GREGOR ZORN

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Cannabis suppository bioavailability

Finding the ideal method of taking cannabis preparations is essential in every patient’s protocol and varies depending on a lot of factors (type and location of disease, preparation accessibility, patient’s personal preferences, patient’s tolerability/sensitivity/endocannabinoid tone…).

The use of cannabis suppositories has lately seen an increase, especially in some parts of Europe. In recent months, there has been a debate on the internet, about the efficacy of cannabis suppositories. There have been several online articles claiming that taking cannabis the rectal way was a good option, due to its high bioavailability and lack of unwanted side effects (1,2). The reasoning behind these claims was that cannabinoids in suppositories, if inserted correctly, bypassed the first-pass metabolism of the liver and went directly into the blood stream. I have to admit that I too believed in this theory and did not research it as I should have. I decided to do an in-depth report and here are my findings.

Suppositories

Suppositories are defined as solid dosage forms intended for insertion into body orifices (rectum, vagina, urethra) where they melt, soften or dissolve and exert a systemic effect. Rectal suppositories are conically shaped, 2-3 centimeters in length and weight 2 grams. They are placed into the rectum (the last 15-20 cm of the gastrointestinal tract) where they can be absorbed by 3 separate veins; the lower, middle and upper rectal (haemorrhoidal) veins. The lower and middle rectal veins drain directly into the general circulation, while the upper drains into the portal vein which flows to the liver.

Figure 1: The lower (inferior), middle and upper rectal (superior) veins
Figure 1: The lower (inferior), middle and upper rectal (superior) veins

Several physiological (quantity of available fluid, properties of rectal fluid, contents of the rectum, circulation route) and physiochemical drug factors (drug solubility in the vehicle, particle size, nature of the base, spreading capacity) have an effect on rectal absorption.

As an example, regarding drug solubility in vehicle, substances that are highly soluble in the vehicle (like THC in lipid bases) tend to have a slow release rate into the rectal fluid.

The research

When we evaluate a certain method of taking medicine, one of the important parameters is absorption effecting the systemic bioavailability; how much of the drug is actually gets into our bodies. It is usually measured in the blood as a percentage of the taken drug. Different drugs/molecules have different properties, affecting their absorption rates and bioavailability.

Most of the studies on cannabinoid rectal absorption were done on delta-9-trans-tetrahydocanabinol (Δ-9-THC) or other tetrahydrocannabinol (THC) derivatives. Δ-9-THC, as most cannabinoids, is highly lipophilic (“likes” fats) and essentially water-insoluble (3). A study published in the mid 80’s, done on monkeys, has shown that Δ-9-THC taken via suppositories (in a lipophilic or hydrophilic base) was not detected in the blood leading to the conclusion, that it was not absorbed via the rectal route (4). This has led to the search of more appropriate derivatives of Δ-9-THC, that would have better bioavailability. At the beginning of the 90’s, El Sohly’s team found that Δ-9-THC hemisuccinate (Δ-9-THC-HS) had 13,5% bioavailability in suppositories administered to monkeys (5). Δ-9-THC hemisuccinate, a prodrug hemiester of Δ-9-THC, is prepared in the laboratory and is not present in cannabis or cannabis extracts. The same team also tested different types of Δ-9-THC esters (hemisuccinate, N-formyl alaninate, N-methyl carbamate and methoxy acetate) in different suppository bases, this time on monkeys and dogs. The results showed that Δ-9-THC-HS had the highest absorption rate and the bioavailability for each base was found to range from 52-61% and 13,5%, in dogs and monkeys respectively. Δ-9-THC-HS was then tested on humans (3 females) and compared to an oral formulation of Δ-9-THC in sesame oil (Marinol ®). The results showed that “areas under the curves for plasma THC were more than 30-fold higher than after oral dosing” (6). A pilot study done two patients evaluating the effects of oral (Marinol ®) or rectal (Δ-9-THC-HS) administration of cannabinoids concluded that the bioavailability of the rectal route was approximately twice that of the oral route due to higher absorption and lower first-pass metabolism (7). In an animal study showed analgesic and reinforcing properties in adjuvant-arthritic rats suggesting that “Δ-9-THC-HS has therapeutic potential and is unlikely to possess an abuse liability when used in the context of chronic pain” (8).

