Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide

Other Names

(2E,4E,8Z)-N-isobutyldodeca-2,4,8,10-tetraenamide(2E,4E,8Z,10E)-N-(2-methylpropyl)-2,4,8,10-dodecatetraenamide(2E,4E,8Z,10Z)-N-(2-methylpropyl)-2,4,8,10-dodecatetraenamide2,4,8,10-Dodecatetraenamide, N-(2-methylpropyl)-, (2E,4E,8Z,10Z)-2,4,8,10-Dodecatetraenamide, N-(2-methylpropyl)-, (E,E,Z,Z)-alkamide 8alkamide 9Dodeca-2,4,8,10-tetraenoic acid isobutylamideDodeca-2,4,8,10-tetraenoic acid isobutylamide E,E,Z,Z-isomerDodeca-2E,4E,8Z,10E-tetraenoic acid isobutylamideDodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamideDODECATETRAENOIC ACID ISOBUTYLAMIDE, (2E,2E,8Z,10Z)-DODECATETRAENOIC ACID ISOBUTYLAMIDE, (2E,4E,8Z,10Z)-N-(2-methylpropyl)-2,4,8,10-dodecatetraenamideN-isobutyl-2E,4E,8Z,10Z-dodeca-2,4,8,10-tetraenamideN-isobutyl-2E,4E,8Z,10Z-dodecatetraenamidetetraenes

Synopsis

Dodeca-2E,4E,8Z,10Z/10E-Tetraenoic Acid Isobutylamide

1. Identity and Chemical Characterization

Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide — commonly referred to alongside its geometric isomer dodeca-2E,4E,8Z,10E-tetraenoic acid isobutylamide and collectively denoted by the abbreviation DTAI — is a fatty-acid amide (alkylamide, or alkamide) belonging to the class of unsaturated N-alkylamides found in plants of the genus Echinacea. The compound is also referred to systematically as N-isobutyldodeca-2E,4E,8Z,10Z-tetraenamide, reflecting its isobutyl group connected via an amide bond to a twelve-carbon (dodecyl) chain bearing four conjugated and unconjugated double bonds. Dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide (CAS 866602-52-0) is a naturally occurring metabolite in Echinacea, one of the most widely used traditional herbal medicines.

This reference substance is a mixture of the 10E- and 10Z-isomers. The two geometric isomers differ only in the configuration of the terminal double bond (C-10), and they co-occur in Echinacea plant material and commercial preparations. The major alkamide is dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide, and it is used as the primary reference standard for quantification of echinacea products.

Alkamides are suspected to contribute to the activity of Echinacea preparations. They are mainly derived from undeca- and dodecanoic acid and differ in the degree of unsaturation and the configuration of the double bonds. In their isolated form, these compounds appear as off-white crystalline solids with a low melting point. The compounds should be handled at low temperatures or in a manner that minimizes heat exposure to prevent melting. Additionally, alkamides are susceptible to oxidative degradation, making it essential to limit their exposure to air.

1.1 Botanical Source

Many over-the-counter natural products are produced using either Echinacea purpurea (E. purpurea) or Echinacea angustifolia (E. angustifolia). In Echinacea purpurea, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide is the predominant compound, whereas in Echinacea angustifolia, the two tetraenes are present in roughly equal concentrations. Both species belong to the family Asteraceae and are native to North America. In total, seventeen alkamides have been identified in E. purpurea. A total of 24 alkylamides were identified by LC-MS in studies analyzing roots of both E. angustifolia and commercial dietary supplements. The alkylamide is concentrated principally in the roots and aerial parts of these species, with roots of E. angustifolia particularly rich in this class of lipophilic compounds.

Alkamides (alkylamides; fatty acid amides) are characteristic constituents of E. angustifolia roots, but are also found in roots and aerial parts of E. purpurea. On extraction, depending on the ratio of plant to solvent and fresh or dry, the data indicate that there is variability in the alkylamide classes extracted. For example, the acetylene alkylamides appear to extract under different concentrations, as well as degrade faster than the olefinic alkylamides. In addition, the alkylamides are found to degrade significantly in both cut/sift and powdered forms of echinacea root.

