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Hemp Future Week, Day 4: Cannabiotics

Richard Rose

Your CannaCoach, Pioneer in the Hemp Industry for 24 Years. Consult the Consultant your Consultant consults.

CBD and other Cannabinoids or Terpenes as a MRSA or VRE antibiotic, and/or a preservative?

“Antibacterial Cannabinoids from Cannabis sativa: A Structure-Activity Study” J. Nat. Prod. 2008, 71, 1427–1430

“Results and Discussion

The antibacterial cannabinoid chemotype is poorly defined, as is the molecular mechanism of its activity. Since many simple phenols show antimicrobial properties, it does not seem unreasonable to assume that the resorcinol moiety of cannabinoids serves as the antibacterial pharmacophore, with the alkyl, terpenoid, and carboxylic appendices modulating its activity. To gain insight into the microbiocidal cannabinoid pharmacophore, we have investigated how the nature of the terpenoid moiety, its relative position compared to the n-pentyl group, and the effect of carboxylation of the resorcinyl moiety are translated biologically, assaying the major cannabinoids and a selection of their precursors and regioisomeric analogues against drug-resistant bacteria of clinical relevance.

Within these, we have selected a panel of clinically relevant Staphylococcus aureus strains that includes the (in)famous EMRSA-15, one of the main epidemic methicillin-resistant strains,13 and SA-1199B, a multidrug-resistant strain that overexpresses the NorA efflux mechanism, the best characterized antibiotic efflux pump in this species.14 SA-1199B also possesses a gyrase mutation that, in addition to NorA, confers a high level of resistance to certain fluoroquinolones. A macrolide-resistant strain (RN4220),15 a tetracycline-resistant line overexpressing the TetK efflux pump (XU212),16 and a standard laboratory strain (ATCC25923) completed the bacterial panel.

D9-Tetrahydrocannabinol (THC, 4b), cannabidiol (CBD, 1b), cannabigerol (CBG, 3b), cannabichromene (CBC, 2), and cannabinol (CBN, 5) are the five most common cannabinoids.17 They could be obtained in high purity (>98%) by isolation from strains of C. sativa producing a single major cannabinoid (THC, CBD, CBG), by total synthesis (CBC),6 or by semisynthesis (CBN).18 Their antimicrobial properties are listed in Table 1. All compounds showed potent antibacterial activity, with MIC values in the 0.5-2 µg/mL range. Activity was exceptional against some of these strains, in particular the multidrug-resistant (MDR) SA-1199B, which has a high level of resistance to certain fluoroquinolones. Also noteworthy is the potent activity demonstrated against EMRSA-15 and EMRSA-16, the major epidemic methicillin-resistant S. aureus strains occurring in U.K. hospitals.13,19 These activities compare highly favorably with the standard antibiotics for these strains. The potent activity against strains possessing the NorA and TetK efflux transporters suggests that cannabinoids are not substrates for the most common resistance mechanisms to current antibacterial agents, making them attractive antibacterial leads. Given their nonpsychotropic profiles, CBD (1b) and CBG (3b) seemed especially promising, and were selected for further structure-activity studies. Thus, acetylation and methylation of their phenolic hydroxyls (compounds 1c-e and 3c-e, respectively) were both detrimental for activity (MIC >100 µg/mL), in accordance with the essential role of the phenolic hydroxyls in the antibacterial properties. However, in light of the potent activity of the monophenols CBC (2), THC (4b), and CBN (5), it was surprising that monomethylation of the diphenols CBD (1b) and CBG (3b) was so poorly tolerated in terms of antibacterial activity. Cannabinoids are the products of thermal degradation of their corresponding carboxylic acids (pre-cannabinoids).17 Investigation of the antibacterial profile of the carboxylated versions of CBD, CBG, and THC (compounds 1a, 3a, and 4a, respectively) showed a substantial maintenance of activity. On the other hand, methylation of the carboxylic group (compounds 1f and 3f, respectively) caused a marked decrease of potency, as did esterification with phenethyl alcohol (compounds 1g and 3g, respectively). This operation is associated with a potentiation of the antibacterial properties of phenolic acids, as exemplified by phenethyl caffeate (CAPE), the major antibacterial from propolis, compared to caffeic acid.20 Remarkably, the synthetic abnormal cannabinoids abn-CBD (6)21 and abn-CBG (7)22 showed antibacterial activity comparable to, although slightly less potent than, their corresponding natural products, while olivetol (10) showed modest activity against all six strains, with MICs of 64-128 µg/mL, and resorcinol (11) did not exhibit any activity even at 256 µg/mL. Thus, the pentyl chain and the monoterpene moiety greatly enhance the activity of resorcinol.

