Sweet Wormwood

Generic name: Artemisia Annua L.
Brand names: Artemether, Artemisinin, Artemotil, Artesunate, Qinghaosu, Quinghao (Chinese), Sweet Annie, Sweet Sagewort, Sweet Wormwood, Wormweed

Usage of Sweet Wormwood

The clinical efficacy of artemisinin and its derivatives against all forms of human malaria, particularly P. falciparum and including uncomplicated and complicated malaria, have been proven by hundreds of published studies, most from Asia and Africa; only select investigations will be discussed in this monograph. Pharmacoeconomic studies support the cost effectiveness of artemisinin-based combinations in combating malaria in developing countries.(Morel 2005)

Antiviral activity is associated with the sterols sitosterol and stigmaterol of A. annua. Camphor stimulates the CNS, while the other plant essential oils produce depression, reduce spontaneous activity, and increase the hypnotic action of pentobarbital. The lipids and essential oils also have been used in cosmetics and perfumes and to treat or prevent inflammation, including of the skin.(Khan 1991, Perazzo 2003, Ulchenko 2005) Other reported pharmacological activity includes cytotoxic activity against cancer cells, inhibition of the growth of the gram-positive bacterium Enterococcus hirae by the essential oil, and growth inhibition of several phytopathogenic fungi by extracts.(Juteau 2002, Liu 2001)

Antibacterial/Antiparasitic activity

Animal and in vitro data

A novel gelatin wound dressing containing A. annua demonstrated in vitro antibacterial activity against Staphylococcus aureus, without toxicity to nonbacterial cellular proliferation.(Mirbehbahani 2020) A systematic review identified 22 animal and in vitro studies documenting activity of A. annua and other Artemisia spp. against Trypanosoma spp. (ie, Trypanosoma brucei, Trypanosoma congolense). In one study, an Artemisia extract (concentration of 10 mg/kg) cleared parasitemia in T. brucei–infected mice.(Naβ 2018)

Anticancer activity

The endoperoxide bridge is required for the anticancer activity of artemisinin and its derivatives through formation of a free radical, which causes molecular damage and cell death.(Beekman 1998)

Artemisinin derivatives may be effective in treating cancers that overexpress transferrin receptors. This mechanism of action involves the influx of iron in tumor cells, which then causes the formation of free radicals from artemisinin that cause molecular damage leading to cell death.(Lai 1995)

Artesunate, the semisynthetic derivative of artemisinin, induced apoptosis in human umbilical vein endothelial cells. Overexpression of the BCl-2 protein protects cells from apotosis, whereas activation of Bax drives apoptosis. Artesunate activates Bax, causing cell apoptosis and inhibiting the expression of the bcl-2 protein in a concentration- and dose-dependent manner.(Wu 2004)

Animal and in vitro data

Of 9 wormwood terpenoids and flavonoids studied in vitro, only artemisinin exhibited cytotoxicity toward the human tumor cell lines P-388, A-549, HT-29, MCF-7, and KB.(Dhingra 2000, Zheng 1994)

Artemisinin inhibited the growth of Ehrlich ascites and HeLa tumor cells, with a half-maximal inhibitory concentration (IC50) of 0.98 mcmol/L, unlike deoxyartemisinin, which lacks the endoperoxide bridge.(Beekman 1997)

Dimers of dihydroartemisinin were cytotoxic to Ehrlich ascites and HeLa tumor cells, as well as to normal murine bone marrow progenitor cells. The endoperoxide bridge and an ether linkage played a role in cytotoxicity. Artemisinin derivatives were subjected to the National Cancer Institute 60-cell screening program.(Beekman 1998)

An A. annua extract prepared via pressurized cyclic solid-liquid extraction possessed a higher toxicity and induced apoptosis to a greater degree when compared with traditional extracts in 3 cancer cell lines.(Curluciello 2021)