1.2 Common Forms and Preparations

Common formulations include teas, extracts, and capsules. Because DTAI is highly lipophilic, it is most effectively extracted into ethanolic (alcohol-based) preparations. Echinacea preparations are used for the treatment and prevention of upper respiratory tract infections. The phytochemicals believed responsible for the immunomodulatory properties are the alkylamides found in ethanolic extracts, with one of the most abundant being the N-isobutyldodeca-2E,4E,8Z,10Z-tetraenamide. The compound is found in standardized tinctures, pressed-juice preparations, tablets, lozenges, sprays, and glycerites. In commercial quality control, DTAI serves as the analytical marker compound for alkylamide content in standardized echinacea products.

2. Traditional and Historical Use

2.1 Indigenous North American Use

The botanical source plants — primarily E. angustifolia — have been used medicinally by indigenous peoples of North America for centuries. Purple coneflower (Echinacea angustifolia) and other Echinacea species have been the most widely utilized and important medicinal plants used by indigenous people of the Great Plains. The plant is still being harvested and used traditionally today in many tribal communities.

It has been used by at least 15 tribes in the region for a variety of ailments, including coughs, colds, inflammation, rabies, snakebite, sore throats, toothache, worms, and as a painkiller. The Kiowa used it for coughs and sore throats, the Cheyenne for sore throats, the Pawnee for headaches, and many tribes, including the Lakota, used it as a pain medication. A total of 19 tribes have been documented using Echinacea species, with Echinacea angustifolia being the best documented, primarily because little ethnobotany was reported from eastern and southern tribes in the USA.

Preparations employed in traditional indigenous contexts included chewing of the root — which produces the characteristic tingling sensation now understood to reflect alkylamide activity on sensory receptors — as well as decoctions and poultices applied to wounds, burns, insect bites, and skin infections. Archaeological digs have found evidence of echinacea use by the Lakota Sioux dating back to the 17th century.

2.2 Adoption into Western Herbal and Eclectic Medicine

Lewis and Clark learned about it during their Expedition and in 1805 shipped the roots and seeds back to President Jefferson as one of their more important finds. Euro-American medical botanists recognized Echinacea in publications as early as 1830. By the latter half of the 19th century, Echinacea preparations became widely used within the American Eclectic medical tradition. These extracts were a previously popular remedy relied on by U.S. physicians, one of the top sellers in the natural products industry, and are currently a frequently physician-prescribed remedy in Germany. The traditional contexts of use — upper respiratory infections, wound healing, pain, and inflammatory conditions — have directly shaped the research questions that modern scientists have pursued with the alkylamide fraction.

3. Key Constituents and Active Compounds

3.1 The Alkylamide Class in Echinacea

Four classes of compounds are known to contribute to the immunomodulatory activity of Echinacea extracts: alkamides, glycoproteins, polysaccharides, and caffeic acid derivatives (CADs). Alkamides, caffeic acid derivatives, polysaccharides, and glycoproteins are considered to be the compounds responsible for this plant's immunostimulatory and anti-inflammatory effects. Among these, the alkylamides — and specifically DTAI — are considered the most bioavailable and pharmacologically active fraction in ethanolic preparations.

Over 20 different alkylamides are found in the Echinacea species used therapeutically, with the two major ones being the N-isobutyldodeca-2E,4E,8Z,10E/Z-tetraenamides. The biological activities of Echinacea are considered to be the result of a combined action of several alkylamides, rather than of a single compound. Nevertheless, DTAI is consistently the single most abundant alkylamide and has been the primary focus of pharmacological investigations.

3.2 Isolation and Analytical Characterization

From roots of E. angustifolia, isolation procedures have yielded dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide (38.9 mg, 97% purity), dodeca-2E,4E,8Z-trienoic acid isobutylamide (4.4 mg, 92% purity), dodeca-2E,4E-dienoic acid isobutylamide (3.2 mg, 99% purity), and dodeca-2E,4E-dienoic acid 2-methylbutylamide (0.3 mg, 92% purity). The identity and purity of the isolated alkylamides were confirmed by LC-ESI-MS and ¹H NMR and ¹³C NMR data.

Alkylamides are a class of compounds present in plants of the genus Echinacea (Asteraceae), which have been shown to have high bioavailability and immunomodulatory effects. For the most abundant alkylamides — dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (DTAI) — an LC-MS/MS assay has been developed and validated for quantification in human plasma.

