Chlorophyll

Chlorophyll: A Comprehensive Reference

1. Identity, Nomenclature, and Natural Sources

Chemical Identity and Types

Chlorophyll is the green pigment found in cyanobacteria and chloroplasts of algae and plants and is critical in photosynthesis, as it allows plants to absorb energy from light. The basic skeleton is composed of a large planar structure of four pyrrole rings joined together with a central metal atom of magnesium and a phytol hydrophobic group. There are several types of chlorophyll, with chlorophyll a and b being the most prevalent in higher plants and green algae. These molecules absorb light most efficiently in the blue and red parts of the electromagnetic spectrum, while reflecting green light — which is why plants appear green.

At least six chlorophyll molecules are known: chlorophylls a, b (higher plants), c, d, and e (algae), and bacteriochlorophylls (photosynthetic bacteria). The most widely distributed in plants is chlorophyll a. Chlorophyll a and chlorophyll b represent about 99% of the chlorophyll species found in edible plants, while some algae and microalgae contain minor quantities of chlorophyll c pigments.

The long hydrocarbon (phytol) tail attached to the porphyrin ring makes chlorophyll fat-soluble and insoluble in water. Chlorophyll a and b only have a small difference in one of the side chains but an intact phytol tail, while the common characteristic of chlorophyll c isoforms is the absence of a phytol tail. These structural differences cause each type of chlorophyll to absorb light at slightly different wavelengths.

Chlorophyllin: The Semisynthetic Derivative

Commercial sodium copper chlorophyllin (SCC) contains two related copper-containing compounds — trisodium copper chlorin e6 and disodium copper chlorin e4 — both of which have porphyrin ring structures with a central copper atom replacing the magnesium atom found in natural chlorophylls. They lack a phytol tail and are water-soluble. Chlorophyllins are derivatives of chlorophyll in which the central magnesium atom is replaced by other metals, such as cobalt, copper, or iron.

Most "chlorophyll water" and liquid supplement products sold commercially are not natural chlorophyll from food, but rather chlorophyllin, a semisynthetic sodium copper salt derivative of chlorophyll. Chlorophyllin was developed to be water-soluble, since natural chlorophyll is fat-soluble and does not dissolve into water cleanly.

Natural Sources and Food Content

Chlorophylls are abundant in leafy fresh vegetables, including spinach, kale, lettuce, and basil. Dietary chlorophyll can be found as chlorophyll a and chlorophyll b in fresh fruits and vegetables, and as metal-free pheophytins and pyropheophytins in thermally processed fruits and vegetables. Dietary chlorophyll is predominantly composed of lipophilic derivatives including chlorophyll a and b (fresh fruits and vegetables), metal-free pheophytins and pyropheophytins (thermally processed fruits and vegetables), as well as zinc-pheophytins and zinc-pyropheophytins (thermally processed green vegetables).

Chlorophylls are principally extracted commercially from grass, alfalfa, nettles, and spinach. Common sources of chlorophyll used specifically for medicinal preparations include alfalfa (Medicago sativa).

Regulatory Status as a Food Additive

Under EU regulations, two natural colorants — chlorophyll (E140i) and chlorophyllin (E140ii), both oil-soluble — and their corresponding copper homologs, copper-chlorophyll (E141i) and copper-chlorophyllin (E141ii), which are water-soluble, are all permitted. The addition of copper improves stability by avoiding color change from green to brown. EFSA concluded that E140 chlorophylls are natural dietary constituents present in relatively high concentrations in a number of foods, and that the exposure resulting from the use of E140 as a food additive is lower than the exposure to chlorophylls from the regular diet; at the reported usage levels, E140 does not pose any safety concerns. The U.S. Food and Drug Administration (FDA) also recognizes chlorophylls as safe for use in foods.

2. Traditional and Historical Use

Chlorophylls are the most common green pigments found in plants and play a key role in photosynthesis. They have been included in the human diet throughout history as an integrated part of vegetable foodstuffs. Chlorophylls also have a wealth of applications in basic science, medicine, and as colorants. Considering that there has been more than 200 years of chlorophyll research, one would think that all has been said on these pigments.

