A Comprehensive Review of Herbal Supplements Used for Persistent Symptoms Attributed to Lyme Disease

Abstract

Context

Lyme disease is the most common, tick-borne disease in the USA. While most patients successfully recover with antibiotics, some patients experience persistent symptoms for months to years. Patients who attribute chronic symptoms to Lyme disease commonly use herbal supplements. The complexity, variability in dose and formulation, and lack of data for these herbal compounds make it difficult to assess their efficacy and safety.

Objective

This review examines the evidence for the antimicrobial activity, safety, and drug-drug interactions of 18 herbal supplements that patients commonly use for treatment of persistent symptoms attributed to Lyme disease.

Design

The research team performed a narrative review by searching the PubMed, Embase, Scopus, Natural Medicines databases, and NCCIH website. The search used the keywords for 18 herbal compounds: (1) andrographis (Andrographis paniculate), (2) astragalus (Astragalus propinquus), (3) berberine, (4) cat’s claw bark (Uncaria tomentosa), (5) cordyceps (Cordyceps sinensis), (6) cryptolepis (Cryptolepis sanguinolenta), (7) Chinese skullcap (Scutellaria baicalensis), (8) garlic (Allium sativum), (9) Japanese knotwood (Polygonum cuspidatum), (10) reishi mushrooms (Ganoderma lucidum), (11) sarsaparilla (Smilax medica), (12) Siberian ginseng (Eleutherococcus senticosus), (13) sweet wormwood (Artemisia annua), (14) teasle root (Dipsacus fullonum), (15) lemon balm (Melissa officinalis), (16) oil of oregano (Origanum vulgare), (17) peppermint (Mentha x piperita), and (18) thyme (Thymus vulgaris). The team also searched for terms related to protocols, including Dr. Rawls’ protocol and the Buhner protocol.

Setting

University of Maryland Medical Center, Baltimore MD.

Results

Seven of the 18 herbs reviewed had evidence for in-vitro activity against B. burgdorferi. These compounds included: (1) cat’s claw (2) cryptolepis, (3) Chinese skullcap, (4) Japanese knotweed, (5) sweet wormwood, (6) thyme, and (7) oil of oregano. With the exception of oil of oregano these compounds also have anti-inflammatory activity. In vivo data and clinical trials are lacking. Clinicians should be cautious as many of the identified compounds have drug interactions and additive effects that could lead to increased risks for bleeding, hypotension, and hypoglycemia.

Conclusions

Many of the herbs that alternative and integrative practitioners use to treat Lyme disease have anti-inflammatory effects that may contribute to patients’ perceptions of symptomatic improvement. Some herbs have limited demonstrated anti-borrelial activity in vitro, but in-vivo data and clinical trial data is lacking. Further research is required to determine the efficacy, safety and appropriate use of these herbs for this patient population.

Lyme disease is the most common, tick-borne disease in the USA. The deer tick Ixodes scapularis transmits the causative agents: Borrelia burgdorferi (B. burgdorferi) and Borrelia mayonii (B. mayonii). It’s estimated that up to 476 000 people contract Lyme disease each year.¹ Medical practitioners successfully treat the majority of patients with Lyme disease with antibiotic therapy. However, some patients develop posttreatment Lyme disease syndrome (PTLDS), and they can experience persistent symptoms for months to years.

The 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease from the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) provide the proposed criteria for PTLDS, including a history of appropriately treated Lyme disease and the subjective symptoms, such as fatigue, musculoskeletal pain, and cognitive difficulties, that can appear within six months of a patient’s diagnosis with Lyme disease and for at least six months after antimicrobial therapy.²

Some use the term chronic Lyme disease (CLD), including Lyme-literate medical doctors (LLMDs), patient advocacy groups, and the public. While the term includes patients with PTLDS, it also includes many misdiagnosed patients with similar, nonspecific, symptom complexes for which no convincing evidence exists for infection with B. burgdorferi.

Regardless of the differences in PTLDS, CLD, and misdiagnosed Lyme groups, patients in these groups attribute their symptoms to Lyme disease, but they differ in the presence or absence of a documented Borrelia infection.

