Anatabine
Identity and Chemical Characterization
Anatabine is one of the minor alkaloids found in plants in the family Solanaceae, which includes the tobacco plant and tomato. Anatabine has the molecular formula C10H12N2, a molecular weight of 160.22 g/mol, and is chemically designated as 1,2,3,6-tetrahydro-2,3′-bipyridine. It falls within the category of pyridine alkaloids and demonstrates both photosensitivity and hygroscopic properties.
Anatabine features a chiral center at the C-2 position of the partially hydrogenated ring, resulting in the formation of two enantiomers: (R)-anatabine and (S)-anatabine. The (S)-enantiomer is the dominant form, representing approximately 85% of the naturally occurring compound. Both anatabine and nicotine contain a pyridine ring and a basic nitrogen atom—features critical for bioactivity.
Natural Sources
Commercial tobacco plants typically produce alkaloids at levels between 2% and 4% of total dry weight, with nicotine accounting for about 90% of the total alkaloid content, and the related compounds anatabine, nornicotine, and anabasine making up nearly all the rest. These compounds are thought to be biologically active, and part of plants' natural defense system against insects.
Beyond tobacco, anatabine is found at trace levels in several widely consumed vegetables. Anatabine is an alkaloid found in plants of the Solanaceae family, including tobacco, tomatoes, potatoes, peppers, and eggplants. Anatabine is among the pharmacologically active alkaloids present in tobacco and a variety of foods, including green tomatoes, green potatoes, ripe red peppers, tomatillos and sundried tomatoes, albeit in low concentrations.
Biosynthesis
Radiolabeling experiments have demonstrated that the biosynthesis of anatabine differs from that of the other tobacco alkaloids in that both rings are derived from nicotinic acid. Although the specific enzymes have still not been identified, it has been suggested that 3,6-dihydronicotinic acid is involved in the biosynthetic pathway.
Commercial Preparations and Salts
The commercial dietary supplement Anatabloc contained the dietary ingredient anatabine citrate — the citrate salt form of anatabine — found in a variety of Solanaceae plants. Anatabine citrate, combined with vitamins A and D3, was formulated as an anti-inflammatory support product. Anatabine may be extracted from tobacco and presumably from other sources in the food supply, or prepared synthetically.
Traditional and Historical Use
Anatabine does not have a documented tradition of deliberate isolation or use as a distinct therapeutic agent in any historical medical system. As a trace constituent of common dietary vegetables, anatabine has been in the human food supply and in human use for centuries. Humans are exposed to anatabine in tobacco products and common and widely consumed food crops such as potatoes, peppers, eggplants, and tomatoes.
The modern commercial history of anatabine as an intentional supplement is brief and specific. Anatabine was marketed from 2011 to 2014 (Anatabloc, Star Scientific Inc.) as a dietary supplement and as an active ingredient in a facial cream with anti-inflammatory properties. Star Scientific developed and sold the compound as a dietary supplement primarily through GNC up until mid 2014. Subsequently, Rock Creek Pharmaceuticals (formerly a subsidiary of Star Scientific) began developing anatabine as a drug. The dietary supplements were known as Anatabloc and CigRx; the company also marketed cosmetics with the Anatabloc brand.
In 2013, Star Scientific became embroiled in political scandal involving the governor of Virginia; the accumulated legal costs from the defense of Jonnie Williams in the McDonnell scandal overwhelmed the company's finances and it filed for bankruptcy in 2016. As a consequence, the development and clinical trials of anatabine were halted indefinitely.
Regulatory History
In a December 20, 2013 warning letter, the FDA claimed Star Scientific needed to submit a New Dietary Ingredient (NDI) notification to the agency because anatabine was a new ingredient that had not been present in the food supply in a form that had not been chemically altered. While acknowledging that "anatabine is present as an inherent constituent of foods such as cauliflower, eggplant, potatoes, and tomatoes," FDA said it was unaware of any information indicating that anatabine itself had been marketed as an article of food.
The FDA's letter stated that anatabine, used in two of the company's products — Anatabloc and CigRx — was a new dietary ingredient that required premarket notification to the agency. It also stated that the company's products were unapproved new drugs based on statements on the company's website. According to the FDA, tobacco and its constituents, including anatabine, are barred from dietary supplement status. In 2013 the FDA warned Star Scientific for unlawfully promoting CigRx and Anatabloc before anatabine was proved to be safe. Subsequently, new management and a mostly new board under the banner of Rock Creek Pharmaceuticals withdrew the dietary supplement because of the FDA's concerns.