The chlorophyll and its derivatives have a long history in traditional medicine, with documented uses dating back to the mid-twentieth century, including wound healing, as an anti-inflammatory agent, and as an internal deodorant. The use of chlorophyll derivatives, especially sodium copper chlorophyllin (SCC), in traditional medical applications is well documented.

In the late 1950s, SCC was added to papain- and urea-containing ointments used for the chemical debridement of wounds in order to reduce local inflammation, promote healing, and control odor. SCC-containing papain/urea ointments are still available in the US by prescription. Chlorophyll has been marketed as an "internal deodorant" since the 1950s. One study, published in January 1980, found that the administration of chlorophyllin was "helpful in controlling body and fecal odors" in 62 geriatric nursing home patients.

Although these applications illustrate various medicinal uses of chlorophyll, recent research has been more focused on its role as a potent anti-mutagen and anti-carcinogen, and also as a photosensitizer in photodynamic therapy. Commercially in the United States, chlorophyll products were extracted in large quantities from alfalfa, and found increasing use not only in the manufacture of deodorants but also in medicinal preparations for treating anemia and hypertension, as a healing agent, and in oral hygiene.

3. Key Constituents and Mechanisms of Action

Structural Properties Underlying Bioactivity

Chlorophylls have several positive benefits, one of which is antioxidant activity, helping to prevent oxidative DNA damage and lipid peroxidation by decreasing reactive oxygen species (ROS) and chelating metal ions. The chemical nature of the porphyrin ring allows chlorophylls to function as hydrogen donors, stopping chain oxidation processes.

Chlorophylls present significant antioxidant activity through chelation of reactive ions and scavenging of free radicals, preventing DNA damage and lipid peroxidation, as well as antimutagenic and antigenotoxic activity through the prevention of mutagen migration and its coupling to DNA by the formation of a chlorophyll–mutagen complex, which facilitates the degradation of the mutagen.

Carcinogen Binding and Chemoprevention

Chlorophyll and sodium copper chlorophyllin are able to form tight molecular complexes with certain chemicals known or suspected to cause cancer, including polyaromatic hydrocarbons found in tobacco smoke, some heterocyclic amines found in cooked meat, and aflatoxin B1. The binding of chlorophyll or SCC to these potential carcinogens may interfere with gastrointestinal absorption, reducing the amount that reaches susceptible tissues.

Biological activities attributed to chlorophyll derivatives consistent with cancer prevention include antioxidant and antimutagenic activity, mutagen trapping, modulation of xenobiotic metabolism, and induction of apoptosis.

Phase 2 Enzyme Induction

Chlorophyll may decrease the absorption of dietary carcinogens by forming tight complexes with the carcinogens and by inhibiting cytochrome P450 enzymes (CYP). The compound has also been documented to induce phase 2 cytoprotective genes in mammalian systems, a complementary detoxification pathway.

Thylakoid-Related Satiety Mechanisms

Thylakoids — chlorophyll-containing membranes from green leaves — have gained interest for their anti-obesity effects. They primarily function by delaying fat digestion, which promotes the secretion of satiety hormones like GLP-1 and suppresses ghrelin. When added to refined food, chloroplast membranes (thylakoids) suppressed food intake in rats, lowered blood lipids, and raised the satiety hormones CCK and enterostatin. The mechanism for satiety appears to be retardation of fat digestion, allowing fat products to stay longer in the intestine.

Antimicrobial and Wound-Healing Properties

The latest studies have reviewed cancer-preventive, antioxidant, and antimutagenic activities, as well as mutagen trapping, modulation of xenobiotic metabolism, induction of apoptosis, antimicrobial properties, and anti-inflammation activity in chlorophyll derivatives, considered to be closely related to their specific chemical structure.

4. Bioavailability and Pharmacokinetics

Little is known about the bioavailability and metabolism of chlorophyll in humans, although it is known that chlorophyll undergoes extensive metabolism once consumed. Animal model studies show only about 1–3% of chlorophyll is absorbed, while the rest is excreted in the feces, primarily as pheophytin and pyropheophytin metabolites, indicating that significant transformation and microbial metabolism occur in the gastrointestinal tract.