The efficacy of artemisinin in preventing breast cancer development was examined for 40 weeks in rats treated with a single oral dose of 7,12-dimethylbenz[a]anthracene 50 mg/kg, which is known to induce breast tumors. The experimental rat group (n=12) was fed a powdered rat chow containing artemisinin 0.02%, and the control group (n=22) received plain, powdered food. Artemisinin delayed (P<0.002), and in some rats prevented (57% of artemisinin-fed versus 96% of the controls; P<0.01), breast cancer development. In the artemisinin-fed rats that developed a tumor, tumor size was smaller (P<0.05), and time to tumor development was longer (29.4 vs 15.3 weeks) compared with controls.(Lai 2006)

Antiviral activity

In vitro data

An in vitro study reported activity against SARS-CoV-2 and 2 of its variants by several cultivars of A. annua leaf powder obtained from 6 different countries on 4 continents (Brazil, Burundi, China, Ethiopia, Kenya, and United States). Artemisinin content varied among the cultivars and ranged from approximately 20 to 150 mcg/mL. All cultivars exhibited activity against the virus and the B1.1.7 (UK) and B1.351 (South Africa) variants. On a microgram of artemisinin per milliliter of tea basis, IC50 of the samples ranged from 0.03 to 2.5 mcg/mL. However, IC50 was inversely correlated to the artemisinin or total flavonoid content. Leaf samples remained potent even after 12 years of storage, as well as after freezing and thawing. Human bioavailability of a 3 g oral dose tested in 1 volunteer revealed 36% of original artemisinin was detected in serum at 2 hours and 0.8% at 5 hours postingestion, which corresponded to a 2-hour level of 2.35 mcg/mL of serum per gram of dried leaf powder consumed.(Nair 2021)

Arthritis

In vitro data

In vitro studies suggest an anti-inflammatory effect of A. annua.(Hunt 2015, Stebbings 2016)

Clinical data

In a phase 2, randomized, placebo-controlled, double-blind clinical trial (ARTH01 trial; N=42), effects of an A. annua extract (150 mg or 300 mg given twice daily for 12 weeks) on pain, stiffness, and functional limitation in osteoarthritis of the hip or knee were evaluated. Improvements in pain and stiffness were demonstrated; mean change in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score at 12 weeks was −12.2 with A. annua extract (standard deviation [SD], 13.84; P=0.0159 vs placebo) and mean change in visual analog scale score was −21.4 mm (SD 23.48 mm; P=0.0082 vs placebo).(Stebbings 2016) In the open-label, 6-month extension to ARTH01, 28 patients continued to receive the same A. annua extract (150 mg capsule twice daily), which maintained the reduction in WOMAC scores observed during the double-blind phase. Adverse events considered possibly related to treatment with A. annua extract and leading to treatment withdrawal included stomach pain, flatulence, constipation, and diarrhea.(Hunt 2016)

An open-label, randomized controlled trial in adults with active rheumatoid arthritis (RA) (N=159) investigated adjunctive use of A. annua ethanolic extract 30 g once daily in combination with a disease-modifying antirheumatic drug (DMARD) regimen for 48 weeks. Patients had not received other medication for treatment of active RA in the 4 weeks prior to study enrollment. The A. annua extract led to significant improvement in pain/use of nonsteroidal anti-inflammatory drugs in the first 3 weeks compared with control (P<0.01). At 24 and 48 weeks, overall efficacy was also significantly better in the extract group compared with control, with 61% and 28%, respectively, exhibiting an "excellent" outcome, defined as overall improvement of at least 70% (P<0.01). At week 48, tenderness score, the number of painful joints, number of swollen joints, quality of life, C-reactive protein, rheumatoid factor levels, and anticyclic citrullinated protein antibodies were significantly improved in the extract group compared with control (P<0.01 or P<0.05 for all). The extract was well tolerated, with no withdrawals due to adverse events and significantly fewer adverse events than with control (3.8% vs 16.3%, respectively).(Yang 2017)