4. Mechanisms of Action

4.1 Cannabinoid Receptor Binding (CB2 and CB1)

The most extensively studied molecular mechanism of DTAI involves binding to cannabinoid receptors, particularly the cannabinoid type 2 (CB2) receptor, which is expressed predominantly on immune cells. The alkylamides dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1) and dodeca-2E,4E-dienoic acid isobutylamide (A2) bind to the CB2 receptor more strongly than the endogenous cannabinoids. The Ki values of A1 and A2 (CB2 approximately 60 nM; CB1 >1500 nM) were determined by displacement of the synthetic high-affinity cannabinoid ligand [³H]CP-55,940. This nanomolar affinity for CB2 with markedly lower affinity for CB1 suggests a peripheral immunomodulatory action without the psychoactive effects associated with CB1 activation.

Molecular modeling suggests that alkylamides bind in the solvent-accessible cavity in CB2, directed by H-bonding and pi-pi interactions. In a screen with 49 other pharmacologically relevant receptors, it could be shown that A1 and A2 specifically bind to CB2 and CB1.

4.2 Modulation of TNF-α and Cytokine Expression via Multiple Signal Transduction Pathways

A study of the main constituents of echinacea extract showed that the alkylamides dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (1/2), trienoic (3) and dienoic acid (4) derivatives are responsible for TNF-α mRNA modulation. The upregulation of TNF-α mRNA was found to be mediated by CB2 receptors, increased cAMP, p38/MAPK and JNK signaling, as well as NF-κB and ATF-2/CREB-1 activation. This study was the first to report a possible molecular mechanism of action of Echinacea, highlighting the role of alkylamides as potent immunomodulators and potential ligands for CB2 receptors.

The immune-modulatory effects of DTAI are context-dependent and bidirectional. This implies a bidirectional, homeostatic capacity: the ability to downregulate pro-inflammatory mediators (such as TNF-α and IL-6) via CB2 activation during states of hyperinflammation, while simultaneously maintaining or enhancing innate surveillance mechanisms (such as phagocytosis) to protect against infection.

4.3 CB2-Dependent and CB2-Independent Effects

A1, A2, anandamide, the CB2 antagonist SR144528, and also the non-CB2-binding alkylamide undeca-2E-ene,8,10-diynoic acid isobutylamide all significantly inhibited lipopolysaccharide-induced tumor necrosis factor alpha, IL-1β, and IL-12p70 expression (5–500 nM) in a CB2-independent manner. Overall, alkylamides, anandamide, and SR144528 potently inhibited lipopolysaccharide-induced inflammation in human whole blood and exerted modulatory effects on cytokine expression, but these effects are not exclusively related to CB2 binding. This finding is important because it demonstrates that DTAI operates through multiple and partially redundant molecular pathways.

4.4 Pleiotropic Effects on the Endocannabinoid System

N-alkylamides act in concert and exert pleiotropic effects modulating the endocannabinoid system by simultaneously targeting the CB2 receptor, endocannabinoid transport, and degradation. In vitro synergy studies demonstrate that superadditive action of N-alkylamide combinations was seen at the level of intracellular calcium release as a function of CB2 receptor activation. Likewise, synergism of the radix and herba tinctures was observed in experiments measuring LPS-stimulated cytokine expression from human PBMCs. While the expression of the anti-inflammatory cytokine IL-10 was significantly superstimulated, the expression of the pro-inflammatory TNF-α protein was inhibited more strongly upon combination of the extracts.

4.5 Macrophage Stimulation

Using male Sprague–Dawley rats (425–475 g), an in vivo study was conducted to examine the immunomodulatory effects of various dose levels of three components isolated and purified from Echinacea purpurea. The components were cichoric acid, polysaccharides, and alkylamides. The rats were gavaged orally two times per day for 4 days with three different concentrations of each of the Echinacea components. Among the components, alkylamides at the dose level of 12 µg/kg body weight/day significantly increased the phagocytic activity as well as the phagocytic index of the alveolar macrophages. This represents animal (rodent) evidence only; the specific dose–response relationship in humans has not been directly reproduced.