A recent study in eight healthy adults found pheophytin and pheophorbide derivatives in the blood of most subjects following consumption of 1.2 kg boiled spinach, a concentrated source of chlorophyll. Studies showed that after supplementation with freeze-dried ground spinach leaves (18 mg chlorophyll/day) for 10 days, the average apparent absorption of chlorophyll derivatives was 3.4%, with pheophytinization identified as the major degradation process.

The pharmacokinetic profiles of many chlorophyll derivatives remain poorly characterized, complicating assessments of their bioavailability, metabolism, and dose optimization in human systems. The collective findings from both in vitro and in vivo studies using native chlorophylls indicate that the potential health benefits associated with chlorophyll a and b are likely attributed to their metal-free derivatives.

Chlorophyll stability during digestion varies widely (15–85%) and may be influenced by salt content. Most absorbable chlorophylls in mixed micelles are pheophytins due to their high digestive stability. While food composition can affect digestive outcomes to some extent, chlorophyll bioaccessibility is primarily determined by its chemical structure, especially pheophorbide content.

Based on estimates for daily chlorophyll intake (26–86 mg/d) and bioavailability (~5%), it is possible that chlorophyll absorption could reach 1.3–4.3 mg/d. While a diet rich in vegetables and green fruits may provide a substantial amount of chlorophylls, their bioavailability, metabolism, and the effects of food processing influence their potential impact on human health. Early studies assumed that humans did not absorb chlorophylls, resulting in limited research; however, a few studies have demonstrated that native chlorophylls undergo significant transformation during the digestive process.

5. Scientific Evidence by Area of Use

5.1 Cancer Chemoprevention: Aflatoxin Exposure

This is the best-studied area of chlorophyllin's clinical use in humans. Chlorophyllin (CHL), a water-soluble form of chlorophyll, was evaluated as a chemopreventive agent in a population at high risk for exposure to aflatoxin and subsequent development of hepatocellular carcinoma. CHL is thought to form molecular complexes with carcinogens, thereby blocking their bioavailability. In the clinical trial, administration of CHL three times a day led to a 50% reduction in the median level of urinary excretion of aflatoxin-N7-guanine compared to placebo.

Epidemiologic studies in Asia and Africa have revealed a positive association between dietary aflatoxins and liver cancer. High levels of aflatoxins in combination with infection with hepatitis B seem to act synergistically to increase risk of hepatocellular carcinoma. Chlorophyll and chlorophyllin were shown previously to reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings were partially extended to humans, where CHL reduced excretion of aflatoxin B1-DNA repair products in Chinese individuals unavoidably exposed to dietary AFB1.

A crossover study in three volunteers that used accelerator mass spectrometry to study the pharmacokinetics of an ultra-low dose of aflatoxin B1 found that a 150-mg dose of either SCC or chlorophyll could decrease absorption of aflatoxin B1.

Evidence assessment: The evidence for chlorophyllin's ability to reduce aflatoxin biomarkers in humans is supported by clinical trials, including a randomized, placebo-controlled trial and a crossover pharmacokinetic study. However, these trials were conducted specifically in high-exposure populations in China, and no clinical outcomes data (such as actual cancer incidence) are yet available from human trials. The evidence is promising but limited in scope.

5.2 Wound Healing (Topical Use)

In the late 1950s, SCC was added to papain and urea-containing ointments used for the chemical debridement of wounds in order to reduce local inflammation, promote healing, and control odor. SCC-containing papain/urea ointments are still available in the US by prescription. Several studies have reported that such ointments are effective in wound healing. A spray formulation of the papain/urea/SCC therapy is also available.

Some studies have demonstrated chlorophyllin's effectiveness on infected wounds by slowing the growth of bacteria such as Staphylococcus aureus. When applied topically to wounds, SCC has been reported to cause mild burning or itching in some cases.

Evidence assessment: Topical SCC has decades of clinical use in wound management, particularly in combination with papain and urea, and prescription-grade formulations exist. However, the supporting studies are older and generally small; rigorous modern randomized controlled trials are limited.