Figure 2: Δ-9-THC (left) and Δ-9-THC-HS (right) structure comparison
Figure 2: Δ-9-THC (left) and Δ-9-THC-HS (right) structure comparison

Several studies have been published on methods of stabilising (9,10,11,12) and enhancing (13) Δ-9-THC-HS prodrug which led to a number of patents over the years (14,15).

A 2014 study, looking at the release rate of cannabinoids from suppositories, using plant extract in theobroma oil (cocoa butter) as the suppository base with different percentages of polysorbate 85, found that “release profile of marijuana from the suppository bases was generally low” ranging from 0.0030 to 0.065 % at 150 min. It should be noted, that the extract was prepared using fresh cannabis leaves and was done in a laboratory setting (16).

If we look at review studies of cannabinoid pharmacokinetics, under rectal administration, they all cite studies and bioavailability of Δ-9-THC-HS (17,18).

Patient cases and anecdotal evidence

We have had some very interesting results with suppositories in different types of health problems. Whole plant cannabis extract suppositories, with different ratios of THC and CBD, have been very efficient in localised anal or vaginal health problems. Regarding the bioavailability, we have had some reports of some patients experiencing classical THC side effects. A particular case of a cancer patient comes to mind, where she took one suppository and was high for 3 consecutive days. This is an extreme case, where we have to account the patient’s high sensitivity to THC, but it shows that there definitely was absorption into the blood.

Here are a few examples of efficacy with cannabinoid suppository use:

Haemorrhoids – with protocol of only a few suppositories we have seen very good results in haemorrhoids, with patients reporting that they were completely free from any symptoms. Even patients with chronic haemorrhoids, who have tried all the classical treatments and had undergone surgery, without any results, cannabinoid suppositories were effective and got rid of the problems.

Inflammatory bowel disease – a patient had a colonoscopy and the doctor diagnosed it as Crohn’s disease. After taking 10 suppositories he had another colonoscopy and the doctor could not find any signs of the disease. In other cases of IBD this method has been very successful, due to the fact of applying cannabinoids right were the problem occurs.

Cancer – in 2 cases, patients using suppositories have had positive results with negative CT scans of existing tumours. In both cases however, they were also using oral/sublingual extracts so it is hard to make any conclusions.

Vaginal suppositories – while this article focuses mainly on the rectal route of administration, vaginal suppositories are also showing positive results. They are very effective in alleviating pain, such as menstrual cramps, inflammation and have an antibacterial effect. Women with hormonal imbalance problems, such as lack of regular menstruation, have also had great results in reinstating a normal balance.

Conclusions

The topic of cannabis suppositories is a hot one, with patients and caregivers who swear by them and others who are not so convinced. The truth is that we don’t have any real studies, done with natural cannabis extracts in suppositories, evaluating all the variables (different cannabinoids, different suppository bases, different cannabinoid concentrations, different rectal insertion lengths…) measuring the systematic bioavailability of cannabinoids in the blood. This does not mean that patients shouldn’t use them, especially if they have good results with this method. Suppositories for localised problems are extremely effective and have shown very good results in practice.

On the other hand, using only suppositories as an efficient systemic absorption method is at least questionable if not irresponsible. In diseases such as cancer, where usually higher doses of cannabinoids are needed, cannabis suppositories should always be used in conjunction with other more proven methods, such as sublingual drops.

This is a great time for cannabis research and the number of studies on cannabis/cannabinoids/endocannabinoid system is bound to surpass 3000 for 2016 – that’s 8 new studies per day! We can also learn a lot from patients/doctors/caregivers experiences with treating specific ailments with different methods of cannabinoid intake. So what are your experiences with cannabis suppositories? If you have any, I’d invite you to share them with us in the comments section.

