannabis constituents are absorbed directly into the blood and to the brain after smoking, when ingesting cannabis or cannabinoids orally they undergo significant metabolism before reaching the blood and brain. This metabolism begins in the stomach and gut and continues in the liver before getting to the blood.

 

THC is primarily metabolized to 11-OH-THC, another psychoactive compound that contributes significantly to the psychoactive effects associated with cannabis use. Whether 11-OH-THC contributes to other therapeutic benefits is uncertain but it is known that 11-OH-THC crosses the blood-brain barrier even more quickly than THC. 11-OH-THC is then further metabolized into THC-COOH, a pharmacologically inactive compound which is then eliminated in the urine and feces. Thus, orally  ingesting cannabis or THC results in higher blood levels of the 11-OH-THC metabolite compared with smoking.

 

THC concentrations decrease in brain tissue slower than in blood but the slowest THC elimination is seen in fat tissue, where THC may still be present for months after chronic use. 11-OH-THC is only found at high concentrations in the liver.

 

After taking cannabis orally, the average levels of 11-OH- THC vary from 25% of THC to more than 300% of THC levels, depending on the study. This compares with blood levels of 11-OH-THC in the blood after smoking cannabis that are only about 5% of THC levels, which is probably not enough to feel any effects from the 11-OH-THC.

 

The pharmacokinetics of an oral synthetic THC, (Marinol®), which is approved and available in the U.S., have been evaluated. In a study of the plasma concentrations of THC and its metabolites 11-OH-THC (active) and THC-COOH (inactive) were measured after ingestion of a single Marinol® capsule (10 mg of THC). Mean peak plasma concentrations of 3.8 ng/ml of THC (range 1.1 −12.7 ng/ml), 3.4 ng/ml of 11-OH-THC (range 1.2−5.6 ng/ml), and 26 ng/ml of THC-COOH (range 14−46 ng/ml) were found 1−2 hours after ingestion. Thus similar THC and 11-OH-THC concentrations were noted with consistently higher THC-COOH concentrations. Also, two THC peaks were frequently observed due to enterohepatic circulation.

 

After oral THC dosing, THC-COOH concentrations are generally higher than those of THC almost immediately after dosing, in contrast to what is found after smoking. Concentrations of 11-OH-THC also are higher than those of THC, with an extended detection window. It is suggested that ratio of (11-OH-THC)/(THC) >1 – 1.5 within 2 hours after consumption is a strong indications for oral intake of THC.

 

Due to low bioavailability of oral THC formulations, alternative routes of drug administration, including oromucosal or sublingual dosing and rectal administration, have been developed to improve the amount of delivered cannabinoids.

 

When THC is ingested orally as compared to smoking, onset of clinical effects are delayed, peak concentrations are lower, and duration of clinical effects generally are longer with a delayed return to baseline.

 

THC-containing bakery items and foods, i.e., hemp oil, beer, and other products, are commercially available for oral consumption in other states. Incidentally, hemp oil produced from cannabis seed, is an excellent source of essential amino acids and ω-linoleic and linolenic fatty acids (omega-3). The THC content depends upon the cannabis-seed-cleaning and oil-filtration processes but hemp oil without THC is available in Louisiana.

 

Oro-mucosal & Sublingual THC

Due to significant loss of bioavailability associated with oral ingestion  and the breakdown of cannabis/cannabinoids by the stomach and liver, formulations designed to be absorbed from buccal (cheek) or sublingual (under the tongue) applications offer beneficial alternatives. While specific products of this nature to be made available in Louisiana have not yet been identified, Sativex® a prescription cannabis-based drug is approved in Canada for the treatment of neuropathic pain associated with multiple sclerosis, and in three European countries for a number of other indications.

 

Sativex® contains two standardized cannabis extract preparations, Tetranabinex®, which is high in THC, and Nabidiolex®, which is high in CBD. Sativex® contains equal proportions of Tetranabinex® and Nabidiolex®, and, hence, almost equal amounts of THC and CBD. THC and CBD represent approximately 70% of the product, with 5% of other cannabinoids, the remainder being terpenoids, flavonoids, sterols, alkanes, and other chemicals.

 

Rectal THC

The bioavailability of the rectal route is approximately twice that of the oral route due to higher absorption and lower first-pass metabolism by the liver. Rectal administration of 2.5−5 mg of THC (Marinol®) produces maximum plasma concentrations of 1.1−4.1 ng/ml within 2−8 hours. This compares with oral administration of 10−15 mg doses resulting in THC concentrations that peak within 1−8 hours and range between 2.1 to 16.9 ng/ml.

 

Transcutaneous Cannabanoids: THC vs CBD

Topical administration is another route of cannabinoid dosing that avoids first-pass metabolism and improves THC bioavailability. Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion process.  Permeability of CBD has been found to be 10-fold higher than for THC. Additional research is planned with combinations of cannabinoids to increase drug absorption and hopefully reduce negative side effects seen with inhalation and oral dosing.

 

Metabolic Interactions with Other Drugs

The major cannabinoids, THC and CBD are both metabolized in the liver by the CYP450 enzymes 2C9 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 fully known. 

