Interactions between cannabinoids and other medicines

Medikament Cannabis

Like any medicine, medical cannabis can interact with other prescribed and pharmacy medicines. Cannabis patients are often seriously ill and therefore often take many medicines. Since the cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD), like various other active substances, are broken down by enzymes in the liver, interactions are possible when certain medicines are taken at the same time. There may be undesirable side effects like enhancement or reduction of the effect of both the cannabinoid and the other drugs. Some interactions are therapeutically useful: For example, many chronic pain patients achieve a better reduction of their symptoms by combining cannabis with opiate painkillers.

Consequences of interactions

Chronically ill and elderly patients are particularly affected by interactions, as they are often multimorbid. This means that they have many underlying diseases and take several medicines. Experts speak of polymedication when patients take more than five medicines on a permanent basis [1]. Data from the statutory health insurance funds from 2015 showed that patients over 65 years of age take an average of 3.9 daily doses of various medicines which increases the risk of potentially dangerous effects. The turnover of medicines in this age group alone was 43 percent. The most frequent prescriptions were in the 80- to 89-year-old group [1]. Drug interactions can have serious consequences: Up to 7 percent of all inpatient treatments are due to adverse interactions [2].

In addition to prescribed medicines over-the-counter and non-prescription medicines can also cause interactions. For example St. John’s wort can lead to the increased production of liver enzymes which causes various drugs including THC and CBD to be broken down more quickly. Certain foods can also influence the metabolism of medicines.  For example grapefruit and grapefruit juice block certain liver enzymes and can delay the breakdown of cannabinoids and other drugs.

However interactions do not necessarily have to result in negative consequences. Certain active ingredients are combined to achieve synergistic effects, i.e. a mutual enhancement of effects. [12].

Why does interaction occur?

More than 50 percent of all drugs are broken down in the liver by so-called cytochrome P450-dependent enzymes (CYP enzymes) [3].

Since the cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD) are also broken down via CYP enzymes, interactions are possible when taken simultaneously with certain medicines.

Cannabis-based medicines can also increase the effects and side effects of other medicines, such as sedatives and sleeping pills.

Metabolism of cannabinoids

THC and CBD are broken down in the liver by different types of CYP enzymes which are also involved in the metabolism of many other active substances:

CannabinoidDegradative enzymesInhibited enzymes
THCCYP2C9 CYP3A4 (auch 11-Hydroxy-THC)CYP2C9
CBDCYP3A4CYP2C19* CYP3A4*

* high dosage

  • Tetrahydrocannabinol: THC is converted via CYP2C9 and CYP3A4 to the also psychotropically active 11-hydroxy-THC which is further oxidised via CYP3A4 to the ineffective THC-carboxylic acid. THC-carboxylic acid is excreted as water-soluble glucuronide. THC is possibly an inhibitor of CYP2C9 [5].
  • Cannabidiol: CBD is degraded via CYP3A4. Oral intake of high doses of CBD inhibits the CYP2C19 and CYP3A4 enzymes.

Which enzymes are influenced also depends on the application method of the cannabinoids. If cannabis is smoked alone or with tobacco, CYP1A2 enzymes are increasingly formed. [4].

Cannabinoids and their interactions with other active substances

The following active substances can increase the effect of cannabinoids:The following substances can reduce the effect of cannabinoids:Cannabinoids can influence the effect of the following active substances through enzyme inhibition:
   
Antidepressants (SSRI) (e.g. fluoxetine)Benzodiazepines (increased sedation)Opioids (increased pain relief)Antifungals (e.g. ketoconazole) AmiodaroneMacrolides (clarithromycin,   erythromycin)IsoniazidAntiviral agentsCalcium antagonists  Proton pump inhibitors (omeprazole, pantoprazole)St. John’s wortCarbamazepinePhenytoin Phenobarbital TroglitazoneRifampicin RifabutinRisperidone Omeprazole Warfarin Diclofenac

Mutual effect enhancement (additive effects) in combination of medicinal cannabis and other medicinal products
Since cannabis has a sedative (tranquillising) effect, interactions with other medicines that also have a depressant effect on the central nervous system. These include, for example sleeping pills and sedatives as well as opiate painkillers [4] and muscle relaxants. Severe drowsiness, dizziness and an increased risk of falling may occur. Alkohol

Alcohol consumption at the same time is particularly dangerous: Studies on healthy subjects have shown that alcohol increases THC blood levels, causing psychotropic effects to reinforce each other. THC and alcohol together lead to greater impairment than taking one substance alone. Side effects of alcohol such as nausea and vomiting, loss of control and the risk of mental disorders (e.g. anxiety disorder) increase [11]. Therefore alcohol consumption is strongly discouraged.