Taken together, these observations show that the cannabinoid antibacterial chemotype is remarkably tolerant to structural modification of the terpenoid moiety and its positional relationship with the n-pentyl chain, suggesting that these residues serve mainly as modulators of lipid affinity, and therefore cellular bioavailability. This view was substantiated by the marked decrease of activity observed when the antibacterial activity of CBG (3b) was compared to that of its polar analogue carmagerol (8).23 The results against the resistant strains confirm this suggestion, and it is likely that the increased hydrophilicity caused by the addition of two hydroxyls greatly reduces the cellular bioavailability by substantially reducing membrane permeability. Conversely, the addition of a further prenyl moiety, as in the bis-prenylated cannabinoid 9,21 while increasing membrane solubility, may result in poorer aqueous solubility and therefore a lower intracellular concentration, similarly leading to a substantial loss of activity. A single unfunctionalized terpenyl moiety seems therefore ideal in terms of lipophilicity balance for the antibacterial activity of olivetol derivatives. The great potency of cannabinoids suggests a specific interaction with a bacterial target, whose identity is, however, still elusive.

Given the availability of C. sativa strains producing high concentrations of nonpsychotropic cannabinoids, this plant represents an interesting source of antibacterial agents to address the problem of multidrug resistance in MRSA and other pathogenic bacteria. This issue has enormous clinical implications, since MRSA is spreading throughout the world and, in the United States, currently accounts for more deaths each year than AIDS.24 Although the use of cannabinoids as systemic antibacterial agents awaits rigorous clinical trials and an assessment of the extent of their inactivation by serum,25 their topical application to reduce skin colonization by MRSA seems promising, since MRSA resistant to mupirocin, the standard antibiotic for this indication, are being detected at a threatening rate.26 Furthermore, since the cannabinoid anti-infective chemotype seems remarkably tolerant to modifications in the prenyl moiety, semipurified mixtures of cannabinoids could also be used as cheap and biodegradable antibacterial agents for cosmetics and toiletries, providing an alternative to the substantially much less potent synthetic preservatives, many of which are currently questioned for their suboptimal safety and environmental profile.27″

In Kabelik’s “Hemp as a Medicament” while it specifically refers to Cannabis Indica resin, such a material also has significant levels of CBD as well as THC, neither of which were yet elucidated by that time (1955):


Within the scope of a systematic study of antibacterially effective substances present in the flora growing in the temperate climate of Czechoslovakia, the researchers have undertaken to investigate more than 3,000 different plant species. In this way they came upon the Indian hemp plant – Cannabis sativa var. indica – which has been investigated in detail. The subsequent finding of the antibacterial effect of the extract from Cannabis indica – direct evidence was provided some years ago at our Institute of Hygiene – stimulated much interest in cannabis from the medical point of view, and resulted in numerous reports published from different institutes and departments. Independently from the Kabelik’s team, the antibacterial effect of the extracts from Cannabis sativa was described and studied some years later, particularly by Ferenczy and Drobotko. The interest of Czech clinicians was aroused in this respect by the very good results achieved with the antibacterially effective substances from various plants referred to in the literature.

The preliminary results obtained were published in 1952 in the Czechoslovakian medical journal Lekarske listy and in a compilation of communications submitted at the scientific conference held by the university in Olomouc in 1955. A survey of their work was published in the journal, Die Pharmazie, 1957-1959.


A positive response due to antibiotics obtained from hemp could be observed in patients with otitis, ulcers of the anterior narines, and furuncular otitis. With chronical otitis positive results could be obtained in most cases — failure, however, in patients with pyocyaneum and proteus infections. The most striking effect could be observed with sinusitis, particularly with both-sided sinusitis maxillaris when one side had been treated with penicillin on control with negative result, whilst the other side had been healed by three punctures of hemp extract. The sinus resultlessly [unsuccessfully] treated with penicillin showed an immediate positive response to hemp thereafter.”


Local application of cannabis indica was experienced in 18 patients suffering from chronic otitis media, and in 4 patients after mastoidectomy. A significant improvement was noticed in 13 cases of chronic otitis. Up to the present, our experiences are of a rather short time, i.e. of three weeks only. It will be necessary to test cannabis with other more proper vehicles that would gradually liberate antibiotica on a satisfactory scale.”

Hemp Future Week, Day 5: Hobacco, Not-Pot and Nobacco.

Hemp Future Week is a service of the American Hemp Association and the Medicinal Hemp Association.

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