and with dietary supplements or medicinal products based on rosemary constituents
Rosemary (Salvia rosmarinus; synonym Rosmarinus officinalis) is a species of the genus Salvia and an evergreen subshrub of the family Lamiaceae (mint family). The name Rosmarin or Rosmarinus is derived from the Latin ros marinus and means “dew (ros) of the sea (marinus)”, that is “sea dew”. The reason often given is that rosemary bushes grow on the coasts of the Mediterranean and that dew collects in their flowers at night. An older interpretation of the origin of the name traces it back to the Greek term rhops myrinos (balsamic shrub) [1].
Because of the possible anti-inflammatory effects of rosemary, preparations containing rosemary are worth discussing for the treatment of rheumatic diseases [11].
In Germany about 300 preparations containing rosemary are listed; however, most of them are categorised as non-medicinal products. Several rosemary preparations are offered as herbal over-the-counter, pharmacy-only medicinal products (source: Gelbe Liste Pharmindex [2]), for example:
Rosmarin Diamant Natuur Caps. 400 mg, PZN: 07031541 (Diamant Natuur B.V);
Rosmarin ointment 10 %, PZN 03141480 (Weleda);
Rosmarin Oleum Aeth. 10 %, PZN 02088803 (Wala Heilmittel);
Rosmarinus officinalis drops, LM 1 dilution, PZN 13680396 (Aracana Dr. Sewerin).
However, no product information sheets / package leaflets exist for these rosemary preparations. In addition, the precise indications for the use of such rosemary preparations are unclear [3].
Chemical and pharmacological composition
Rosemary contains between 1 % and 2.5 % essential oils together with various terpene compounds (cineole, α-pinene, ursolic acid, borneol, camphor, camphene, verbenone, isobornyl acetate, carnosol, oleanolic acid, betulin, betulinic acid, carnosic acid, rosmanol, α-terpineol), and furthermore 8 % tannins (mainly rosmarinic acid), flavonoids, glycolic acid, caffeic acid, bitter substances and saponins, etc. The concentrations of individual active substances differ markedly between leaves and stems [4].
Effects in vitro and in animal models
A 2022 review analysed data on the potential anti-inflammatory effect of Rosmarinus officinalis in in-vivo models in rats or mice. A search of the PubMed, Scopus and Web of Science databases was carried out. Rosemary was used more often as the whole plant, and the extraction methods were maceration and hydrodistillation. The most common routes of administration were gavage, intraperitoneal (IP) administration or oral administration with a dose dependent on the route of administration. A significant anti-inflammatory effect through inhibition of neutrophil activity and modulation of NF-κB activity was shown at a dose of 60 mg/kg carnosic acid and a dose of 10 mg/kg rosmarinic acid (each given IP), as well as at a dose of 400 mg/kg of total Rosmarinus officinalis extract given by gavage [5].
Carnosic acid (CA), carnosol and rosmanol are important diterpenes of the rosemary plant (Rosmarinus officinalis). They possess a phenolic structural unit and are able to remove reactive oxygen species (ROS) either by direct scavenging or indirectly by inducing antioxidant substances. Their diverse biological effects in the animal models studied are based on the modulation of various inflammatory signalling pathways, including NF-κB, STAT3 and NLRP3. As a result, they prevent the expression of pro-inflammatory cytokines (e.g. TNF-α, IL-1 and IL-6), adhesion molecules, chemokines and prostaglandins [6, 10]. In vitro, rosmanol shows stronger antioxidant properties than carnosol [10].
The anti-inflammatory effect of CA was investigated in vitro on osteoclasts and fibroblast-like synoviocytes as well as in vivo in the rat collagen-induced arthritis model. The pro-inflammatory factors suppressed by CA included TNF-α, IL-1β, IL-6, IL-8, IL-17, matrix metalloproteinase-3 (MMP-3) and the receptor activator of nuclear factor κB ligand (RANKL). In addition to inhibition of osteoclastogenesis and bone resorption, the RANKL-induced activation of NF-κB and of protein kinases was also down-regulated [7].
In the chondrosarcoma cell line SW1353 and in primary human chondrocytes, CA and carnosol inhibited IL-1β-induced catabolic enzymes such as MMP-13 and a metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS-4). These enzymes contributed to cartilage erosion, while the expression of anabolic enzymes, including Col2A1 and aggrecan, was shifted by CA and carnosol toward the physiological state [8].
In a collagen-induced arthritis db/db mouse model, micro-computed tomography showed an improvement in bone loss with CA (30 or 60 mg/kg, i.p. daily for 4 weeks). In vitro, CA suppressed osteoclastogenesis induced by RANKL and macrophage colony-stimulating factor (M-CSF) in bone marrow cells and osteoblasts [9].
Using the murine model of type II collagen-induced arthritis, a positive effect of oral administration of rosmanol and carnosol was demonstrated on the arthritis index and on serum levels of pro-inflammatory cytokines (IL-6, TNF-α). An anti-arthritic effect was also assumed to be mediated through blockade of the TLR4/NF-κB/JNK and p38-MAPK signalling pathways in synovial tissue [10].