Opioids

Pharmacodynamic interactions can also have a positive benefit. Severe chronic pain is often treated with opiate-based analgesics, which can have unpleasant effects such as constipation in long-term use. There is also a risk of tolerance development and physical dependence. Various studies have shown that Cannabinoids enhance the analgesic effect of opioids. Many patients can reduce the dose of opioid-based painkillers and reduce side effects.

In preclinical studies morphine in combination with THC showed an effect at concentrations 3.6 times lower than in trials with the opiate alone [12]. This effect was also shown in clinical studies: In an Israeli study published in 2018 with a total of 2,736 people over 65 years of age, the patients reported an average pain reduction from 8 to 4 points on the numerical rating scale of 0 – 10 after 6 months of cannabis therapy. In addition 18.1 percent of the patients were able to reduce the dosage of their opiate medication or stop taking the medication altogether. [13]

THC can negatively affect the cardiovascular system and lead to short-term side effects such as palpitations (tachycardia) and increased blood pressure (hypertension). Blood pressure drops after rapid changes of position (orthostatic hypotension) for example when the affected person stands up quickly, are also possible, as THC reduces the resistance of the blood vessels [14]. Sympathomimetics, i.e. drugs that put the body on heightened alert such as amphetamine derivatives, can additionally increase the side effects on the heart [10]. Caution is also advised with other drugs that affect the heart such as antihypertensives. Patients with cardiovascular and heart diseases should therefore be closely monitored by a doctor during cannabis therapy.

Enhancement or attenuation of the cannabinoid effect by other drugs
THC and CBD are degraded by CYP3A4, and THC additionally by CYP2C9. If these degrading enzymes are blocked in their function by other drugs (CYP inhibitors), the cannabinoids are degraded more slowly which increases the blood levels of the cannabinoids and consequently the effect increases. On the other hand CYP inducers are drugs that increase the enzyme activity, whereby the cannabinoids are broken down more with the result of a reduced active substance level and thus a reduced effect.

In 2013 a scientific team carried out a pharmacokinetic study on 36 volunteers with cannabinoids in the form of a spray containing THC and CBD and the three drugs rifampicin, ketoconazole and omeprazole [6]:

  • Rifampicin an antibiotic agent is an inducer of CYP3A4 and CYP2C19. The THC levels decreased by -36 % as a result. CBD levels also fell by more than half (-52 %). The strongest decrease with -87 % was found in the THC metabolite 11-hydroxy-THC. Since St. John’s wort also induces CYP3A4, it should be avoided [4].
  • Ketoconazole an agent against fungal infections, is an inhibitor of CYP3A4. The blood levels of all three cannabinoids studied increased: THC by +27 percent, CBD by +89 percent and 11-hydroxy-THC by +204 percent. The group taking ketoconazole experienced the most side effects. CYP3A4 inhibitors can thus enhance the psychotropic effects of THC. Dose-related side effects of CBD such as drowsiness or an increase in liver enzymes may also increase. These side effects can also occur with other drugs (e.g. verapamil) that inhibit this enzyme [4].
  • Omeprazole, a stomach medication used for heartburn is an inhibitor of CYP2C19. In “test tube” experiments, so-called in vitro experiments, THC and CBD are degraded by CYP2C19. However the study results of the test persons did not show any significant influences on the blood levels of THC, CBD and 11-hydroxy-THC. The scientific team therefore concluded that interactions with CYP2C19 inhibitors hardly have any effects in practice.

Influencing the effect of other medicines by medicinal cannabis

Interactions between medicinal cannabis and drugs with a narrow therapeutic range (e.g. antiepileptic drugs, anticoagulants) are particularly critical. These must be precisely dosed in the patient and individually adjusted, as even slight overdoses can lead to severe side effects.

  • Warfarin: One of these drugs is the anticoagulant warfarin which is metabolised via CYP2C9. Studies suggest that THC inhibits this enzyme [6]. This slows down the breakdown of warfarin and blood levels rise, which can lead to bleeding. This is shown by increased INR values (International Normalized Ratio), a laboratory value for the extent of anticoagulation [7].
  • Antidepressants: How cannabinoids and antidepressants interact has not yet been conclusively clarified. Preclinical studies have shown that activation of the CB1 receptor can influence serotonin production in different ways. Thus, low doses of THC were able to increase serotonin levels and thus had an antidepressant effect. Higher amounts of the cannabinoid, on the other hand, caused reduced serotonin levels and increased depressive symptoms. The reason for the different effects on the serotonin balance could be the activation of CB1 receptors which are located on different cell types such as serotonergic, GABAergic or glutamatergic nerve cells [15]. The risk of interaction between medicinal cannabis and antidepressants is considered low to moderate. Patients are nevertheless advised to discuss concomitant use with their doctor as some active substances from the class of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine can also influence CYP enzymes. Cannabinoids can also increase the side effects of tricyclic antidepressants such as amitriptyline: Heart rate increase, blood pressure decrease and sedative effects increase [16].