Key Constituents and Active Compounds
Anatabine itself is the primary active compound of interest in all studied preparations. Commercially, it was formulated as its citrate salt. Target prediction using the SwissTargetPrediction database indicates that anatabine and nicotine share common target proteins, reflecting their closely related chemical structures.
Established Mechanisms of Action
Inhibition of NF-κB and STAT3 Signaling
The most extensively studied mechanism of anatabine is its inhibition of two central pro-inflammatory transcription factors. At the molecular level, anatabine inhibits the activity of two transcription factors that are involved in cellular inflammatory response — NF-κB (nuclear factor-kappa B) and STAT3 (signal transducer and activator of transcription 3) — both in vivo and in vitro. In addition, it decreases lipopolysaccharide (LPS)-induced TNFα and IL-6 levels in a dose-dependent manner while increasing the levels of the anti-inflammatory cytokine IL-10 in vivo.
Data show that anatabine prevents STAT3 and NFκB phosphorylation induced by LPS or TNF-α in SH-SY5Y cells, HEK293 cells, human microglia, and human blood mononuclear cells. Using human whole blood, anatabine was found to prevent IL-1β production induced by LPS.
Nicotinic Acetylcholine Receptor Activity
It has been proposed that the in vitro and in vivo inhibition of NF-κB and STAT3 activity by anatabine was downstream of α7 nicotinic acetylcholine receptor (nAChR) binding. This hypothesis was in line with findings that anatabine was capable of stimulating both α7 and α4β2 nAChR subtypes with differential potency. Furthermore, this is consistent with the notion that activation of non-neuronal α7 nAChRs can downregulate the intracellular JAK2–STAT3–NF-κB and PIK3/Akt–Nrf2 pathways in immune cells, leading to suppression of pro-inflammatory cytokine production.
Anatabine was found to be a weaker agonist for nAChRs than nicotine. The mechanism of action of dietary anatabine on thyroid autoimmunity remains to be elucidated, but it may produce immunomodulatory effects through activation of α4β2 or α7 cholinergic receptors similar to nicotine and other structurally related agonists.
NRF2 Pathway Activation
Systems pharmacology research has verified, using an appropriate luciferase reporter cell system, that anatabine treatment results in NRF2 translocation. This finding, published in Frontiers in Pharmacology (2022), adds a cytoprotective and antioxidant pathway to the previously identified anti-inflammatory mechanisms, though the relative contribution of NRF2 activation to anatabine's overall effects remains under investigation.
Monoamine Oxidase Inhibition
At maximal or saturating inhibition concentrations, anatabine was effective at inhibiting monoamine oxidase (MAO) activity by approximately 60%. This result suggested that anatabine may be much safer as a medication than standard MAO enzyme inhibitors. Anatabine was effective at inhibiting the enzyme at all time points in the reaction, and was equally effective in inhibiting both MAO A and MAO B activities. This activity was demonstrated in vitro and reported in a U.S. patent application; its relevance at dietary exposure levels has not been confirmed in human clinical studies.
iNOS and COX-2 Suppression
Multiple preclinical studies have demonstrated that anatabine has anti-inflammatory effects in vitro and in vivo. Anatabine has been shown to inhibit NF-κB and STAT3 phosphorylation in animal models of Alzheimer's disease and multiple sclerosis, acting to reduce the production of pro-inflammatory cytokines and other markers of inflammation, and to reduce cell and tissue damage caused by overproduction of these molecules. Anatabine administration was found to attenuate multiple manifestations of thyroid autoimmunity in an animal model of Hashimoto's thyroiditis, and in vitro it dose-dependently suppressed macrophage production of iNOS and COX-2, two enzymes that increase dramatically during proinflammatory states.
Pharmacokinetics
In vivo pharmacokinetics and anti-inflammatory profile of anatabine were characterized in rodents. Anatabine was found to be bioavailable and brain-penetrant following systemic administration. In particular, it has been shown that anatabine inhibits NF-κB signaling and readily crosses the blood-brain barrier, suggesting it could represent a suitable agent to treat neuroinflammatory disorders.
Scientific Evidence by Area of Use
1. Inflammation and Systemic C-Reactive Protein
Preclinical (animal/in vitro) evidence: Anatabine's anti-inflammatory activity was assessed in vivo using an acute model of inflammation by challenging wild-type mice with LPS. Anatabine reduced pro-inflammatory cytokine production (IL-6, IL-1β, and TNF-α) in the plasma, kidney and spleen of the animals following injection of LPS and concomitantly opposed STAT3 phosphorylation induced by LPS.