 

Genetic Polymorphisms of CYP2C9

One study published in 2009 evaluated the impact of the CYP2C9 polymorphisms on the pharmacokinetics of orally administered 9-tetrahydrocannabinol (THC). In patients with CYP2C9*3/*3 homozygotes (poor metabolizers), the median area under the curve of THC was threefold higher and that of the metabolite 11-nor-9-carboxy-9-tetrahydrocannabinol was 70% lower. CYP2C9*3 carriers also showed a trend toward increased sedation following administration of THC. Therefore, the CYP2C9*3 variant may influence both the therapeutic and adverse effects of THC.

 

The results of this study suggest that some individuals, likely <10% of the population, may be more sensitive to THC based on their CYP2C9 genetics but also that patients exposed to strong CYP2C9 inhibitors may also experience heightened impact with THC exposure.

 

Metabolic Effects of Medications on Cannabinoids

CYP3A4 Inhibitors Effect on Cannabinoids

Treatment with CYP3A4 inhibitors such as ketoconazole can produce an increase in Cmax and AUC of THC (1.2- and 1.8- fold, respectively). The increase in Cmax and AUC of the primary active metabolite of THC, 11-OH-THC,  can be 3 and 3.6-fold, respectively, and of that of CBD (2- and 2-fold, respectively). Therefore, if concomitant drug treatment with CYP3A4 inhibitors (e.g. itraconazole, ritonavir, clarithromycin) is started or stopped during treatment with cannabinoids, a dose adjustment may be required.

 

CYP3A4 Inducers Effect on Cannabinoids

Treatment with CYP3A4 inducers such as rifampicin can reduce the Cmax and AUC of THC (by 40% and 20%, respectively), 11-OH-THC (by 85% and 87%, respectively), and CBD (by 50% and 60%, respectively). Therefore, concomitant treatment with strong enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s Wort) should be avoided whenever possible. Again, if concomitant drug treatment with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s Wort) are started or stopped during treatment with cannabinoids, a dose adjustment may be required within two weeks of starting or stopping the inducer.

 

Metabolic Effects of Cannabinoids on other Medications

CYP2D6

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 (Norc0, Vicodin, Zohydro, Hysingla) and other opioids including tramadol and codeine. As such, use of CBD with tramadol, codeine or hydrocodone may significantly reduce the analgesic effectiveness of these opioids. Other common medications that may be affected include antidepressants.

 

CBD is also a potent inhibitor of CYP3A enzymes, especially CYP3A5. While CYP3A4 is the dominant CYP3A isoform in the metabolism of most drugs, some drugs such as diltiazem (Cardizem), are more efficiently metabolized by CYP3A5 than by CYP3A4. Also, CYP3A5 is a major isoform of CYP3A found in extrahepatic tissues that plays an important role in the metabolism of endogenous and exogenous compounds in these tissues. Thus, the inhibition of CYP3A5 by CBD may cause interactions with other medications and may also disturb normal metabolism of endogenous compounds.

   

Since cannabinoids are readily distributed in various tissues due to a high lipophilicity, tissue concentrations of CBD may be even higher than the blood concentration, suggesting that the inhibition of human CYP3A by CBD might be caused during and/or after marijuana smoking.

 

This section remains incomplete and is still being edited for accuracy and completeness.

   

Resources:

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

 

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

 

References:

Politics of Medical Marijuana – Louisiana

  1. louisiana-medical-marijuana-expansion-bill-signed-into-law-may-20-2016
  2. louisiana-2016-sb180-chaptered
  3. medical-marijuana-in-louisiana-who-will-get-access-june-2015
  4. now-in-effect-louisiana-medical-marijuana-law-shields-patients-and-caregivers-from-prosecution-aug-5-2016
  5. La house committee passes bill to allow medical marijuana prescription 4-5 2018

      

Medical Marijuana – Driving

  1. Establishing legal limits for driving under the influence of marijuana – 2014
  2. Medical Marijuana and Driving – a Review – 2014

 

Medical Marijuana – Opioids

  1. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. – PubMed – NCBI
  2. Cannabinoid–Opioid Interaction in Chronic Pain
  3. Synergistic interactions between cannabinoid and opioid analgesics. – PubMed – NCBI
  4. FDA approves CBD drug – Epidiolex – The Washington Post

Medical Marijuana – Opioid Drug Interactions

  1. The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness – 2014
  2. Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6 – 2011
  3. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol. – Role of phenolic hydroxyl groups in the resorcinol moiety – 2011
  4. Interindividual variation in the pharmacokinetics of Delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. – PubMed – NCBI

Medical Marijuana – Pharmacokinetics

  1. Human Cannabinoid Pharmacokinetics – 2007
  2. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  3. Cannabis and cannabis extracts – greater than the sum of their parts? – 2001
  4. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI
  5. Pharmacogenetics of Cannabinoids – 2018
  6. Adverse effects of medical cannabinoids – a systematic review – 2008
  7. Cannabimimetic effects modulated by cholinergic compounds. – PubMed – NCBI
  8. Antagonism of marihuana effects by indomethacin in humans. – PubMed – NCBI
  9. Pharmacokinetics and pharmacodynamics of cannabinoids. – PubMed – NCBI
  10. Clinical Pharmacodynamics of Cannabinoids – 2004
  11. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016
  12. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. – PubMed – NCBI
  13. Pharmacology of Cannabinoids
  14. The Cannabis sativa Versus Cannabis indica Debate – An Interview with Ethan Russo, MD – 2016
  15. Human Metabolites of Cannabidiol – A Review on Their Formation, Biological Activity, and Relevance in Therapy 2016

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