Flavonoids Apigenin and Chrysin Non-Addictive Alternatives To Benzodiazepines for Anxiety Relief and Mild Sedation

When you are anxious and need a little sedative help to sleep, the flavonoids apigenin and chrysin may be good supplements to try. They are reputed to have strong effects at countering anxiety but more mild sedative effects than many benzodiazepine drugs and sleep drugs such as Lunesta and Ambien. Both also appear to have less effect on muscles, learning, and memory than common anxiety and sleep drugs.

Apigenin: A Flavonoid Anxiolytic With Many Health Uses

Apigenin is found in plants and plant-based supplements. Common foods and herbs that include relatively high levels of apigenin include parsley, onions, apples, basil, celery root, tea, peas, artichoke, feverfew, chamomile, orange juice, grapefruit juice, and alfalfa. Of these, if you are using any benzodiazepine anti-anxiety medications, you should avoid grapefruit juice because it affects liver metabolism of benzodiazepines, tending to raise the levels of the drug in the blood.

Apigenin is probably best known for its chemopreventative effects against cancers. Researchers have found that it also has anti-inflammatory and antioxidant properties. They have also observed that apigenin appears to have strong anxiolytic and mild sedative effects that may explain the long-reputed calming benefits claimed for chamomile tea.

While apigenin is common, it is not present in high enough concentrations that most people would get significant amounts of it on a daily basis in a typical diet. Therefore if a person wants to get the effects of apigenin, it is best consumed as a nutritional supplement.

It appears that apigenin’s anxiolytic effect does not operate solely on the GABA(A) benzodiazepine receptor which may explain why it does not have some of the side effects of benzodiazepines.

Apigenin is being investigated as a treatment for certain thyroid cancers which are currently lacking any effective treatments from mainstream medicine.

The following quote from a Life Extension article on flavonoids illustrates many of the wide ranging benefits of apigenin.

(from What’s Missing From Multivitamin Supplements?)

A potent flavonoid

Apigenin is a flavonoid found in parsley, artichoke, basil, celery and other plants. Over the last three years, a large number of published studies have demonstrated the anti-cancer properties of apigenin.

To study the effects of various plant constituents, an examination was made of 21 different flavonoids on the growth of human breast cancer cells. Apigenin was shown to the most effective anti-proliferative flavonoid tested.(69) A related study showed that flavonoids such as apigenin bind to estrogen receptor sites on cell membranes in order to prevent over-proliferation of these cells in response to estrogen.(70)

A study assessed the antioxidant potencies of several dietary flavonoids compared with vitamin C. Pretreatment with all flavonoids and vitamin C produced dose-dependent reductions in oxidative DNA damage. When ranked in order of potency, only apigenin, rutin and quercetin were more effective than vitamin C in reducing DNA oxidative damage.(71)

Apigenin was tested to ascertain its effect on human leukemia cells. Apigenin was shown to induce apoptosis more effectively than quercetin and other flavonoids tested. The researchers attributed a unique mechanism of inducing apoptosis to the cancer preventive activity of apigenin.(72) Another study showed that apigenin and another flavonoid called luteolin strongly inhibited the growth of human leukemia cells and induced these cells to differentiate.(73) Topoisomerases are involved in many aspects of leukemic cell DNA metabolism such as replication and transcription reactions. In one study, quercetin or apigenin were shown to inhibit topoisomerase-catalyzed DNA irregularities.(74) In a study of various agents used to induce differentiation of human promyelocytic leukemia cells, apigenin and luteolin were among the flavonoids shown to cause these leukemia cells to mature into healthy moncytes and macrophages.(75)

In studies against thyroid cancer cell lines, apigenin and luteolin were the most effective inhibitors found. Apigenin was shown to inhibit cancer cell signal transduction and induce apoptosis. The scientists concluded that apigenin may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available.(76) Another study compared the effects genistein, apigenin, luteolin, chrysin and other flavonoids on human thyroid carcinoma cell lines. Among the flavonoids tested, apigenin and luteolin were shown to be the most potent inhibitors of these cancer cell lines. The scientists noted that because these thyroid cancer cells lacked an anti-estrogen receptor binding site and an estrogen receptor, that apigenin and luteolin are inhibiting these cancer cells via previously unknown mechanisms. The scientists concluded that apigenin and luteolin may represent a new class of therapeutic agents in the management of thyroid cancer.(77)

In a study on colorectal cancer cell lines, apigenin or quercitin were shown to interfere with epidermal growth factor cell stimulation. The researchers speculated that these flavonoids could be primary components in fruits and vegetables that reduce the risk colorectal cancer by inferring with the cancer cell growth signaling pathway.(78)

The epidermal growth factor signal transduction pathway is an essential component of both cancer cell growth and differentiation. Certain gelatinases are expressed in human cancers and are thought to play a critical role in tumor cell invasion and metastasis. Apigenin was shown to inhibit these gelatinases and interfere with the growth factor signaling pathways. The scientists concluded that compounds like apigenin may provide a novel means of controlling growth and invasive potential of certain tumors via these dual mechanisms.(79) In a related study, apigenin was shown to prevent the degradation of tissue components by cultured human carcinoma cells, a mechanism by which cancer spreads to other parts of the body.(80)