Following intraperitoneal administration (1, 2, and 5 mg/kg), anatabine caused a dose-dependent reduction in carrageenan-induced paw edema in rats; in mice, it inhibited the production of pro-inflammatory cytokines and simultaneously elevated the levels of an anti-inflammatory cytokine in a dose-dependent manner 2 hours after lipopolysaccharide challenge.
Human/clinical evidence: A clinical trial was registered (NCT01607619) to evaluate the effects of anatabine dietary supplementation on blood levels of C-reactive protein in human subjects. The main purpose of this study was to evaluate the effects of the dietary supplement on normal human inflammatory function. Compounds chemically similar to anatabine have been shown to reduce inflammatory responses, and laboratory studies showed anti-inflammatory properties for anatabine. The investigators sought to explore this further in human studies. However, full published results of this trial are not available in the peer-reviewed literature, as clinical development was halted following the company's bankruptcy in 2016.
Evidence strength: Preclinical evidence is robust across multiple cell types and animal models. Definitive human clinical evidence for general anti-inflammatory use is absent.
2. Autoimmune Thyroiditis (Hashimoto's Disease)
Preclinical evidence: Caturegli et al. investigated the effects of anatabine in a mouse model of autoimmune thyroiditis and found that anatabine significantly reduced several markers of systemic inflammation.
Human clinical evidence: A clinical trial was designed to assess the effects of anatabine dietary supplementation in patients with Hashimoto's thyroiditis. This was a multicenter, double-blind, placebo-controlled, randomized clinical trial. A total of 146 patients (70 treated with anatabine and 76 with placebo) completed the study. Approximately 50% of patients in each group were taking levothyroxine. Anatabine lozenges (9–24 mg/day) or placebo, each containing vitamins A and D3, were administered orally three times a day for 3 months.
Anatabine-treated patients had a significant reduction in absolute serum thyroglobulin antibody (TgAb) levels from baseline by study end relative to those receiving placebo (P = .027); however, there were no significant changes or differences in treatment group means for thyroperoxidase antibody (TPOAb) or TgAb levels. There was a 20% drop in TgAb levels in the anatabine group compared to the placebo group (P = .023). Overall, the anatabine supplement was safe and well tolerated.
The results of this trial suggested that further studies of anatabine in Hashimoto's thyroiditis and other autoimmune disorders, including studies that monitor changes for longer time periods and elucidate its mechanism of action, are warranted.
Evidence strength: This is the highest-quality human clinical evidence for anatabine, comprising a published randomized controlled trial (RCT) in a peer-reviewed journal (Journal of Clinical Endocrinology & Metabolism, 2014). The result is statistically significant but limited in scope: only TgAb was reduced (not TPOAb), the trial ran only 12 weeks, the study was funded by Rock Creek Pharmaceuticals, and clinical development was subsequently discontinued. No independent replication has been published.
3. Joint Pain and Musculoskeletal Conditions
Human evidence: An internet-based survey study provided evidence that anatabine supplementation could improve chronic joint pain disorders. Anatabine had demonstrated anti-inflammatory effects in vivo and in vitro, and was considered potentially useful for musculoskeletal aches and pains. The purpose of this internet-based survey study was to provide more information about anatabine users who report benefits for joint pain or stiffness.
There are several limitations to this study. First, it is a questionnaire-based survey study and not a controlled trial, and thus does not control for concomitant pain medication and other dietary supplements. Second, the study relies on self-report information from a sample of individuals chosen based upon their repeated supplement purchases, and thus the reliability of the responses cannot be verified, and the results may not be generalizable. This study reports the experience of regular, long-term anatabine users with joint pain, not the larger set of all users.
Evidence strength: Very weak. This is a self-report survey study — not a controlled trial. No randomized controlled trial evaluating anatabine for joint pain in humans has been published.
4. Rosacea (Topical Use)
Clinical evidence: Anatabine is an alkaloid from the plant family Solanaceae that has been shown in several preclinical studies to modulate proinflammatory signaling pathways. A cream containing anatabine was developed and evaluated in an open-label case series study for safety and effects on the appearance of skin in 10 patients with mild to moderate rosacea. Patients applied the cream to the face twice daily for a period of 30 days. Patients and the study physician completed safety and efficacy assessments at study end.
Results showed that 50% of the patients self-reported improvement in the appearance of their skin, and the physician noted improvement in 70% of the patients.