5.3 Skin Conditions (Topical — Acne and Photoaging)

A few small studies have investigated SCC as a topical treatment for various skin conditions. In a pilot study of 10 adults (ages 18–30 years) who had mild-to-moderate acne vulgaris and enlarged facial pores, twice-daily application of a 0.1% liposomal SCC gel for three weeks improved a number of clinical parameters of the Global Acne Assessment Scale — including facial oiliness, facial blotchiness, presence and size of facial pores, and number of acne lesions — compared to baseline.

A randomized trial tested chlorophyll-a as part of photodynamic therapy, where the compound is applied to the skin and then activated with a specific light device. The treated side of participants' faces showed significant reductions in acne lesion counts, acne severity grades, and oil production compared to the side treated with light alone. This involved a clinical light therapy setup. Whether over-the-counter chlorophyll serums and drops deliver the same results without the light activation component is largely untested.

There is no rigorous clinical evidence that oral chlorophyllin treats acne. Topical chlorophyllin has more evidence for skin benefits — a small 2015 pilot study showed improvement in photo-aged skin — but this is different from oral supplementation.

Evidence assessment: Preliminary. The pilot acne study was uncontrolled (no placebo), involved only 10 participants, and measured change from baseline rather than against a control group. Photodynamic therapy uses chlorophyll only as a photosensitizer under clinical light activation, and results from that setting cannot be extrapolated to dietary or topical supplementation.

5.4 Internal Deodorization

One study published in January 1980 found that the administration of chlorophyllin was "helpful in controlling body and fecal odors" in 62 geriatric nursing home patients. These claims often stem from older research from 1953 that suggested chlorophyll could reduce body odor in people with colostomies, ileostomies, incontinence, or chronic wounds. There is little modern evidence for this benefit in healthy people.

SCC has been used orally as an internal deodorant and topically in the treatment of slow-healing wounds for more than 50 years without any serious side effects.

One study in a small number of Japanese patients with trimethylaminuria found that oral SCC (60 mg three times daily) for three weeks significantly decreased urinary trimethylamine.

Evidence assessment: Weak to moderate for specific populations (colostomy patients, trimethylaminuria). The evidence in healthy individuals is largely anecdotal or drawn from small, dated studies. The most robust finding concerns trimethylaminuria, a specific metabolic disorder, not general body odor in healthy people.

5.5 Satiety, Weight Management, and Appetite Regulation (Thylakoid Research)

Thylakoids — the membrane proteins extracted from green leaves like spinach — can induce satiety through homeostatic and non-homeostatic pathways, according to previous studies. After excluding non-human studies, non-RCTs, duplications, and studies with irrelevant data, eight randomized controlled studies were included in one systematic review. All studies supported the hypothesis that thylakoids reduce the feeling of hunger by increasing postprandial cholecystokinin and leptin and decreasing serum ghrelin.

Several clinical studies have demonstrated that daily supplementation with green plant membranes (thylakoids), which are naturally rich in chlorophyll, can enhance GLP-1 secretion, reduce hunger, and reduce obesity-related risk factors. One report found that a three-month supplementation with green plant membranes in overweight women led to increased GLP-1 levels, body weight loss, and reduced cravings for palatable food.

While many clinical trials report significant weight loss and appetite suppression, recent studies focusing on active or well-trained populations have occasionally yielded inconsistent findings, with several investigations demonstrating no statistically significant changes in glycemic parameters or long-term lipid profiles compared to placebo groups.

A study investigated whether thylakoid supplementation affected the gut microbiota and faecal fat in healthy human volunteers (n = 34) receiving thylakoid or placebo for three months. The total bacteria, and specifically the Bacteroides fragilis group, were increased by thylakoid treatment versus placebo, while thylakoids did not cause steatorrhea. Dietary supplementation with thylakoids thus affects satiety both via appetite hormones and gastrointestinal fullness, and affects microbial composition without causing GI adverse effects such as steatorrhea.

Evidence assessment: The thylakoid satiety evidence base is relatively stronger than most other areas of chlorophyll research: a systematic review of eight RCTs showed consistent satiety-hormone effects. However, thylakoids are complex membrane structures containing many bioactive components in addition to chlorophyll (including galactolipids, carotenoids, and tocopherols), so the effects cannot be attributed to chlorophyll alone. Results are also less consistent in non-obese or athletic populations.