The soy isoflavone genistein has been shown to be a potent inhibitor of cancer cell proliferation and in vitro angiogenesis. Moreover, the concentration of genistein in the urine of subjects consuming a plant-based diet is 30-fold higher than that in subjects consuming a traditional Western diet. Scientists have found in one study that apigenin and luteolin are more potent cancer inhibitors than genistein, and suggest that these plant components may contribute to the preventive effect of a plant-based diet on chronic diseases, including certain cancers. The scientists noted that the consumption of a plant-based diet can prevent the development and progression and growth of solid malignant tumors.(81)

Protein kinase C is over-expressed in many human tumors. One group of scientists has shown that apigenin blocks several points in the process of tumor promotion, including inhibiting kinases, reducing transcription factors and regulating cell cycle.(82) Another group of scientists showed that apigenin and other flavonoids inhibit prostate cancer cell growth by blocking tyrosine kinase activity.(83) Moreover, another study demonstrated that apigenin blocks mammary cell proliferation induced by several kinase-related pathways.(84)

The mutation and oxidation of estrogens is related to the development of certain cancers. The favorable influence of apigenin, genistein and other flavonoids on estrogen metabolism led researchers in one study to speculate that these plant extracts could be used in the prevention or treatment of estrogen-related diseases.(85)

Another mechanism by which cells mutate into malignancies involves a process known as sulfation. One study showed that apigenin and ellagic acid were potent inhibitors of sulfation compared to quercetin.(86)

In a study on human promyelocytic leukemia cells, genistein, followed by apigenin and daidzein, were the most potent inhibitors of toxic free radical byproducts generated by these leukemia cells. Other flavonoids showed no effect. The scientists stated that the antioxidant effects of these flavonoids may contribute to their chemopreventive potentials against human cancers.(87)

Seven men and seven women participated in a randomized crossover trial to study the effect of intake of parsley, containing high levels of apigenin, on biomarkers for oxidative stress. This basic diet was supplemented with parsley providing 3.73-4.49 mg apigenin in one of the intervention weeks. The scientists observed increased activity of the natural antioxidants glutathione reductase and superoxide dismutase in red blood cells during intervention with parsley as compared to people taking the basic diet without added parsley.(88)

A group of scientists studied the potential preventive effects of skin tumor promotion by apigenin. When topically applied, apigenin was shown to inhibit UV-induced skin tumorigenesis in mice. The scientists observed that apigenin facilitated several tumor suppressor factors including the important p53 binding activity.(89)

Grape skin and red wine contain resveratrol, which has been shown to inhibit platelet aggregation both in vivo and in vitro. One study showed that genistein, daidzein or apigenin produced inhibitory effects against an underlying cause of abnormal platelet aggregation similar to those seen with resveratrol.(90)

In order to better understand the mechanisms by which apigenin may prevent cancer, scientists looked at the effects this flavonoid would have on new blood vessel growth. Apigenin was shown to inhibit some factors involved in the process of tumor angiogenesis (new blood vessel growth that feeds rapidly dividing cells).(91)

Many types of cancer cells use cyclooxygenase-2 (COX-2) to propagate. COX-2 inhibiting drugs are being prescribed to cancer patients to slow the growth of existing tumors. One study showed that apigenin or genistein also suppresses formation of COX-2. The scientists conducting this study suggest that apigenin and related flavonoids may be important in the prevention of cancer and inflammation, partly via their COX-2 inhibiting properties.(92)

These studies as a whole provide a basis for cancer patients to consume a diet rich in certain fruits and vegetables as an adjunctive treatment for their disease. Apigenin is an antioxidant flavonoid with chemopreventive properties. It has been shown to arrest the growth of cancer cells, with concomitant inhibition of intracellular signaling cascades and decreased oncogene expression.


Chrysin: Flavonoid Anxiolytic Known For Raising Testosterone and Lowering Estrogen

Chrysin is generally extracted from the blue passion flower (Passiflora caerulea). Chrysin is probably best known for its effects on inhibiting the aromatic conversion of testosterone to estrogen. While this was once believed to be a strong inhibitory affects, more recent research suggests the effect may not be as strong as previously believed. Some believe that the variability in results comes from poor bioavailability of chrysin unless other compounds such as piperine extracts are used to increase its bioavailability.

Because of its possible effects on hormone balances, using chrysin for anxiety may be a better choice for men or women with low testosterone and high estrogen levels. For others, apigenin may be preferable because it is less regarded as having an effect on altering sex hormone balances. Research also suggests that apigenin may be more bioavailable than chrysin, meaning that added ingredients such as piperine extracts may been needed to increase chrysin’s bioavailability to sufficient levels to get an effect from the compound.

Additionally, some research in mice shows that chrysin block thyroid function and could cause weight gain because of this effect. However, similar findings have been made regarding widely used flavonoids such as quercetin yet they are not widely regarded as supplements to avoid due to their impact on thyroid function.

The full picture of flavonoid effects on the thyroid may be more complicated. A recent research published in 2011 by the University of Wisconsin Madison suggests that like apigenin, chrysin may be an excellent therapeutic candidate for anaplastic thyroid cancers which are currently lacking effective treatments.