Evidence strength: Very weak. This was an open-label, uncontrolled case series of only 10 patients. There is no placebo group, no blinding, and the sample size is far too small to draw conclusions. Anatabine cream was reported to be helpful in managing mild to moderate rosacea, but this characterization is based solely on this preliminary uncontrolled study.
5. Alzheimer's Disease and Neurodegeneration
Preclinical evidence: Anatabine is a minor tobacco alkaloid which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. It has been shown to display anti-inflammatory properties and reduce microgliosis and tau phosphorylation in a pure mouse model of tauopathy. The effects of a chronic oral treatment with anatabine were investigated in a transgenic mouse model (Tg PS1/APPswe) of Alzheimer's disease which displays pathological Aβ deposits, neuroinflammation, and behavioral deficits.
A significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This was the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, the data showed that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease-modifying agent for the treatment of AD. Oral anatabine treatment with 10 mg/kg/day or 20 mg/kg/day was started in 10-month-old Tg PS1/APPswe mice and lasted for 6.5 months.
Anatabine was also shown to reduce pro-inflammatory cytokine production (IL-6, IL-1β, and TNF-α) in the plasma, kidney, and spleen following LPS injection in mice. Following chronic oral treatment with anatabine, a reduction in brain TNF-α and IL-6 levels was observed in transgenic Alzheimer's model mice compared to untreated mice. Furthermore, increased STAT3 phosphorylation detected in the brains of these mice was inhibited by anatabine treatment.
Human/clinical evidence: No published human clinical trials for anatabine in Alzheimer's disease exist in the peer-reviewed literature. All evidence is from animal and in vitro models.
Evidence strength: Preclinical only. Results from transgenic rodent models are interesting but have not been translated to human studies. The relevant studies also carry conflicts of interest, as anatabine was supplied by Rock Creek Pharmaceuticals.
6. Multiple Sclerosis (Experimental Autoimmune Encephalomyelitis)
Preclinical evidence: Analyses of cytokine production in the periphery of animals revealed that anatabine significantly reduced Th1 and Th17 cytokines known to contribute to the development of experimental autoimmune encephalomyelitis (EAE). Anatabine appears to significantly suppress STAT3 and p65 NFκB phosphorylation in the spleen and the brain of EAE mice.
Furthermore, anatabine (~10 and ~20 mg/kg/day for 4 weeks; inhalation exposure) had effects in a murine model of multiple sclerosis, reducing neurological deficits and bodyweight loss.
Human/clinical evidence: None published.
Evidence strength: Preclinical only. Evidence is from established animal models of MS, but no human translation has occurred.
7. Intestinal Inflammation (Colitis)
Preclinical evidence: Anatabine, a minor tobacco alkaloid also present in peppers, tomato, and eggplant, presents anti-inflammatory properties in vivo and in vitro. A study evaluated the anti-inflammatory properties of nicotine and anatabine in a dextran sulfate sodium (DSS) mouse model of ulcerative colitis. Anatabine induced a significant decrease in the abundance of pro-inflammatory cytokines and reduced the protein expression of the anti-inflammatory cytokine IL-10 in the colon of DSS-treated mice.
Human/clinical evidence: None published.
Evidence strength: Preclinical only.
8. Traumatic Brain Injury
Preclinical evidence: A study focused on delayed treatment with anatabine, an anti-inflammatory compound, in hTau mice using two different models of repetitive mild traumatic brain injury (r-mTBI). The rationale for using two models of the same impact but different frequencies was chosen to address the heterogeneity of r-mTBI in clinical populations. Following the last injury in each model, three months elapsed before the initiation of treatment, and anatabine was administered in drinking water for 3 months thereafter. Data demonstrated that a 3-month delayed treatment with anatabine mitigated astrogliosis in both TBI paradigms but improved cognitive functions only in more-frequently-injured mice. Anatabine was also found to decrease the phosphorylation of tau protein and NFκB, which were increased after r-mTBI in both models.
Human/clinical evidence: None published.
Evidence strength: Preclinical only.
9. Smoking Cessation
CigRx, a dietary supplement containing anatabine, was supposed to reduce the urge to smoke. Anatabine has been studied in animal models and in cells to see if it might be useful for treating nicotine addiction and inflammation. However, no peer-reviewed randomized controlled trial evaluating anatabine as a smoking cessation aid has been published.
Evidence strength: No published controlled clinical evidence.
Body Systems and Health Areas Associated with Anatabine
- Immune system: Modulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) via NF-κB and STAT3 inhibition; immunomodulatory effects on thyroid autoimmunity in an RCT.