5.6 Blood Glucose and Diabetes-Related Outcomes

Chlorophyllin has been shown to acutely lower postprandial blood glucose levels in humans, as observed in a small-scale glucose tolerance test. While the precise mechanism remains unclear, it has been hypothesized that this effect may involve modulation of intestinal glucose transporters or incretin signaling, possibly acting as a GLP-1 secretagogue.

Pheophorbide a shows limited gastrointestinal absorption. Its inhibitory activity on intestinal α-glucosidase and α-amylase does not require systemic absorption; like acarbose, this action is exerted locally within the intestinal lumen, which may mitigate concerns regarding systemic exposure.

Evidence assessment: Preliminary. The glucose-related evidence in humans is limited to a small glucose tolerance test and mechanistic hypotheses, alongside in vitro enzyme inhibition data. Robust human RCT data for glycemic control are lacking.

5.7 Antimicrobial and Antiviral Effects

In human research, topical chlorophyll stopped viral replication of herpes and the development of lesions related to herpes simplex viruses. Some studies have demonstrated effectiveness on infected wounds by slowing the growth of bacteria such as Staphylococcus aureus.

Evidence assessment: Very limited. The herpes-related reference dates from Soviet-era literature (1971), and contemporary clinical trials are absent. Data on antibacterial wound effects come from small, older studies.

5.8 Gut Microbiota

Recent studies evidenced the supportive role of chlorophyll derivatives as prebiotics, as authors demonstrated that chlorophyllin directly impacts the gut microbiota in mice, reducing the population of Firmicutes and restoring the Bacteroidetes phylum.

Evidence assessment: Primarily preclinical (murine). The thylakoid RCT noted above provides some supporting human evidence, but the contribution of chlorophyll per se, as distinct from other membrane components, cannot be isolated.

6. Body Systems Associated with Chlorophyll Use

• Gastrointestinal System: Carcinogen binding and reduced absorption of dietary mutagens in the gut; modulation of gut microbiota (preclinical and limited human data); deodorization of intestinal odors.
• Hepatic/Detoxification System: Reduction of aflatoxin B1 bioavailability (human clinical trial data); modulation of xenobiotic-metabolizing enzymes including cytochrome P450 inhibition and phase 2 enzyme induction.
• Integumentary System (Skin): Topical wound healing (historical clinical use with prescription formulations); pilot evidence for acne and photoaging (topical).
• Metabolic/Endocrine System: Thylakoid-mediated satiety-hormone modulation (GLP-1, CCK, ghrelin); preliminary human evidence for postprandial glucose reduction.
• Immune and Inflammatory Pathways: In vitro and preclinical anti-inflammatory and antimutagenic effects; induction of apoptosis in cancer cell models.

7. Dosage Forms and Dosages Reported in Studies

Chlorophyll in the form of underutilized greens in fresh vegetables, supplements, liquid solutions, extracts, or tablets can be used effectively as a healthy and beneficial nutrient supplement.

The following dosages have been reported in the cited studies:

• Aflatoxin chemoprevention trial (Qidong, China): Chlorophyllin 100 mg administered three times daily (300 mg/day total) led to a 50% reduction in the median level of urinary aflatoxin-N7-guanine excretion compared to placebo.
• Aflatoxin pharmacokinetic crossover study: A 150-mg dose of either SCC or natural chlorophyll decreased absorption of aflatoxin B1 in a crossover study of three volunteers.
• Topical acne pilot study: Twice-daily application of a 0.1% liposomal SCC gel for three weeks in 10 adults (ages 18–30) with mild-to-moderate acne vulgaris.
• Trimethylaminuria study: Oral SCC 60 mg three times daily (180 mg/day) for three weeks significantly decreased urinary trimethylamine in a small number of Japanese patients.
• Thylakoid weight management study: Participants consumed 5 g/day of a thylakoid supplement 30 minutes before lunch for 12 weeks. The selection of this dose was based on previous clinical evidence demonstrating efficacy in modulating appetite and promoting weight loss.
• Thylakoid acute satiety study: A single meal supplemented with 5 g of thylakoids was found to increase fullness and reduce hunger and prospective intake over the 2-hour period following consumption.
• Dietary chlorophyll absorption study: Supplementation with 0.8% freeze-dried ground spinach leaves (18 mg chlorophyll/day) for 10 days yielded an average apparent absorption of chlorophyll derivatives of 3.4%.