Effective treatment for these symptoms is unknown. The guidelines mentioned above discuss several randomized clinical trials that have shown that prolonged antibiotic therapy is not useful for patients with PTLDS.² In his review, Cameron examined clinical studies that have shown that PTLDS patients have reported higher rates of depression and arthralgia and lower health-related quality of life as compared to the general US population.³ Ali et al found that these patients also demonstrate a lack of satisfaction with conventional healthcare and use of alternative therapies and practitioners, such as integrative-medicine physicians, LLMDs, naturopaths, and acupuncturists.⁴

PTLDS, CLD, and misdiagnosed Lyme patients commonly use herbal supplements for Lyme disease as well as alternative and integrative healthcare providers for the following purposes: (1) to eradicate bacteria, (2) to boost the immune system, (3) to decrease inflammation, and (4) to decrease symptoms and improve quality of life.

These patients use the herbs as single agents and in combination as part of treatment protocols. The herbs are readily available and are well known in the CLD community. The complexity, variability in dose and formulation, and lack of data for these herbal compounds make it difficult to assess their efficacy and safety.

Although researchers have not studied in depth the mechanism responsible for the perceived improved outcomes in humans, they have studied many of the compounds for their effectiveness against bacterial and viral infections as well as their anti-inflammatory and other properties in vitro.

This review intended to examine the available evidence for the efficacy, safety, and drug-drug interactions for 18 herbal supplements that patients commonly use for treatment of persistent symptoms attributed to Lyme disease.

Methods

The study took place at the University of Maryland Medical Center, Baltimore MD. The research team performed a narrative review by searching the PubMed, Embase, Scopus, Natural Medicines databases, and NCCIH website. The research team also reviewed bibliographies from selected articles.

The team based the choice of therapies on their experience with patients at an academic Lyme center, an internet search of patient’s testimonials, and a literature search using the following terms for 18 herbal compounds:

(1) andrographis (Andrographis paniculate), (2) astragalus (Astragalus propinquus), (3) berberine, (4) cat’s claw bark (Uncaria tomentosa), (5) cordyceps (Cordyceps sinensis), (6) cryptolepis (Cryptolepis sanguinolenta), (7) Chinese skullcap (Scutellaria baicalensis), (8) garlic (Allium sativum), (9) Japanese knotwood (Polygonum cuspidatum), (10) reishi mushrooms (Ganoderma lucidum), (11) sarsaparilla (Smilax medica), (12) Siberian ginseng (Eleutherococcus senticosus), (13) sweet wormwood (Artemisia annua), (14) teasel root (Dipsacus fullonum), (15) lemon balm (Melissa officinalis), (16) oil of oregano (Origanum vulgare), (17) peppermint (Mentha x piperita), and (18) thyme (Thymus vulgaris). The team also searched for terms related to protocols, including Dr. Rawls’ protocol and the Buhner protocol.

The review includes articles published in the English language. A total of 514 references were identified from the database searches. Duplicate publications were removed, which left the team with 437 publications. Publications were reviewed for information about safety, efficacy, and drug-drug interactions for the 18 identified compounds. Publications which did not contain relevant information were not included in the review.

The evaluation consisted of a review: (1) of the herbs’ antimicrobial activity, antiborrelia activity, anti-inflammatory, and other relevant symptomatic activity as well as supportive care, and (2) safety data, status as generally recognized as safe (GRAS), and clinically relevant drug-drug interactions.

Results

Table 1 outlines the categories for each compound’s evidence include: (1) activity = +, (2) no activity = -, and (3) mixed activity = +/-.

Table 1.

Activity of Herbal Compounds Commonly That Patients Use for Lyme Symptoms. the categories for each compound’s evidence include: (1) activity = +, (2) no activity = -, and (3) mixed activity = +/-^4-40