Rosmarinus officinalis as a crude extract inhibited the proliferation of human lymphocytes and CD4+ T cells in a dose-dependent manner in vitro by inducing apoptosis. The intracellular STAT3 signalling pathway in T cells was suppressed by Rosmarinus officinalis in a dose-dependent manner [11].
In an experimental study in rats with osteoarthritis (induced by intra-articular injection of 2 mg monosodium iodoacetate), a nano-emulsion containing peppermint and rosemary essential oils was investigated. The treatments were applied topically at a dose of 1 ml daily. Pain was assessed by behavioural tests on days 1, 4, 7 and 14 after application. Application of the nano-emulsion reduced mechanical (p < 0.001) and thermal allodynia (p < 0.05) as well as thermal hyperalgesia (p < 0.05) [12].
In an adjuvant arthritis model in rats it was shown that administration of methotrexate (0.3 mg/kg) in combination with CA (100 mg/kg, p.o.) versus MTX (0.3 mg/kg) as monotherapy over a period of up to 28 days significantly reduced hind-paw swelling and plasma levels of IL-17A and IL-9 [13]. It has also been reported that rosmarinic acid inhibits complement activation both in vivo and in vitro [14].
A PubMed search for scientific articles using the keywords “Rosemary; Rosmarinus officinalis, clinical trials” returned (as of 06 March 2024) 42 references, with “carnosic acid, clinical trials” 13 and with “carnosol, clinical trials” 2 references. The clinical studies predominantly concern non-rheumatological indications such as alopecia, depression, cognitive disorders, Alzheimer’s disease, etc. The majority of clinical studies use rosemary in mixed preparations together with other phytotherapeutic agents such as sage, lemon balm or Rosa canina [12]. Only a few clinical studies are available on rheumatological diseases or joint pain.
In an open-label 8-week observational study, the efficacy of Meta050 (a standardised combination of reduced iso-alpha acids from hops, rosemary extract and oleanolic acid) was investigated for pain (using a visual analogue scale (VAS), a shortened arthritis impact measurement scale (AIMS2) and the fibromyalgia questionnaire). Fifty-four patients with osteoarthritis, rheumatoid arthritis and fibromyalgia received 440 mg of Meta050 three times daily for 4 weeks, which in the majority of patients was switched to 880 mg twice daily for the following 4 weeks. After treatment, a statistically significant decrease in pain of 50 % and 40 % respectively was observed in the patients with osteoarthritis and RA using the VAS (p < 0.0001) and AIMS2 (p < 0.0001). Outcomes in the fibromyalgia patients did not improve significantly. A decreasing trend in CRP was observed in those subjects who had elevated baseline CRP. No serious adverse events were observed. Despite the positive efficacy of Meta050, the results should be viewed critically (uncontrolled study design, sponsored by the manufacturer of the herbal preparation, no further studies of Meta050 since 2005 in RA or osteoarthritis) [15].
The aim of a further pilot study was to determine the change in skin temperature and warmth perception caused by topical rosemary essential oil in patients with systemic sclerosis and secondary Raynaud’s phenomenon. Twelve patients with progressive systemic sclerosis and Raynaud’s phenomenon were enrolled in an open-label pilot study. Each patient received an application of olive oil to both hands as a control and, 3 hours later, an application of a 10 % essential oil of Rosmarinus officinalis L. Skin temperature increased significantly after both olive oil and rosemary oil; the differences between the oils were not significant. Warmth perception increased after rosemary oil but not after olive oil. No adverse effects were observed [16].
In summary, the results of the clinical studies presented do not provide relevant arguments that preparations derived from rosemary could be a possible option for the treatment of rheumatic diseases.
Rosemary preparations are generally well tolerated [15], but they are not free of adverse effects. Some experimental studies also point to potential adverse effects. Thus, a high dose of rosemary extract (500 mg/kg) in a preclinical study in rats led to infertility through a reduction of testosterone levels and spermatogenesis [17]. Carnosic acid interacted with the CYP3A4 and CYP2B6 substrates and likewise showed toxicity in human hepatocytes, with an EC50 value identical to that of tamoxifen [18]. The question of relevant adverse effects of rosemary preparations must therefore still be clarified in controlled clinical studies.
In popular-science articles the following warning has been published: “Excessive doses can trigger states of intoxication and convulsions. Daily doses of 6 g of leaves for tea infusions, 20 drops of essential oil and 50 g for baths should not be exceeded; pregnant women are generally advised against use” [1].
The benefit of using rosemary preparations as oral or topical therapy for rheumatic diseases has not so far been demonstrated by valid scientific studies. Use should be discouraged in favour of better-defined pharmacological treatment approaches.
The effects of rosemary constituents on inflammatory mediators in vitro and in vivo do not exclude a possible therapeutic potential. However, systematic controlled clinical studies of rosemary preparations in case series with clearly defined rheumatological diseases are not available. The scientific evidence is therefore insufficient to recommend the prescription and use of rosemary preparations for patients with inflammatory rheumatic diseases.
Last updated: October 1, 2024