- Central nervous system: Brain-penetrant pharmacokinetics; investigated in models of Alzheimer's disease, multiple sclerosis, and traumatic brain injury; nAChR agonist activity.
- Endocrine system: Studied in Hashimoto's thyroiditis (autoimmune hypothyroidism); TgAb reduction demonstrated in an RCT.
- Musculoskeletal system: Associated with reported reductions in joint pain in a self-report survey; iNOS and COX-2 suppression in vitro.
- Integumentary system: Investigated as a topical agent in rosacea in a small open-label case series.
- Gastrointestinal system: Anti-inflammatory effects in mouse models of colitis.
- Neurotransmitter systems: Neuropharmacological effects of three naturally occurring alkaloids — nicotine, cotinine, and anatabine — were investigated in vitro and in vivo. A single injection of nicotine induced anxiolytic-like behavioral features in mice, while cotinine and anatabine had no detectable effect in this model.
Dosage Forms and Dosages Reported in Studies
- Oral lozenges (Anatabloc): Anatabine lozenges (9–24 mg/day) or placebo, each containing vitamins A and D3, were administered orally 3 times a day for 3 months in the ASAP Hashimoto's thyroiditis RCT.
- Topical cream: A cream containing anatabine was evaluated in an open-label case series study. Patients applied the cream to the face twice daily for a period of 30 days.
- Animal studies — oral administration: Oral anatabine treatment with 10 mg/kg/day or 20 mg/kg/day was used in transgenic Alzheimer's mouse models.
- Animal studies — intraperitoneal: Following intraperitoneal administration at 1, 2, and 5 mg/kg, anatabine caused a dose-dependent reduction in carrageenan-induced paw edema in rats.
- Animal studies — inhalation: Anatabine at approximately 10 and 20 mg/kg/day for 4 weeks via inhalation exposure had effects in a murine model of multiple sclerosis, reducing neurological deficits and bodyweight loss.
Safety Considerations and Interactions
Adverse Events in Human Trials
The most common adverse events reported in the ASAP Hashimoto's thyroiditis RCT were mild dizziness (36%), nausea (8%), headaches (7%), and paresthesia (7%). However, dose adjustments resolved such events in most cases. Overall, the anatabine supplement was reported to be safe and well tolerated at doses of 9–24 mg/day over 3 months in this trial, the only published placebo-controlled human study of its duration.
FDA Regulatory Concerns
In 2013, the FDA warned Star Scientific for unlawfully promoting CigRx and Anatabloc before anatabine was proved to be safe. Although the agency agreed that anatabine occurs naturally in vegetables that are commonly part of the food supply, the FDA stated that the mere presence of anatabine in food, without evidence that the food was specifically marketed for its anatabine content, does not constitute "marketing" of anatabine as a food or a supplement. The FDA has not approved anatabine as a drug, emphasizing that its efficacy and safety as a medical treatment are not established.
MAO Inhibition and Drug Interaction Potential
Anatabine was effective at inhibiting MAO activity at all time points in the reaction, and was equally effective in inhibiting both MAO A and MAO B activities. This partial MAO inhibition (approximately 60% at saturating concentrations in vitro) raises a theoretical concern regarding interactions with serotonergic or adrenergic drugs, foods high in tyramine, and other monoaminergic compounds. However, whether plasma concentrations achieved at dietary supplement doses are sufficient to produce clinically meaningful MAO inhibition in humans has not been established in published clinical research.
Nicotinic Receptor Activity and CNS Effects
In comparative neuropharmacological studies of nicotine, cotinine, and anatabine, a single injection of nicotine induced anxiolytic-like behavioral features in mice, while cotinine and anatabine had no detectable effect. Anatabine was a weaker agonist for nAChRs than nicotine. This suggests a lower risk of nicotine-like CNS stimulant effects, but the clinical significance in humans remains uncharacterized.
Conflict of Interest in Published Research
Anatabine was supplied for research by Rock Creek Pharmaceuticals, which sold anatabine as a dietary supplement, and the CEO of Rock Creek Pharmaceuticals was listed as a study author in several published preclinical studies. This pattern of industry involvement is a significant limitation in interpreting the existing preclinical and clinical literature.
Absence of Long-Term Safety Data
Long-term studies are warranted to confirm the results observed in existing trials, according to the authors of the ASAP trial. Further studies, particularly human clinical trials, are necessary to confirm existing observations and establish any definitive medical claims. The clinical development program was discontinued in 2016 following the company's bankruptcy, leaving a substantial gap in long-term human safety data.
References
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