Common Name	Antibacterial	Anti-borrelia	Anti-inflammatory	Symptomatic (Other)
Andrographis5,6,14	+/-	-	+	+
Astragalus15,30	+	-	+	+
Berberine16,41	+	-	+	+
Cat’s claw5,17	+	+	+	+
Cordyceps18,31	+	-	+	+
Cryptolepis5,19	+	+	+	+
Chinese skullcap5,20,28	+	+	+	+
Garlic21,22	+	-	+	+
Japanese knotweed5,7,8	+	+	+	+
Sweet wormwood5,9,10,29,32,54	+	+	+	+
Reishi mushrooms23	+	-	-	+
Sarsaparilla11,24	+/-	-	+	+
Siberian ginseng25	-	-	+	+
Teasel root13	-	-	-	-
Lemon balm5,33,34	+	-	+	+
Peppermint5,26,35-37	+	-	+	+
Thyme13,27,38,39	+/-	+	+/-	+
Oil of oregano12,40	+	+	-	-

Antimicrobial Activity

Thirteen of the eighteen herbs had evidence of antimicrobial activity in vitro; three had mixed or weak data, and two had no data.^5-27 The thirteen with antimicrobial activity in vitro were: (1) astragalus, (2) berberine, (3) cat’s claw, (4) cordyceps, (5) cryptolepis, (6) Chinese skullcap, (7) garlic, (8) Japanese knotweed, (9) sweet wormwood, (10) reishi mushrooms, (11) lemon balm, (12) peppermint, (13) oil of oregano. The research team found inconclusive data regarding the antimicrobial activity of Andrographis, sarsaparilla, and thyme. No supporting evidence existed for antimicrobial activity in Siberian ginseng and teasel root.

Anti-borrelia Activity

Seven of the 18 herbs reviewed had evidence for in-vitro activity against B. burgdorferi. These compounds included: (1) cat’s claw,⁵ (2) cryptolepis,⁵ (3) Chinese skullcap,⁵ (4) Japanese knotweed,⁵ (5) sweet wormwood,⁵ (6) thyme,^5,13 and (7) oil of oregano.¹²

Recently, Feng et al investigated the anti-borrelia activity of 15 commonly used botanical medicines and three other natural antimicrobial agents, five of which were of interest for this review.⁵ Those researchers evaluated the compounds’ activity against growing and stationary cultures of B. burgdorferi, and they used antibiotic controls, cefuroxime and doxycycline. The researchers’ analysis included: (1) calculating the minimal inhibitory concentration (MIC); (2) determining the residual viability of the stationary phase at different herbal concentrations—1%, 0.5%, 0.25%; and (3) subculturing at 1% and 0.5%. Seven of the compounds studied demonstrated more activity against the stationary phase of B. burgdorferi compared to controls. Those compounds included cryptolepis, black walnut (Juglans nigra), Japanese knotweed, sweet wormwood, cat’s claw, Cistus incanus, and Chinese skullcap.

Those researchers also determined that Japanese knotweed and cryptolepis were the most potent against the replicating organism, with the lowest MICs, at MIC = 0.03-0.06% and MIC = 0.25-0.5%, respectively. Sweet wormwood, black walnut, and cat’s claw resulted in higher MICs, despite their antimicrobial activity against the non-growing forms. While compounds such as black walnut demonstrated activity, the researchers noted the clinically relevant side effect of skin pigmentation. The study also noted, in contrast to previous studies or to assumed anti-borrelia activity, that some of the commonly used products had little or no activity against B. burgdorferi: andrographis, stevia, grapefruit seed extract, Dipsacus spp, colloidal silver, monolaurin, and ashwagandha.

The other two compounds with evidence of anti-borrelia activity were oregano and thyme. Previously in 2017, Feng et al demonstrated in-vitro activity for oregano against B. burgdorferi.¹² Those researchers identified oregano as one of the most active essential oils in vitro given its complete eradication of the stationary phase of B. burgdorferi, even at a 0.05% concentration. Conversely, that study didn’t show any significant anti-borrelia activity for peppermint. In 2019, Goc et al demonstrated that thyme at a 0.2% concentration had bactericidal activity against spirochetes.¹³

It’s important to note that all studies reviewed for anti-borrelia activity were in vitro. Determination of clinical relevance requires further studies.

Symptomatic Activity

The correlation and underlying mechanism of symptoms that patients with PTLDS and CLD experience are unknown. These symptoms include fatigue or lethargy, musculoskeletal pain, arthritis-like pain, and decreased cognition or clarity. A common property of the herbs that the current review studied was anti-inflammatory activity.