4.6 Metabolism by Cytochrome P450 Enzymes

Cytochrome P450 enzymes (P450s) appear to be the principal system responsible for the metabolism of Echinacea components, and most of the main hepatic and some extrahepatic isoforms appear to be involved. Epoxide formation, N-dealkylation, and hydroxylation are the main metabolic pathways mediated by P450s. Interactions with P450s determine the circulating concentrations and duration of action of these phytochemicals, as well as any potential interactions with other chemicals.

In a study examining human liver microsome metabolism of DTAI specifically: In incubations with human liver microsomes and selective inhibitors, CYP2E1 was found to be principally responsible for producing the dominant hydroxylation product, whereas CYP2C9 was the principal source of the epoxides and CYP1A2 was responsible for the dealkylation product. Human liver microsome oxidation of the major alkylamide dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide generates hydroxylated, carboxylated, and epoxidized metabolites.

5. Bioavailability and Pharmacokinetics

5.1 Oral Absorption in Humans

DTAI is notable among phytochemicals for its demonstrated oral bioavailability in humans. The main alkylamides are the isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (DTAI), which are likely to cross the intestinal barrier. Oral bioavailability of DTAI has been demonstrated in rats and humans.

In preliminary experiments, a quantification method for dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides in human blood was developed by which it was possible to detect dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides in human blood after oral application of Echinacea purpurea mother tincture. After oral administration of a commercial preparation (alkamides 9 mg or 0.07 mg), alkamides are already found in the range of 136 or 0.4 ng/ml in human serum after approximately 30 min.

After oral application of a tincture or tablets with an alkamide concentration of 0.07 mg each, the alkamides from the tincture were detectable after 30 min at 0.4 ng/ml and from the tablets after 45 min at 0.12 ng/ml serum. This indicates that liquid preparations achieve faster absorption than solid tablet forms, though both are bioavailable. The trend observed was that the higher the unsaturation of the alkylamide, the higher the absorbability.

5.2 Brain Penetrance

Dodeca-2E,4E,8Z,10Z/E-N-tetraenoic acid isobutylamide is a brain-penetrant substance and the main alkamide in Echinacea preparations. The lipophilic character of the compound is consistent with its ability to cross the blood-brain barrier, a property that distinguishes it from the hydrophilic caffeic acid derivatives (e.g., cichoric acid) also found in Echinacea. Studies using Caco-2 monolayers have shown that Echinacea alkylamides should easily cross the intestinal barrier and be present in plasma, while caffeic acid conjugates are unlikely to pass the intestinal barrier and thus not appear in circulation.

5.3 Bioavailability in Children

A registered clinical bioavailability trial (ClinicalTrials.gov NCT03070314) investigated DTAI pharmacokinetics in pediatric populations. This bioavailability trial was designed to show that the alkylamide dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide (short: tetraen) is bioavailable in children of different age groups after intake of five Echinaforce junior tablets. Six capillary blood draws were taken at the following time points: start (0), after 15, 30, 60, 90, and 270 minutes, and thereafter the bioavailability was measured and calculated.

6. Scientific Evidence by Area of Use

6.1 Upper Respiratory Tract Infections (URTIs) and the Common Cold

This is the primary area of clinical investigation for DTAI-containing echinacea preparations. The body of evidence is large but heterogeneous due to differences in species, plant part, extraction method, and alkylamide standardization across studies.

Cochrane Review (2014): Twenty-four double-blind trials with 4,631 participants, including a total of 33 comparisons of Echinacea preparations and placebo, met the inclusion criteria. A variety of different Echinacea preparations based on different species and parts of plant were used. The majority of trials investigated whether taking Echinacea preparations after the onset of cold symptoms shortens the duration, compared with placebo. Although it seems possible that some Echinacea products are more effective than a placebo for treating colds, the overall evidence for clinically relevant treatment effects is weak. In general, trials investigating Echinacea for preventing colds did not show statistically significant reductions in illness occurrence. However, nearly all prevention trials pointed in the direction of small preventive effects.