References:

  1. Backdoor Medicine: How Cannabis Suppositories Can Save Lives http://cannabisdigest.ca/cannatory/
  2. Cannabis Suppositories: Is the Posterior Superior?https://unitedpatientsgroup.com/blog/2015/01/22/cannabis-suppositories-why-the-posterior-is-superior/
  3. Garrett ER, Hunt CA. Physiochemical properties, solubility, and protein binding of ∆9-tetrahydrocannabinol. J Pharm Sci. 1974; 63 (7): 1056-64
  4. Perlin E, Smith CG, Nichols AI, Almirez R, Flora KP, Cradock JC, Peck CC. Disposition and bioavailability of various formulations of tetrahydrocannabinol in the rhesus monkey. J Pharm Sci. 1985 Feb;74(2):171-4
  5. ElSohly MA, Stanford DF, Harland EC, Hikal AH, Walker LA, Little TL Jr, Rider JN, Jones AB. Rectal bioavailability of delta-9-tetrahydrocannabinol from the hemisuccinate ester in monkeys. J Pharm Sci. 1991 Oct;80(10):942-5.
  6. Mattes RD, Shaw LM, Edling-Owens J, Engelman K, Elsohly MA. Bypassing the first-pass effect for the therapeutic use of cannabinoids. Pharmacol Biochem Behav. 1993 Mar;44(3):745-7
  7. Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther. 1996 Oct;34(10):446-52
  8. Susan L. Broom MA, Kenneth J. Sufka, Mahmoud A. Elsohly & Samir A. Ross. Analgesic and Reinforcing Properties of Δ-9-THC-Hemisuccinate in Adjuvant-Arthritic Rats. Journal of Cannabis Therapeutics, 1(3-4), June 2001
  9. Munjal M, ElSohly MA, Repka MA. Chemical stabilization of a delta9-tetrahydrocannabinol prodrug in polymeric matrix systems produced by a hot-melt method: role of microenvironment pH. AAPS PharmSciTech. 2006;7(3):71.
  10. Munjal M, Stodghill SP, Elsohly MA, Repka MA. Polymeric systems for amorphous delta 9-tetrahydrocannabinol produced by a hot-melt method. Part I: chemical and thermal stability during processing. J Pharm Sci. 2006;95(8):1841–53.
  11. Munjal M, Elsohly MA, Repka MA. Polymeric systems for amorphous delta9-tetrahydrocannabinol produced by a hot-melt method. Part II: effect of oxidation mechanisms and chemical interactions on stability. J Pharm Sci. 2006;95(11):2473–85.
  12. Repka MA, ElSohly MA, Munjal M, Ross SA. Temperature stability and bioadhesive properties of delta9-tetrahydrocannabinol incorporated hydroxypropylcellulose polymer matrix systems. Drug Dev Ind Pharm. 2006;32(1):21–32.
  13. Sampada B. Upadhye, Swapnil J. Kulkarni, Soumyajit Majumdar, Mitchell A. Avery, Waseem Gul, Mahmoud A. ElSohly, and Michael A. Repka. Preparation and Characterization of Inclusion Complexes of a Hemisuccinate Ester Prodrug of Δ9-Tetrahydrocannabinol with Modified Beta-Cyclodextrins. AAPS PharmSciTech. 2010 Jun; 11(2): 509–517
  14. Stable suppository formulations effecting bioavailability of Δ9 -THC. US 5508037 A
  15. Method for effecting systemic delivery of delta-9-tetrahydrocannabinol US 4933363 A
  16. Obonga W. O., Omeje E. O., Nnadi C. O., Osadebe P. O., Attama A. A., Onunkwo G. 2014. Some physical properties of novel Cannabis suppositories formulated with theobroma oil.  African journal of pharmacy and pharmacology, Vol.8(44), pp. 1127-1131
  17. Iain J McGilveray. 2005. Pharmacokinetics of Cannabinoids. Pain Research and Management, vol. 10, no. Suppl A, pp. 15A-22A
  18. Huestis, M. A. 2007. Human Cannabinoid Pharmacokinetics.Chemistry & Biodiversity,4(8), 1770–1804