Almost all the compounds, 15 out of 18, had documented anti-inflammatory properties^{6,8,9,11,15,16-19,22,28,35,36,38} Of those, five were among the previously described compounds that exhibited good anti-borrelia activity in vitro: Cat’s claw, cryptolepis, Japanese knotweed, sweet wormwood, and thyme.

Andrographis, astragalus, berberine, cordyceps, garlic, sarsaparilla, and peppermint lack anti-borrelia activity but possess potent anti-inflammatory properties.^{6,11,15,16,18,41} Oil of oregano was the only herb found to have a significant anti-borrelia activity that lacked any evidence of anti-inflammatory properties.

In addition to anti-inflammatory effects, some of the herbal compounds had potential benefits for other common symptoms of PTLDS and CLD. In a human clinical trial, Piscoya et al found that cat’s claw and Chinese skullcap had benefits for the treatment of pain and joint swelling in patients with osteoarthritis.⁴² Cat’s claw may also improve fatigue.⁴³ In a human clinical trial, Krebs et al studied sweet wormwood and found that it demonstrated a steroid-sparing effect in Crohn’s disease.²⁹ Puri et al studied its synthetic analog, artesunate, for patients with Lyme disease and found improvement with short-term memory.⁴⁴

Specific Compounds

As mentioned above, five herbal supplements and two essential oils demonstrated evidence for anti-borrelia activity in vitro. The compounds identified were Cat’s claw, cryptolepis, Chinese skullcap, Japanese knotweed, sweet wormwood, thyme, and oregano.

Cat’s Claw

Medical practitioners have used cat’s claw for inflammatory conditions for more than 2000 years.³⁰ Cat’s claw has demonstrated antimicrobial and anti-borrelia activity in vitro.⁵ It’s also an effective antioxidant and exerts potent anti-inflammatory effects as an immunomodulator via suppression of tumor necrosis factor alpha (TNF-α).⁴⁵

Preliminary clinical studies in humans have shown decreased pain for patients with osteoarthritis and a reduced number of painful and swollen joints in patients with rheumatoid arthritis in combination with standard treatment.⁴² In a prospective trial, cat’s claw found an increase in quality of life, social functioning, and fatigue for patients with advanced solid tumors.⁴³

Those three studies point to a modest benefit but are limited by small sample sizes (n = 40-51) and specific disease states. In terms of safety, Cat’s claw may be safe when used orally for a short period of time and may be associated with gastrointestinal adverse effects.^30,43

Cryptolepis

Medical practitioners have used Cryptolepis sanguinolenta to treat malaria, diarrhea, and various respiratory conditions.¹⁹ Feng et al found that Cryptolepis can have antibacterial and anti-borrelia activity in vitro.⁷ In a single animal study, Cryptolepis demonstrated analgesic and anti-inflammatory effects in rat-paw edema.¹⁹ Closely related Cryptolepis buchanani has demonstrated in-vivo analgesic, anti-inflammatory, and chondroprotective effects.⁴⁶

The full toxicity profile of Cryptolepis is unknown, but it has caused significant safety concerns in terms of antifertility effects and reproductive toxicity. Animal studies have shown that Cryptolepis may effect human reproductive systems.¹⁹

Chinese Skullcap

Traditional Chinese medicine has used Chinese skullcap as immune support and for various conditions, such as psychiatric disorders, anxiety, seizures, osteoarthritis, viral infections.³⁰ Baicalein and baicalin are two flavonoids commonly isolated from the Scutellaria genus.

Chinese Skullcap has demonstrated antibacterial, anti-borrelia, and anti-inflammatory activity in vitro.^5,20,28 Two studies demonstrated neuroprotective effects for baicalein, a flavonoid commonly isolated from the Scutellaria genus, in vivo and in vitro, and suggested that it may benefit patients with Parkinson’s disease.^47,48 While its neuroprotective effects have been demonstrated in vivo and in vitro, those effects have yet to be evaluated in human clinical studies.⁴⁹ Dinda et al found anti-inflammatory effects for baicalin in-vitro.²⁸

Flavocoxid, a medical food as established by the Food and Drug Administration (FDA), is a compound of two flavonoids, baicalin (Scutellaria baicalensis) and catechin (Acacia catechu). Levy et al found that flavocoxid, when compared to naproxen, can be effective in treating the symptoms of osteoarthritis.⁵⁰ Additionally, Arjmandi et al found that it can decrease perceived pain and stiffness in osteoarthritis of the knee.⁵¹ Flavocoxid has documented clinical safety but may cause sedation and acute liver toxicity⁵²

Japanese Knotweed

Japanese knotweed, also known as hu zhang, originates in Asia. It contains two active constituents, hydroxyanthraquinone and resveratrol. Traditional medicine has used it for various ailments, including wound healing.