Regarding specific risk reduction estimates from this body of evidence: The Cochrane review concluded that there was no plausible evidence for the treatment of the common cold. However, "at least some Echinacea preparations may reduce the relative risk of catching a cold by 10% to 20%." The Cochrane reviewers explicitly attributed a major source of uncertainty to product heterogeneity: the 24 studies included in that review employed an appreciable variety of products, primarily alcohol tinctures, tablets from dried extracts, and pressed juices. Products were derived from either the root, aerial parts, or both, and only some were standardized to one or more different constituents in varying percentages. This heterogeneity, along with a significant number of nondisclosed preparation methods, manufacturers, and extraction methods, was cited as the primary reason for the lack of conclusive evidence.

NCBI/DARE Systematic Review: Thirteen RCTs with 2,416 participants were included in the review. Nine RCTs (n=1,264) evaluated treatment effectiveness, while four RCTs (n=1,152) evaluated prevention. In the treatment of acute URI, 8 of the 9 RCTs reported some evidence of a benefit of Echinacea. There was a moderate degree of methodological deficiency in all of the reviewed studies, and statistical significance was not reached for all outcomes. Nevertheless, the published evidence supports the ability of Echinacea to decrease the severity and duration of acute URI. The evidence for the ability of Echinacea to prevent rather than treat URI was not as promising.

Memorial Sloan Kettering Cancer Center Summary of Clinical Data: Clinical data indicate that echinacea is ineffective in preventing the common cold caused by rhinoviruses or in treating upper respiratory infections, but positive findings were reported with higher doses. Studies of its ability to reduce incidence and duration of the common cold yielded mixed results. Other analyses do not indicate any benefits for treating colds, and weak evidence for a prophylactic benefit; but a large randomized trial found an echinacea formulation to be as effective as oseltamivir for influenza, and with fewer adverse events in the echinacea group.

Higher-Dose Randomized Blinded Controlled Trial (2023): A trial in healthy adults (n=409) tested novel Echinacea formulations at higher therapeutic doses. In this randomized, blinded, controlled trial, healthy adults (n=409) were randomized between November 2018 and January 2019 to one of four Echinacea formulations, which were taken in case of an RTI for up to 10 days. New formulations A (lozenges) and B (spray) delivered an increased dose of 16,800 mg/d Echinacea extract during days 1–3 and 2,240–3,360 mg/d afterward; as controls, conventional formulations C (tablets) and D (drops) delivered a lower daily dose of 2,400 mg. Among those with an identified respiratory virus, viral clearance until day 10 based on real-time PCR from nasopharyngeal swabs was more frequent with new formulations (70 vs. 53%, p=0.046). The majority of adverse events were related to the known and expected "tingling" sensation of alkylamides in the more highly concentrated new formulations.

Air-Travel RCT (Alkylamide-Standardized): 175 adults participated in a randomised, double-blind placebo-controlled trial travelling back from Australia to America, Europe, or Africa for a period of 1–5 weeks on commercial flights via economy class. Participants took Echinacea (root extract, standardised to 4.4 mg alkylamides) or placebo tablets. This study is notable for directly reporting the alkylamide dose used, rather than merely the extract weight.

Cytokine Review (COVID-19 Context): In a review of 17 clinical trials involving 3,363 participants, echinacea supplements were found to affect reductions in pro-inflammatory cytokines that play a role in the progression of cytokine storm and acute respiratory distress syndrome (ARDS).

Overall evidence strength for URTIs: Moderate to low. While most individual RCTs trend toward modest benefit (particularly for treatment duration), the totality of evidence is difficult to interpret because of product heterogeneity. Preparations standardized to alkylamide content, particularly DTAI, are the most pharmacologically characterized and may differ meaningfully from non-standardized or polysaccharide-dominant preparations. The German Commission E, WHO, and Canadian Natural Health Products Directorate have recognized echinacea use for the common cold, as noted by an evaluating meta-analysis. The German Commission E, WHO, and the Canadian Natural Health Products Directorate have advocated echinacea use for the common cold.

6.2 Anti-Inflammatory Activity

The anti-inflammatory evidence for DTAI is substantial at the in vitro and molecular level, but direct human clinical evidence is limited to secondary outcome measurements in URTI trials. Pharmacologically, these alkamides have immunomodulatory and anti-inflammatory activities. CB2 activation by DTAI triggers an intracellular signaling cascade that modulates cAMP levels and downregulates pro-inflammatory cytokines (TNF-α, IL-6) without fully suppressing the immune surveillance machinery. In vitro, LPS-stimulated cytokine expression (TNF-α, IL-1β, IL-12p70) is inhibited by DTAI at concentrations of 5–500 nM in human whole blood. This evidence is preclinical (cell-based or animal), and direct clinical trials targeting inflammation specifically with isolated DTAI do not yet exist.