The following quote from a Life Extension article on using chrysin for improving hormone balances in men also discusses the observed anxiolytic effects.

(from Replenish Testosterone Naturally)

An advantage to using plant extracts to boost testosterone in lieu of drugs is that the plant extracts have ancillary health benefits. Chrysin, for example, is a potent antioxidant that possesses vitamin-like effects in the body. It has been shown to induce an anti-inflammatory effect, possibly through inhibition of the enzymes 5-lipoxygenase and cyclooxygenase inflammation pathways. Aging is being increasingly viewed as a pro-inflammatory process, and agents that inhibit chronic inflammation may protect against diseases as diverse as atherosclerosis, senility and aortic valve stenosis. Chrysin is one of many flavonoids being studied as a phyto-extract that may prevent some forms of cancer. If chrysin can boost free testosterone in the aging male by inhibiting the aromatase enzyme, this would provide men with a low cost natural supplement that could provide the dual anti-aging benefits of testosterone replacement and aromatase-inhibiting drug therapy.

As previously discussed, boosting free testosterone levels can have a dramatic effect on sex drive, performance and satisfaction. Pilot studies indicate that chrysin increases total and free testosterone levels in the majority of men who take it with piperine.

Chrysin has one other property that could add to its libido-enhancing potential. A major cause of sexual dissatisfaction among men is work-related stress and anxiety. Another problem some men have is “sexual performance anxiety” that prevents them from being able to achieve erections when they are expected to. In a study published in Pharmacology Biochemistry and Behavior (1994, Vol 47), mice were injected with diazepam (Valium), chrysin or placebo to evaluate the effects these substances had on anxiety and performance levels. Chrysin was shown to produce anti-anxiety effects comparable with diazepam, but without sedation and muscle relaxation. In other words, chrysin produced a relaxing effect in the brain, but with no impairment of motor activity. The mechanism of action of chrysin was compared to diazepam, and it was shown that unlike diazepam, chrysin can reduce anxiety without inducing the common side-effects associated with benzodiazepine drugs.

A common problem with benzodiazepine drugs is memory impairment. In a study published in a 1997 issue of Pharmacology Biochemistry and Behavior (Vol 58, No 4), chrysin displayed potent anti-anxiety effects in rats, but did not interfere with cognitive performance. In this study, diazepam was shown to inhibit neurological function, but chrysin (and other anti-anxiety flavonoids) had no effect on training or test session performance. The scientists conducting this study pointed out that chrysin selectively inhibits anxiety in the brain but, unlike diazepam, does not induce the cognitive impairment.

Sources for Apigenin and Chrysin

Of the two flavonoids, apigenin is probably the easier and less expensive to find. It’s available from a number of suppliers (see the example product links to the right) plus you can get some in certain foods, too. For instance, sprinkle some parsley into many of your foods and you’ll be picking up some apigenin in your diet.

Chamomile tea or chamomile extracts are also a good source for apigenin.

Another possible source for apigenin is the Turnera aphrodisiaca plant which is known in the Southwestern US as the damiana shrub. It has more mixed reviews with some claiming it has no effect and others talking about its libido-enhancing effects that are not associated with other sources of apigenin. This may or may not be a good thing depending upon your situation.

For men, Life Extension sells a well-known product called Super MiraForte with Standardized Lignans, 120 capsules that contains chrysin along with piperine to enhance the bioavailability plus other compounds such as nettle root, maca, muira puama, and lignans that are reputed to help reduce high levels of estrogen and raise low levels of testosterone.

Further Reading

Reducing Sedative and Addictive Side Effects of Anti-Anxiety Drugs Benzodiazepines (Xanax, Valium, etc.) with L-Theanine, Pregnenolone, and DHEA

L-Theanine for Anxiety, Insomnia, and Depression

Tired All the Time for Months or Years? Here’s A Resource With Many Possible Explanations.

Cortisol Imbalances May Cause Weight Gain, Depression, Anxiety, and Insomnia

Chronic Stress Kills: High Cortisol Levels Damage the Brain, May Lead to Shorter Life and Neurodegenerative Diseases Such As Alzheimer’s and Parkinson’s

Powerful Advances in Natural Cancer Prevention

What’s Missing From Multivitamin Supplements?

Natural Plant Compound Cuts Ovarian Cancer Risk

PubMed Research Papers on Apigenin and Chamomile

A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder

Chamomile: A herbal medicine of the past with bright future

Apigenin: The Anxiolytic Consituent of Turnera aphrodisiaca

Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects

Behavioral characterisation of the flavonoids apigenin and chrysin

Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla

Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rats

Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea

Flavonoids and the central nervous system: from forgotten factors to potent anxiolytic compounds

Overview–flavonoids: a new family of benzodiazepine receptor ligands

No evidence for the in vivo activity of aromatase-inhibiting flavonoids

Iodothyronine deiodinase is inhibited by plant flavonoids

Inhibition of thyroid peroxidase by dietary flavonoids

Antiproliferative Effect of Chrysin on Anaplastic Thyroid Cancer


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