Japanese knotweed has demonstrated antibacterial, anti-borrelia, and anti-inflammatory activity in vitro.^5,7,8 A review of several studies found evidence for antitumor, neuroprotective, and cardioprotective effects in animals, but no human clinical studies have occurred to date.⁷ Insufficient safety data exists for Japanese knotweed due to the lack of clinical data, but a human study of trans-resveratrol showed minimal toxicity with some gastrointestinal upset.⁷

Sweet Wormwood

Sweet wormwood is native to Europe, and traditional medicine has used it for over 2000 years. The herb has demonstrated antibacterial and anti-borrelia in vitro.⁵ In patients with Crohn’s disease, it has demonstrated anti-inflammatory activity in a small clinical study and a steroid-sparing effect in a double-blind study.²⁹

Tu Youyou for her study of sweet wormwood’s active antimalarial constituent, artemisinin, received the 2015 Nobel Prize.⁵³ In a small pilot study, the synthetic analog of the active constituent, artesunate, provided significant improvement in the short-term memory of patients with Lyme disease when combined with IV ceftriaxone.⁴⁴

Full understanding of the effects of sweet wormwood on persistent symptoms attributed to Lyme disease requires a randomized controlled trial. Limited safety data exists for it. Omer et al demonstrated that it’s safe for up to 6 months with some mild gastrointestinal upset at higher doses.⁵⁴ Of note, drinking wormwood oil purchased on the internet has been associated with numerous cases of acute renal failure.⁵⁵

Oregano and Thyme

People have cultivated oregano and thyme for culinary purposes. Both compounds have demonstrated antibacterial and anti-borrelia activity.^5,12 Preuss et al studied the active constituent in oregano, carvacrol, in mice and found that it was a useful agent against Staphylococcus aureus; however, testing related to human infections has yet to occur.⁵⁶

Oil of oregano lacks evidence of anti-inflammatory or other symptomatic activity. However, thyme may have some anti-inflammatory effects due to its ability to scavenge free radicals.³⁰ Both compounds have GRAS status when consumed in common amounts used in food, but insufficient evidence exists of their safety in high amounts.

Safety and Drug-Drug Interactions (DDI)

The importance of a thorough and comprehensive medication review for patients with PTLDS, CLD, or misdiagnosed Lyme can not be overstated. Polypharmacy in this population is common due to numerous comorbid conditions. An evaluation of the risk for drug-drug interactions is important when counseling patients.

The current review used the Natural Medicines Comprehensive Database to identify potential drug-drug interactions for the 18 compounds discussed above. The current research team considered the interactions’ ratings and severity when deciding what interactions to include. Table 2 summarizes the results.

Table 2.

Common Drug-drug Interactions of Herbal Compounds Commonly That Patients Use for Lyme Symptoms