6.3 Antiviral Activity

In vitro, echinacea extract has antiviral activity, especially against enveloped viruses including influenza, parainfluenza viruses, coronaviruses (including SARS-CoV-2), or respiratory syncytial virus, and considerably less antiviral activity against non-enveloped viruses such as rhinovirus and adenovirus. With respect to specific alkylamides: although previous research suggests that the alkylamides present in Echinacea may be responsible for reducing the symptoms associated with the common cold or flu through their immunomodulatory activity, the roles of specific alkylamides and their targets have not been well-elucidated or established. This study tested the antiviral and cytokine regulatory activity of various specific alkylamides that are present predominantly in Echinacea root extracts and found that one specific alkylamide, dodeca-2E,4E-dienoic acid isobutylamide, had potent antiviral activity. Importantly, this study found that the antiviral activity was attributed to the dienoic (2-double bond) alkylamide rather than DTAI itself, although both are present together in extracts and their combined effects are difficult to disentangle clinically.

6.4 Macrophage Phagocytosis and Innate Immunity

Animal-level evidence indicates that the alkylamide fraction, at specific doses, enhances macrophage phagocytic activity. Alkylamides at the dose level of 12 µg/kg body weight/day significantly increased the phagocytic activity as well as the phagocytic index of the alveolar macrophages in rats. This represents animal data only; direct human confirmatory studies with isolated DTAI are lacking.

7. Body Systems and Health Areas

Immune system: The primary body system associated with DTAI. Alkylamides are a group of active components of the widely used herb Echinacea purpurea, which have immunostimulatory and anti-inflammatory effects. Effects span innate immune activation (macrophage phagocytosis, NK cells) and modulation of adaptive immune cytokines.
Respiratory system: Echinacea purpurea extracts are used in the production of standardized herbal medicines for the prevention and treatment of upper respiratory infections. DTAI is understood to contribute to both local (mucosal) and systemic effects via its immunomodulatory and potential antiviral activities.
Endocannabinoid system: Unsaturated N-alkylamide lipids, the main constituent of E. purpurea and E. angustifolia preparations capable of activating the cannabinoid receptor type-2 (CB2), have been suggested to play a role as potential anti-inflammatory and immune-modulatory principles. DTAI is currently considered the principal natural cannabinomimetic of plant origin that selectively targets CB2 over CB1.
Central nervous system: DTAI is brain-penetrant and binds, with much lower affinity, to CB1 receptors. Although this has raised interest in potential anxiolytic or neuromodulatory effects, clinical evidence in this area remains preliminary and is based predominantly on animal studies.
Oral/mucosal tissue: The well-documented tingling or numbing sensation caused by chewing echinacea root — historically used in toothache treatment by Native Americans — is attributed to the local sensory activity of alkylamides on oral mucosa.

8. Dosage Forms and Reported Dosages

Clinical studies have administered DTAI indirectly as part of standardized echinacea extracts. The compound is not currently available as an isolated single-ingredient supplement; all human dosing data involves preparations where DTAI is the dominant alkylamide quantified.

Alkylamide-standardized tablets (air travel RCT): Root extract standardised to 4.4 mg alkylamides per dose.
Mother tincture (bioavailability study): Oral application of Echinacea purpurea mother tincture; detection of DTAI in blood confirmed with a preparation containing 0.07 mg alkamides, yielding serum levels of 0.4 ng/ml at 30 minutes.
High-dose acute RTI treatment (2018–2019 RCT): New formulations delivered an increased dose of 16,800 mg/d Echinacea extract during days 1–3 and 2,240–3,360 mg/d afterward; conventional formulations delivered a lower daily dose of 2,400 mg.
Echinacea root (cold treatment study by Barrett et al.): Subjects consumed two tablets at enrollment, followed by two-tablet doses three more times within 24 hours of enrollment. Dosing then went to one tablet four times daily for the next four days. Each participant ingested the equivalent of 10.2 g of dried echinacea root during the first 24 hours and the equivalent of 5.1 g during each of the next four days.
Rat model (macrophage study): Gavaged orally two times per day for 4 days; alkylamides at the dose level of 12 µg/kg body weight/day significantly increased the phagocytic activity of alveolar macrophages (animal data only).