Hepatoprotective effects

Animal and in vitro data

In a liver failure mouse model, prophylactic administration of A. annua water extract for 14 days improved AST, ALT, and levels of early-stage inflammatory cytokines compared with the positive control (Silybum marianum [milk thistle] extract) and compared with untreated controls. Additionally, rates of survival were improved with prophylactic administration of either the water or an ethanol extract, which was associated with reduced hepatic bleeding. In vitro assays supported these results, showing reduced production of inflammatory cytokines, nuclear factor kappa B, and mitogen-activated protein kinases.(Park 2020) Similar results were reported in a nonalcoholic fatty liver disease mouse model in which an A. annua water extract was more effective than the positive control (S. marianum extract) at inhibiting lipid accumulation and immune cell infiltration in mouse livers. In vitro assays demonstrated marked reductions in intracellular lipid accumulation and potent antioxidant activity.(Choi 2020)

Immunosuppressive effects

Animal data

One animal study identified in a systematic review described immunosuppressive effects of an ethanolic extract of A. annua.(Alesaeidi 2016)

Malaria

Artemisinin and its derivatives are toxic to the malarial parasite at nanomolar concentrations, causing specific membrane structural changes that kill the parasite in the erythrocyte stage. The mechanism of action involves 2 steps: activation followed by alkylation. Iron activates artemisinin into a free radical through an iron-mediated cleavage. Alkylation involves the formation of covalent bonds between the artemisinin-derived free radicals and the malarial proteins.(Balint 2001, Dhingra 2000, Noori 2004, van Agtmael 1999)

Severe malaria

Clinical data

Compressed dried-leaf tablets of A. annua were used successfully to treat 18 patients (14 months to 60 years of age) with severe malaria following development of resistance to 2 other Artemisia therapies (artemisinin combination therapy [Coartem] and intravenous [IV] artesunate). The dried leaves have been previously reported to provide higher artemisinin bioavailability. The patients were within 24 hours of nonresponse to IV artesunate and were started on dried leaf tablets as a last resort, dosed at one 500 mg tablet twice daily for 5 days (adults weighing more than 30 kg), one-half of a tablet for children 15 to 30 kg, and one-fourth of a tablet for children weighing 5 to less than 15 kg. For patients unable to swallow, tablets were crushed, mixed with water, and administered by nasogastric tube. All 18 patients recovered.(Daddy 2017)

Uncomplicated malaria

Clinical data

In a single-blind, randomized clinical trial in 4 districts in Uganda, the efficacy of 3 antimalarial combinations was assessed in patients (younger than 5 years of age) diagnosed with uncomplicated malaria (N=2,061). Patients were evaluated for approximately 1 month and received chloroquine plus sulfadoxine/pyrimethamine (n=677), amodiaquine plus sulfadoxine/pyrimethamine (n=690), or amodiaquine plus artesunate (n=694). The primary end point was cure rate at 28 days. All 3 regimens proved ineffective, perhaps because of the high endemicity of malaria in this region of Africa.(Yeka 2005)

Respiratory disease

Artemisinins appear to act through a combination of antioxidant, anti-inflammatory, tumor inhibitory, and airway remodelling effects.

Animal and experimental data

In mice exposed to cigarette smoke, a reduction in methacholine-induced airway hyperresponsiveness was observed with artesunate treatment. The response was similar in efficacy to that of dexamethasone. Similarly, reductions in airway hyperresponsiveness and nasal symptoms were reported with artemisinin or its derivatives in allergic asthma and allergic rhinitis mouse models, respectively.(Cheong 2020)

Clinical data

In a double-blind, randomized, placebo-controlled trial (N=71), sublingual administration of A. annua drops for 32 weeks in patients with seasonal allergic rhinitis significantly reduced nasal congestion, rhinorrhea, and all other symptoms (except for watery eyes) compared with placebo (P<0.001 for each). Total Nasal Symptom Score decreased significantly during both the first and second peak pollen periods with the Artemisia sublingual drops compared with placebo (P<0.001). Local adverse events with the extract were mild and resolved without treatment, which included tongue/mouth numbness and mouth ulcer. Grade 1 mild urticaria and flushing (1 patient) and grade 3 asthma and chest tightness (1 patient) were also documented and resolved without antihistamine treatment.(Lou 2020)