Common Name	Drug Class Interactions	Mechanism for Drug Interaction	Medications to Avoid
Andrographis30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antihypertensive	Additive hypotension effects	ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, thiazide diuretics
Astragalus30	Lithium	Decreased excretion resulting in increased lithium concentrations
Berberine30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antidiabetes medications	Additive blood glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin
	Antihypertensive	Additive hypotension effects	ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, thiazide diuretics
	CNS depressants	Additive sedative effects	Benzodiazepines, opioid analgesics
	CYP2C9 Substrates	Inhibition of CYP2C9, increased substrate concentrations	Fluoxetine, glimepiride, glipizide, irbesartan, losartan, warfarin
	CYP2D6 Substrates	Inhibition of CYP2D6, increased substrate concentrations	Duloxetine, fluoxetine, metoprolol, ondansetron, oxycodone, paroxetine, tramadol, venlafaxine
	CYP3A4 Substrates	Inhibition of CYP3A4, increased substrate concentrations	Amiodarone, atorvastatin, diazepam, methadone, simvastatin, tacrolimus, warfarin
Cat’s Claw Bark30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antihypertensive	Additive hypotension effects	ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, thiazide diuretics
	CYP3A4 Substrates	Inhibition of CYP3A4, increased substrate concentrations
Cordyceps30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
Cryptolepis30
Chinese Skullcap30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antidiabetes medications	Additive blood glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin
	Antihypertensive	Additive hypotension effects	ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, thiazide diuretics
	CNS Depressants	Additive sedative effects	Benzodiazepines, opioid analgesics
	CYP2C19 Substrates	Inhibition of CYP2C19, increased substrate concentrations	Citalopram, diazepam, phenytoin, warfarin
	Lithium	Decreased excretion resulting in increased lithium concentrations
Garlic30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antidiabetes medications	Additive blood glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin
	Antihypertensive	Additive hypotension effects	ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, thiazide diuretics
	CNS depressants	Additive sedative effects	Benzodiazepines, opioid analgesics
	CYP3A4 Substrates
Japanese Knotwood30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	CYP2C19 Substrates	Inhibition of CYP2C19, increased substrate concentrations	Citalopram, diazepam, phenytoin, warfarin
	CYP3A4 Substrates	Inhibition of CYP3A4, increased substrate concentrations
Sweet wormwood30	None/ unknown
Reishi mushrooms30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antidiabetes medications	Additive blood glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin
	Antihypertensive	Additive hypotension effects	ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, thiazide diuretics
Sarsaparilla30	Digoxin	Increased absorption, increased concentrations
	Lithium	Decreased excretion, increased concentrations
Siberian Ginseng30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antidiabetes medications	Additive blood glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin
	CYP2D6 Substrates
	CYP3A4 Substrates	Inhibition of CYP3A4, increased substrate concentrations
	QTC prolonging medications	Possible increase of the QT interval and increasing the risk of ventricular arrhythmias	Fluoroquinolones, methadone
Teasel Root, teazle30	Limited information available
Lemon balm30	Antidiabetes medications	Additive blood-glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin
	CNS Depressants	Additive sedative effects	Benzodiazepines and opioid analgesics
Peppermint30	CYP2C19 substrates	Inhibition of CYP2C19, increased substrate concentrations	Fluoxetine, glimepiride, glipizide, irbesartan, losartan, warfarin
	CYP2C9 substrates	Inhibition of CYP2C9, increased substrate concentrations
	CYP3A4 substrates	Inhibition of CYP3A4, increased substrate concentrations
Thyme30	Anticholinergic	Inhibition of acetylcholinesterase, decreased efficacy of anticholinergic agents
	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Cholinergic	Increased effects
	Estrogens	Estrogen-receptor binding activity competitively inhibits the effects of estrogen replacement therapy
Oil of oregano30	Anticoagulant/ Antiplatelet	Additive antiplatelet effects	NSAIDs, warfarin, LMWH, Factor Xa inhibitors, direct thrombin inhibitors
	Antidiabetes medications	Additive blood-glucose lowering effects	Sulfonylureas, thiazolidinediones, meglitinides, insulin

Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; CYP2C19, cytochrome P450 family 2 subfamily C member 19; CYP2C9, cytochrome p450 family 2 subfamily c member 9 CYP3A4, cytochrome P450 family 3 subfamily A member 4 member; LMWH, low-molecular-weight heparins; NSAIDs, non-steroidal anti-inflammatory drugs.

It’s important to note that drug-drug interaction data for these compounds is in its infancy. The majority of the interactions are possible, with minimal data to fully elucidate the extent of the interaction. Clinicians should be particularly cautious in patients requiring medications for anticoagulation, hypertension, and diabetes as many of the identified compounds have additive effects and could lead to increased risks for bleeding, hypotension, and hypoglycemia. Patients for whom medical practitioners deem that the benefits for these compounds outweigh the risks should receive counseling to monitor for potential adverse effects related to DDIs.