No officially established recommended daily intake (RDI) or tolerable upper intake level (UL) for chlorophyll or chlorophyllin has been set by major regulatory bodies such as the NIH or EFSA for supplemental use. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has established an Acceptable Daily Intake (ADI) of 0–15 mg/kg body weight for copper chlorophylls as a food additive, which is unlikely to be exceeded under normal dietary conditions.

8. Safety Considerations and Drug Interactions

General Safety Profile

Natural chlorophylls are not known to be toxic, and no toxic effects have been attributed to chlorophyllin despite more than 50 years of clinical use in humans.

When taken orally, supplemental chlorophyll or sodium copper chlorophyllin may cause green discoloration of urine or feces, or yellow or black discoloration of the tongue. There have also been occasional reports of diarrhea related to oral SCC use. When applied topically to wounds, SCC has been reported to cause mild burning or itching in some cases. Oral chlorophyllin may result in false positive results on guaiac card tests for occult blood.

Pregnancy and Lactation

Since the safety of chlorophyll or chlorophyllin supplements has not been tested in pregnant or lactating women, they should be avoided during pregnancy and lactation.

Photosensitivity

Chlorophyllin maintains some of chlorophyll's ability to act as a photosensitizer. This is relevant in the context of photodynamic therapy applications, where it is exploited therapeutically, but may represent a risk consideration in individuals with photosensitivity conditions taking high supplemental doses.

Wilson's Disease and Copper Metabolism

Individuals with rare disorders of copper metabolism, such as Wilson's disease, should limit exposure to copper additives, including supplemental sodium copper chlorophyllin, given its copper content.

Drug Interactions

A case of delayed methotrexate clearance was reported following administration of a complementary medication containing chlorophyll (reported in Journal of Oncology Pharmacy Practice, 2014). This suggests a potential pharmacokinetic interaction with at least one chemotherapy agent, though it remains an isolated case report.

Chlorophylls and SCC form tight molecular complexes with some chemicals known or suspected to cause cancer. However, carefully controlled studies have not been undertaken to determine whether a similar mechanism might limit uptake of required nutrients or co-administered medications.

Regulatory Safety Evaluation (Copper Chlorophyllin E141ii)

EFSA scientific reviews indicate that data on the toxicological profile of copper-chlorophyllins are contradictory. In several in vitro and in vivo studies, they showed antioxidant properties and the ability to reduce cell damage caused by reactive oxygen species. However, there are studies where dose-dependent adverse effects were observed, including stimulation of tumor cell growth in laboratory animals. Following its review, the EFSA Panel on Food Additives noted that reliable data on absorption, metabolism, genotoxicity, carcinogenicity, reproductive, and developmental toxicity of copper chlorophyllin complexes (E141ii) are still insufficient. As a result, the existing ADI for E141ii has been withdrawn, and the safety of the substance cannot be considered definitively established. In the European Union, E141ii is authorized for use under "quantum satis" conditions.

Evidence Limitations and Overall Research Status

While native chlorophylls have been the focus of limited research, both in vitro and in vivo studies have shed light on the therapeutic potential of chlorophyll derivatives, which exhibit a range of beneficial effects including antioxidant, antimutagenic, antigenotoxic, anticarcinogenic, and anti-obesogenic properties. Nevertheless, additional research is required to validate the efficacy of dietary chlorophylls in treating various diseases and to explore their therapeutic potential in other medical conditions.

The precise pharmacokinetics of dietary chlorophylls and their derivatives, which play a crucial role in conferring health benefits, remain poorly understood and need further investigation.

On average, only about 5% of therapies tested in animal models ultimately gain regulatory approval for human use, underscoring the limitations of preclinical approaches — a consideration directly applicable to many chlorophyll-related health claims that rest primarily on animal and in vitro data.

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