Uncomplicated cutaneous leishmaniasis

Clinical data

Subsequent to demonstration of antileishmaniasis activity by A. annua leaf powder in vivo and in vitro, 2 patients with uncomplicated cutaneous leishmaniasis were treated with 30 g of the leaf powder for 20 days. By the end of treatment, ulcers decreased by 20% to 35% and by day 45, both patients exhibited complete cure and remained disease free at the 2-year follow-up. Treatment was well tolerated, with no adverse events reported by either patient.(Mesa 2017)

Sweet Wormwood side effects

Data collected between 2004 and 2013 from 8 US centers in the Drug-induced Liver Injury Network revealed that 15.5% (130) of hepatotoxicity cases were caused by herbals and dietary supplements, whereas 85% (709) of cases were related to prescription medications. Of the 130 cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanics/Latinos compared with non-Hispanic whites and non-Hispanic blacks. Liver transplant was also more frequent with toxicity from non-bodybuilding supplements (13%) than with conventional medications (3%) (P<0.001). Overall, the proportion of severe liver injury cases was significantly higher for supplements than for conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, 175 had identifiable ingredients, of which sweet wormwood was among the 32 (18%) single-ingredient products.(Navarro 2014)

A case of acute cholestatic hepatitis due to A. annua tea was documented in a 51-year-old male who consumed 1.25 g/day of A. annua powdered tea for 4 weeks as malarial prophylaxis. He had no medical history and no genetic variants related to cholestatic liver diseases. The patient's wife also consumed the tea and did not experience any adverse effects. The patient recovered with prednisone treatment followed by ursodeoxycholic acid.(Ruperti-Repilado 2019)

Clinical trial data document adverse effects reported with artemisinin derivatives (particularly injection forms), including GI complaints (eg, abdominal pain, diarrhea, nausea, vomiting), rash, pain and abscess development at the injection site, cardiovascular changes (eg, bradycardia, prolongation of the QT interval), and metabolic changes (eg, hypoglycemia).(McIntosh 2000)

Before taking Sweet Wormwood

Avoid use during the first trimester of pregnancy. Artemisinin derivatives, in particular artemether, have a toxic effect at the embryonic stage; animal studies in pregnant mice, rats, or rabbits, suggest teratogenicity may be limited to early pregnancy. No abnormalities were found in children born to mothers treated with artemisinin or artemether during the second or third trimester of pregnancy. In a 2004 report, 28 pregnant women from eastern Sudan were treated with intramuscular (IM) artemether, with 1 perinatal death documented following premature delivery. The remaining women delivered full-term healthy infants. In another case, 4 accidental pregnancy exposures to artemether/lumefantrine and 2 to dihydroartemisinin/piperaquine resulted in favorable pregnancy outcomes. In Thailand, 81 women in the second and third trimesters of pregnancy received 3 days of artesunate-atovaquone-proguanil; no differences in congenital abnormality rates were observed in newborns, or in growth and development assessments in the infants followed for 12 months.(Ashley 2005, Balint 2001, van Agtmael 1999, WHO 2007)

How to use Sweet Wormwood

Arthritis

A. annua extract 150 mg twice daily for 12 weeks was evaluated in a small study of patients with osteoarthritis.(Stebbings 2016)

Malaria

Dried leaf A. annua dosed at 500 mg twice daily for 5 days was evaluated in a study of patients with severe malaria resistant to previous Artemisia therapies.(Daddy 2017)

Warnings

The risk of cumulative neurotoxicity may prohibit the prophylactic use of artemisinin-based drugs. Animal studies in rats and dogs using 5 to 7 times the usual dose of artemether or arteether showed a high fatality rate because of neurotoxicity to cerebellar and brain-stem nuclei. However, primates were not as susceptible to the neurotoxicity. Neuropathology studies also found damage to auditory and vestibular nuclei. Dihydroartemisinin was the most toxic compound tested, while artelinic acid and artemisinin were the least toxic.(Dhingra 2000, van Agtmael 1999)

What other drugs will affect Sweet Wormwood

Clinically important effects may occur in patients because of the potent inhibition of CYP1A2 enzyme by artemisinin. Caution may be warranted in patients with diabetes; some patients in an artemether trial developed hypoglycemia.

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