Discussion

Many areas of controversy exist with respect to the treatment of Lyme disease. At the crux of the controversy is the issue of whether B. burgdorferi can cause a chronic, persistent infection. Researchers have proposed morphologic variants of B. burgdorferi, described as L-forms, cyst forms, spheroplasts or round bodies, and biofilm-like colonies, as causative agents of the persistent symptoms in CLD patients.

It should be noted that many other bacteria can assume these L-forms under certain conditions and can produce biofilms. A systematic literature review of morphologic variants did not support the role of B. burgdorferi variants in causing chronic persistent infection.⁵⁷

To the current research team’s knowledge, no human clinical studies have occurred that show a causative link between variants or between B. burgdorferi biofilms and persistent clinical disease. However, that link has been the basis for prolonged use of antibiotics and herbal supplements for anti-borrelia eradication by alternative practitioners who provide care to patients experiencing persistent symptoms attributed to Lyme disease.

Patients use many of the herbs reviewed in this article alone or in combination for an antimicrobial effects as well as for other reasons. The current review has demonstrated that some of the herbs that PTLDS, CLD, and misdiagnosed Lyme patients use for relief of persistent symptoms do have in-vitro activity against B. burgdorferi, but many do not.

The current review found that Cat’s claw, Cryptolepis, Chinese skullcap, Japanese knotweed, sweet wormwood, thyme, and oil of oregano can have anti-borrelial activity in vitro; however, their clinical efficacy against B. burgdorferi hasn’t been assessed, and therefore, their role in therapy is unclear.

It’s worth noting that many herbal medicines for HIV have been shown to have in vitro activity, but none of them have translated into effective antiviral therapy comparable to conventional antiretroviral therapy. Some herbs have shown antimicrobial activity but no anti-borrelial activity, such as peppermint, highlighting the fact that the extrapolation of antimicrobial activity in general may not translate into antimicrobial activity against Borrelia.

In addition, bacteria may develop resistance to essential oils after exposure. However, researchers have not studied the antimicrobial resistance of B. burgdorferi to these herbs, so it is unclear for what period they would have in-vitro efficacy after exposure. The effects of these herbs on the gastrointestinal (GI) microbiome is also unclear.

The symptoms that PTLDS, CLD, and misdiagnosed Lyme patients with chronic symptoms have attributed to Lyme disease include fatigue, musculoskeletal pain, cognitive issues, poor sleep, and mood issues. Almost all of the herbs reviewed have anti-inflammatory effects with the exception of oil of oregano and reishi mushrooms.

Notably, researchers have studied cat’s claw and Chinese Skullcap in human clinical trials, and they have shown benefits for pain and joint swelling in patients with osteoarthritis.^42,50 Similarly, almost all of the herbs have various symptomatic effects with the exception of teasel root and oil of oregano.

The 2020 guidelines for Lyme disease recommend that early infections be treated with 10-14 days of oral antibiotics; disseminated disease, with cardiac and neurologic involvement, with 14-21 days of intravenous (IV) or oral antimicrobial therapy; and arthritis or severe neurologic disease with 28 days of IV or oral antibiotics.² These are the recommended current therapies for Lyme disease, which can decrease risk of permanent infection-related damage.

While some of the herbs show in-vitro anti-borrelial activity, no clinical data exists for humans currently. More important, research has not shown that herbal therapy can prevent the development of the disseminated manifestations of Lyme disease. The authors do not recommend herbal treatment of Lyme disease attributed to an active infection.

In addition, many of the 18 herbs in the current study, individually and in combination, lack safety data. Drug interactions with anticoagulants, antihypertensives, antidiabetic, antiseizure, and other medications highlight the need for providers to be familiar with these supplements. Physicians and other care providers should ask all patients presenting for a Lyme evaluation about their use of herbal supplements and educate them regarding the lack of in-vivo efficacy, symptomatic effects, and drug interactions.

Conclusions

Many of the herbs that alternative and integrative practitioners use to treat Lyme disease have anti-inflammatory effects that may contribute to patients’ perceptions of symptomatic improvement. Some herbs demonstrated limited anti-borrelial activity in vitro, but in-vivo data and clinical trial data is lacking. Further research is required to determine the efficacy, safety and appropriate use of these herbs for the patient population.