Accurate Education - Marijuana (Cannabis): Side Effects & Drug Interactions

Marijuana (Cannabis):

Side Effects & Drug Interactions

Side effects with the use of marijuana (cannabis)- based products are not uncommon and are reviewed below. The extent to which the constituents of cannabis interact with other drugs and herbal supplements is not fully understood at this time but is explored below. The following information is provided as an introduction but there will surely be more information to come.

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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.

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Marijuana – Side Effects & Drug Interactions

Marijuana – Side Effects

Overall, the adverse side effects of medical cannabis are within the range tolerated for other common medications. Multiple studies have demonstrated that there is no higher incidence of serious adverse events in cannabis subjects following medical cannabis use compared with control subjects, although non-serious adverse events were significantly higher in cannabinoid groups. Dizziness is the most common non-serious adverse effect reported. Other common adverse effects include:

Euphoria, altered consciousness
Acute panic or paranoid reaction (What to do if cannabis causes anxiety, panic or paranoia)
Altered motivation
Sedation
Fatigue
Impaired attention, short and long term memory, and psychomotor performance including
Tachycardia, orthostatic hypotension (drop in blood pressure associated with sitting to standing)
Dizziness and vertigo
Dry mouth
Increased appetite
Auditory and visual hallucinations
Impaired reaction times
Cognitive impairment, including the ability to learn and remember new information, has been associated with long term illicit cannabis use but has been shown to be reversible after a period of abstinence.
Long-term heavy cannabis smokers have increased risk of pulmonary symptoms such as chronic bronchitis and COPD but have no increased incidence of lung cancer

As expected, cannabis-naive patients tend to have more frequent adverse side effects compared with regular users. The effects of THC can change over time, with therapeutic effects more resistant to tolerance development than adverse side effects. Careful attention. to appropriate dosage, delivery method, and ratio of cannabinoids can reduce many of the adverse side effccts.

Cannabinoid Hyperemesis Syndrome (CHS)

Cannabinoid Hyperemesis Syndrome (CHS) is a condition characterized by cyclic vomiting and abdominal pain. It is estimated that there are 2.75 million cases in the US each year. Symptoms improve with stopping use of cannabis products and may be reduced with taking a hot shower. Fatal cases have been reported.

Cannabis for the Management of Pain – Assessment of Safety Study (COMPASS) – 2015

In this large, 2015 study evaluating 215 patients taking a standardized herbal cannabis product (12.5% tetrahydrocannabinol) for a 1-year period, adverse affects were evaluated. Among these 215 patients,the frequency of side effects assessed as certainly/very likely related to cannabis were: sleepiness (5 people, .6%), memory loss (4 people, .5%), cough (4 people, .5%), nausea (4 people, .5%), dizziness (3 people, .4%), euphoric mood (3 people,, .4%), hyperhidrosis (2 people,, .2%), and paranoia (2 people, .2%). Moreover, the results indicated that the rate of non-serious side effects among ‘‘current cannabis users’’ was lower than that among ‘‘ex-cannabis users’’ or ‘‘naive users.’’

Of note, neurocognitive function did not decline in the cannabis group. This finding differs from that found in studies of long term recreational users of cannabis; a meta-analysis of 15 studies investigating the effects of recreational cannabis use on neurocognitive performance6 suggested that long-term cannabis users performed significantly poorer on tests of memory and attention than short-term users. In that study, both groups consumed similar amounts of cannabis (median = 7 grams/week, range = .3–57 grams/week), but there was no difference in memory and attention between short-term users and non-cannabis users.

There are several limitations to this study. There was a significant drop-out rate, which may represent a source of selection bias. Losses to follow-up were estimated at 30% over an average follow-up of 12 months. Factors associated with drop- out included side effects, perceived lack of effectiveness, and/or a dislike of the study product. Also, most study participants in the cannabis group (66%) were experienced cannabis users. Due to the small number of cannabis-naive patients in the study, the safety of medical cannabis use in cannabis-naive individuals could not be addressed.

It is important to point out that the adverse effects of medical cannabis cannot be equated with the adverse effect of illicit marijuana use. The amounts and ratios of the different cannabinoid constituents vary dramatically between different marijuana plants, whereas medical marijuana is anticipated to be formulated with specific standardized doses and ratios of the different cannabinoid components. The use of illicit marijuana does not allow for any accurate prediction of dosing.

Marijuana – Interactions With Other Drugs and Herbal Preparations

Cannabinoids and Opioids

There appears to be a synergistic analgesic (pain-relieving) benefit when cannabinoids are added to opioids for treatment of 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 off opioids.

Additionally, animals 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 cannabanoids due to the very low density of cannabinoid (CB) receptors in brainstem cardiorespiratory centers. Cannabinoids are not reported to have any significant effecct on opioid metabolism, however there does appear to be a potential to do so (See below).

For more information, See Cannabinoids and Opioids

Alcohol and Benzodiazepines

The combination of cannabinoids with alcohol and benzodiazepines may increase sedation and cognitive impairment. Furthermore, a 2015 study evaluating 32 adult cannabis smokers found that drinking low- dose alcohol (with approximately 0.065% peak breath- alcohol concentration) 10 min before inhaling low-dose (2.9%) THC, or high-dose (6.7%) THC vaporized cannabis raised blood THC (and 11-hydroxy THC, the primary psychoactive metabolite of THC) levels significantly. The implications of this study suggest that there may be greater cognitive impairment with drinking and using THC products, at least initially after use, and may further impact driving safety.