Conclusion

The number of studies on the effects and metabolism of cannabinoids is currently limited. Many of the studies dealing with interactions were conducted with healthy subjects and are therefore not directly transferable to ill persons. Further clinical studies are needed to better understand the processes in patients. Therefore it is all the more important to determine the dose at the beginning of a cannabinoid therapy according to the principle “start low and go slow”. Thus low doses of THC or CBD are started and the cannabinoid dosage is slowly increased, depending on the response of the person concerned and the side effects that occur, until the optimal amount is reached [10].

Patients taking many medications should be aware that some drugs can increase the psychotropic effects of THC and cannabinoids can alter the effects of other medications. Therefore it is important that patients inform doctors and pharmacists about all preparations including over-the-counter medicines and food supplements, so that possible interactions can be recognised.

Sources:

[1] Schaufler J., Telschow C. (2016) Arzneimittelverordnungen nach Alter und Geschlecht. In: Schwabe U., Paffrath D. (eds) Arzneiverordnungs-Report 2016. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-50351-5_49

[2] Drug Interactions Principles, Examples and Clinical Consequences Dtsch Arztebl Int 2012; 109(33-34): 546-55. DOI: 10.3238/arztebl.2012.0546

[3] Arzneimittelinteraktionen Prinzipien, Beispiele und klinische Folgen Drug interactions Dtsch Arztebl Int 2012; 109(33-34): 546-56; DOI: 10.3238/arztebl.2012.0546 Cascorbi, Ingolf

[4] Arzneimitteltherapiesicherheit: Das Interaktionspotenzial der Cannabinoide Dtsch Arztebl 2018; 115(47): [28]; DOI: 10.3238/PersOnko.2018.11.23.05 Petri, Holger

[5] Drug interactions with cannabinoids Tony Antoniou, Jack Bodkin, Joanne M.-W. Ho CMAJ Mar 2020, 192 (9) E206; DOI: 10.1503/cmaj.191097

[6] Stott C, White L, Wright S, Wilbraham D, Guy G.  A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy                  volunteers. Springerplus. 2013 May 24;2(1):236. doi: 10.1186/2193-1801-2-236. PMID: 23750331; PMCID: PMC3671111.

[7] Damkier P, Lassen D,Christensen MMH, Madsen KG, Hellfritzsch M,Pottegård A. Interaction between warfarin and cannabis. Basic Clin Pharmacol Toxicol. 2019;124:28–31.https://doi.org/10.1111/bcpt.13152DAMKIER ET AL.|31

[8] Stephen M. Stout & Nina M. Cimino (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review, Drug Metabolism Reviews, 46:1, 86-95, DOI: 10.3109/03602532.2013.849268

[9] Anderson, G.D., Chan, LN. Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. Clin Pharmacokinet 55,1353–1368 (2016). https://doi.org/10.1007/s40262-016-0400-9

[10] The pharmacokinetics and the pharmacodynamics of cannabinoids. Catherine J. Lucas, Peter Galettis, Jennifer Schneider First published: 12 July 2018 https://doi.org/10.1111/bcp.13710

[11] Yurasek, A.M., Aston, E.R. & Metrik, J. Co-use of Alcohol and Cannabis: A Review. Curr Addict    Rep 4, 184–193 (2017). https://doi.org/10.1007/s40429-017-0149-8

[12] Nielsen, S., Sabioni, P., Trigo, J. et al. Opioid-Sparing Effect of Cannabinoids: A . Systematic Review and Meta-Analysis. Neuropsychopharmacol 42,1752–1765 (2017). https://doi.org/10.1038/npp.2017.51

[13] Abuhasira R, Schleider LB, Mechoulam R, Novack V. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. Eur J Intern Med. 2018 Mar;49:44-50. doi: 10.1016/j.ejim.2018.01.019. PMID: 29398248.

[14] Alshaarawy O, Elbaz HA. Cannabis use and blood pressure levels: United States National Health and Nutrition Examination Survey, 2005-2012. J Hypertens. 2016;34(8):1507-1512. doi:10.1097/HJH.0000000000000990

[15] Cohen K, Weizman A, Weinstein A. Modulatory effects of cannabinoids on brain neurotransmission. Eur J Neurosci. 2019 Aug;50(3):2322-2345. doi: 10.1111/ejn.14407. Epub 2019 Apr 8. PMID: 30882962.

[16] https://www.pharmazeutische-zeitung.de/ausgabe-412013/erkennen-erklaeren-ersetzen/

About Minyi

Minyi Lü leidet an chronischen Schmerzen aufgrund ihrer Fingerarthrose. Ihre Beschwerden behandelt sie seit 2017 sehr erfolgreich mit medizinischem Cannabis. Als PTA und Pharmaziestudentin bringt sie nun ihr Know-how ein, um über die neuesten wissenschaftlichen Erkenntnisse rund um Medizinalcannabis zu berichten.

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