Because commercial products vary substantially in alkylamide content and because DTAI is not sold in isolation for human use, no universal human dose of DTAI itself has been established by any regulatory authority or pharmacopoeial monograph.

9. Safety Considerations and Drug Interactions

9.1 General Tolerability

The number of patients dropping out or reporting adverse effects did not differ significantly between treatment and control groups in prevention and treatment trials. Although adverse events with echinacea are not commonly reported, gastrointestinal upset and rash have been reported. Much more work needs to be done to elucidate the safety of prolonged therapy since its effect on the rate-corrected QT interval, blood pressure, and other safety parameters is not well known.

A characteristic sensory effect of DTAI — a tingling or numbing sensation on oral mucosa — is a pharmacodynamic effect rather than an adverse event, but it is reported more frequently at higher alkylamide concentrations. The majority of adverse events in the higher-dose trial were related to the known and expected "tingling" sensation of alkylamides in the more highly concentrated new formulations.

9.2 Allergic and Hypersensitivity Reactions

There was one severe adverse event with a potential hypersensitivity reaction in a recipient of the novel spray formulation in a 2023 RCT. Individuals with known hypersensitivity to plants of the Asteraceae/Compositae family should exercise caution with echinacea products, as cross-reactivity has been described.

9.3 Cytochrome P450 and Drug Interactions

There is conflicting evidence about whether echinacea interacts with some drugs metabolized by the liver, and there are theoretical reasons to suspect that echinacea might interact with immunosuppressants or caffeine.

In vitro research has demonstrated mild CYP inhibitory activity by alkylamides. However, at the level of CYP gene transcription: neither Echinaforce nor the alkylamides produced any significant changes in the steady-state CYP3A4 mRNA levels in HepG2 cells at clinically relevant concentrations. We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs.

A dedicated clinical pharmacokinetic interaction study was conducted with the cancer drug docetaxel: The multiple treatment of E. purpurea did not significantly alter the pharmacokinetics of docetaxel in this study. The applied E. purpurea product at the recommended dose may be combined safely with docetaxel in cancer patients. However, a case report has described a potential interaction with etoposide, and theoretical concerns remain for other CYP-metabolized drugs. In two small studies, no impact of echinacea on docetaxel or etravirine pharmacokinetics was found; however, a case report describes an interaction with etoposide.

Most research to date has focused on the potential of Echinacea to interact with other drugs. Literature reports are equivocal and comparisons between studies are difficult as the phytochemical composition of the preparations examined is rarely assessed. This last point is especially significant: the alkylamide content — and specifically DTAI concentration — of the preparation studied is often undisclosed, making it impossible to attribute interaction findings to any specific constituent.

9.4 Immunosuppressant Concern

Because DTAI and related alkylamides modulate immune function via CB2 and related pathways, there are theoretical reasons to suspect that echinacea might interact with immunosuppressants. This concern is based on pharmacological reasoning rather than documented clinical cases, but it is acknowledged in monograph literature.

9.5 Pregnancy and Lactation

Some studies of the use of solid or liquid extracts of E. purpurea and E. angustifolia suggest it is possibly safe for up to 7 days during the first trimester of pregnancy. Little is known about whether it's safe to use echinacea while breastfeeding. Evidence specific to DTAI in pregnancy is not separately available.

9.6 Product Variability and Standardization

Most consumers and physicians are not aware that products available under the term Echinacea differ appreciably in their composition, mainly due to the use of variable plant material, extraction methods, and the addition of other components. Because DTAI degrades on heat exposure and oxidation, and because alkylamide content varies substantially between dry powders and ethanolic extracts, the effective DTAI dose delivered by any commercial product may differ substantially from the labeled extract weight. Alkylamides are found to degrade significantly in both cut/sift and powdered forms of echinacea root.

References

Health Conditions

Health conditions that Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide may help support.

No conditions available.

Body Systems

Body systems that Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide may help support.

No body systems available.