It was noted in this study the alcohol did not affect THC metabolism and therefore its effecct on THC levels may be due to increased absorption of THC from the gut (especially as it was noted that the AUC for THC was unchanged). To offset this effect, it may be worth eating when drinking alcohol and using THC products to slow absorption, but more importantly separate the use of alcohol and a THC product by at least one hour or more.

NSAIDS (Non-Steroid Anti-inflammatory Drugs)

NSAIDs such as ibuprofen and naproxen, particularly indomethacin, may suppress the effects of THC.

Anticoagulants, anti-platelet drugs, herbs and supplements that reduce blood clotting

Cannabis may change how the body processes these drugs and supplements, possibly increasing the risk of bleeding.

Anticholinergic drugs (Tricyclic antidepressants (TCAs) and some muscle 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.

Protease Inhibitors (antiviral drugs)

Cannabis use (especially delta-9 THC) with use of protease inhibitors (antiviral drugs) may reduce their effectiveness.

Sedative Drugs

Cannabis-based drugs may increase the sedation association with sedative drugs

Selective Serotonin Reuptake Inhibitors (SSRIs)

Taking cannabis-based products with this SSRIs (Prozac, Paxil etc.) may increase the risk of mania.

Herbal Preparations

Sedative agents such as sleep aids (includes supplements containing GABA, melatonin, 5-HTP, skullcap, or valerian) – Use caution when taking these products and cannabis products together because of the potential for increased drowsiness.

Drug Metabolic Interactions

The major cannabanoids, 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 known.

The bioavailability of medications are generally described in terms of maximum blood level (Cmax) and maximum overall absorption into the blood (AUC).

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), the primary active metabolite of THC, 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 combined drug treatment with CYP3A4 inducers (e.g. itraconazole, ritonavir, clarithromycin) 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

CBD Inhibits 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 (Norco, Vicodin, Zohydro, Hysingla). As such, use of CBD with tramadol or codeine may significantly reduce the analgesic effectiveness of these two opioids. Hydrocodone is metabolized to a small extent (15-20%) to hydromorphone by CYP2D6. Since hydromorphone is four times more potent as an analgesic compared to hydrocodone, inhibition of CYP2D6 by cannabinoids may result in less analgesic contribution by hydromorphone when cannabinoids are added to a hydrocodone regimen. This effect has not yet been definitively established.

CBD Inhibits CYP3A4 and CYP 3A5

CBD is also a potent inhibitor of CYP3A enzymes, especially CYP3A5. While CYP34 is the dominant CYP3A isoform in the metabolism of most drugs, some drugs such as diltiazem, are more efficiently metabolized by CYP3A5 than by CYP3A4. Also, CYP3A5 is a major isoform of CYP3A found in extrahepatic tissues and 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 but 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 even after marijuana smoking.

CBD Inhibits CYP2C9

CBD has also been reported to inhibit CYP2C9. Warfarin (coumadin), an important blood thinner prescribed to reduce the risk of blood clots in the prevention of heart attacks, strokes and peripheral artery clots, may have blood levels reduced when CBD is added. This could result in an increased risk of the conditions Warfarin is being taken to prevent. Caution should be used when combining CBD with Warfarin and the prescribing physicians should be notified and consulted prior to combining.

THC Induces CYP1A2

Tizanidine (Zanaflex)

THC has been reported to induce, or increase, levels of CYP 1A2, the enzyme that metabolizes tizanidine (Zanaflex) a commonly prescribed muscle relaxer used for neck pain and spasm. Tizanidine is a medication with a narrow therapeutic margin, meaning there may be a small range of optimal levels in which a little too low is ineffective but a little more may be too strong and associated with side effects. Thus adding, or discontinuing THC may result in significant changes in the clinical effects of tizanidine and caution should be applied to avoid loss of benefit or possible side effects respectively.

Resources:

National Academy of Sciences

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

International Cannabinoid Research Society

International Cannabinoid Research Society – Home page

You Tube video marijuana education links:

Cannabis The Evil Weed (2009) part 1 of 16

MediHuanna – Medicinal Cannabis Education for Physicians (July 2018)

Lay-person Websites

These lay-person websites appear to be good resources for exploring medical marijuana. However, as is the case generally regarding medical applications of marijuana and its constitnuents, there is a huge amount of information that is not based in good science and relies on anecdotal (word-of-mouth) evidences. Reader, beware:

References:

Politics of Medical Marijuana – Consequences

Politics of Medical Marijuana – Louisiana

Politics of Medical Marijuana – Colorado

The Clinical Conundrum of Medical Marijuana – 2017

Medical Marijuana – Prescribing Guidelines

Medical Marijuana – Potential Harms Associated with Cannabis Use

Brief Review of Human Studies Regarding Increased Risk of Harm with Cannabis Use – State of Minnesota – 2016

Medical Marijuana – Driving

Medical Marijuana – Opioids

Medical Marijuana – Drug Interactions

Medical Marijuana – Opioid Drug Interactions

Medical Marijuana – Pain

Medical Marijuana – Pharmacokinetics

Human Cannabinoid Pharmacokinetics – 2007

Medical Marijuana – Tolerance Reversal

www.Healer.com

Medical Marijuana – Product Evaluation

Medical Marijuana – Sleep & Sleep Apnea

Medical Marijuana –Misc

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Accurate Education – Marijuana (Cannabis): Side Effects & Drug Interactions