High Dose Melatonin Therapy - An

Ideal Adjuvant Anti-cancer

Therapy

FRANK SHALLENBERGER, MD, HMD

CARSON CITY, NV USA
Melatonin Facts

 Produced and released in pineal gland in darkness. Immediately

suppressed by all light but red light.
 Not a soporific. You can take it during the day, as well as at
bedtime, without any adverse effect.
 Side effects: no serious side effects. Some patients report sleep
disturbances and AM sleepiness.
 Dr. Pierpaoli, one of the world’s leading melatonin researchers, has
successfully used daily dosages ranging from 0.1 to 200 mg. That’s
a 2,000-fold difference between the lowest dose and the highest!
Studies on mice show that even at astronomical doses of 300 mg
per day for two years, there were no side effects.
Melatonin Facts
• Testing for melatonin – AM urine for 6-sulfatoxy
melatonin. ZRT Laboratory. Ph 866-600-1636 Fax: 503-
466-1636 | [email protected]
• Peak plasma level after PO ingestion is about 1 hour.
Levels sustained for 3-4 hours.
• Rapidly enters the central nervous system and crosses
the blood-brain barrier.
• Exogenous melatonin does not alter the levels of any
other hormones
• No negative feedback inhibition
Melatonin in the treatment of cancer: a systematic review
of randomized controlled trials and meta-analysis.
Mills, E., P. Wu, et al. J Pineal Res. 2005 November;39(4):360-6.

 Melatonin activates anti-neoplastic immune reactivity

 Direct anticancer action
 Protects against chemo radiation damage
 On average, the combined results of these studies showed that
melatonin reduced the risk of dying by 44%.
 The effects were consistent no matter what dose they used.
 None of the patients had any significant side effect from the melatonin.
 “The substantial reduction in risk of death, low adverse events reported,
and low costs related to this intervention suggest great potential for
melatonin in treating cancer.”
Basic mechanisms involved in the anti-cancer
effects of melatonin.
Mediavilla MD1, Sanchez-Barcelo EJ, et al. Curr Med Chem 2010;17(36):4462-81.

 “Melatonin has oncostatic properties in a wide variety of

tumors.”
 Mitochondrial stimulant.
 Regulation of estrogen receptor expression and transactivation.
 Modulation of the enzymes involved in the local synthesis of
estrogens.
 Modulation of cell cycle and induction of apoptosis.
 Inhibition of telomerase activity
 Inhibition of metastasis
Basic mechanisms involved in the anti-cancer effects
of melatonin.
Mediavilla MD1, Sanchez-Barcelo EJ, et al. Curr Med Chem 2010;17(36):4462-81.

• Direct anti-neoplastic effects.

• Decreases cell proliferation at low concentrations.
• Direct cytotoxic effect occurs with high concentrations
• Stimulation of cell differentiation
• Induction of apoptosis
• Anti-angiogenesis
• A synergistic effect has been found in several cancer types
when it is administered in combination with chemotherapy.
Cancer metastasis: Mechanisms of inhibition
by melatonin.
Su SC, Hsieh MJ, Yang WE, J Pineal Res. 2017 Jan;62(1).

 “Due to the broad range of melatonin's actions, the mechanisms

underlying its ability to interfere with metastases are numerous.
These include modulation of cell-cell and cell-matrix interaction,
extracellular matrix remodeling by matrix metalloproteinases,
cytoskeleton reorganization, epithelial-mesenchymal transition,
and angiogenesis.”
 “The evidence discussed herein will serve as a solid foundation for
urging basic and clinical studies on the use of melatonin to
understand and control metastatic diseases.”
Melatonin uptake through glucose transporters: a new
target for melatonin inhibition of cancer.
Hevia D, González-Menéndez P, J Pineal Res. 2015 Mar;58(2):234-50.

 “Some functions of melatonin are mediated by its membrane receptors

but others are receptor-independent. For the latter, melatonin must enter
into the cell.”
 “Herein, it is demonstrated that members of the SLC2/GLUT family glucose
transporters have a central role in melatonin uptake.”
 “Glucose concentration and the presence of competitive ligands of
GLUT1 affect the concentration of melatonin into cells.”
 “As a regulatory mechanism, melatonin reduces the uptake of glucose
and modifies the expression of GLUT1 transporter in prostate cancer cells.
More importantly, glucose supplementation promotes
prostate cancer progression in TRAMP mice, while melatonin attenuated
glucose-induced tumor progression and prolonged the lifespan of tumor-
bearing mice.“
Melatonin reduces endothelin-1 expression and secretion in
colon cancer cells through the inactivation of FoxO-1 and NF-κβ.
León J, Casado J, et al. J Pineal Res. 2014 May;56(4):415-26.

 “Endothelin-1 (ET-1) is a peptide that acts as a survival factor in

colon cancer, inducing cell proliferation, protecting carcinoma
cells from apoptosis, and promoting angiogenesis.”
 “The data presented show that melatonin inhibits edn-1 mRNA
expression, the first step in ET-1 synthesis.”
 “In conclusion, melatonin may be useful in treating colon
carcinoma in which the activation of ET-1 plays a role in tumour
growth and progression.”
Melatonin as a potential anticarcinogen
for non-small-cell lung cancer.
Ma Z, Yang Y, Fan C. Oncotarget. 2016 Jul 19;7(29):46768-46784

 “Melatonin exerts pleiotropic anticancer effects against a variety

of cancer types.”
 “Herein, we review the correlation between the disruption of
the melatonin rhythm and NSCLC incidence.”
 “We also evaluate the evidence related to the effects
of melatonin in inhibiting lung carcinogenesis. Special focus is
placed on the oncostatic effects of melatonin, including anti-
proliferation, induction of apoptosis, inhibition of invasion and
metastasis, and enhancement of immunomodulation.”
 “We suggest the drug synergy of melatonin with radio- or
chemotherapy for NSCLC could prove to be useful.”
Melatonin as a treatment for gastrointestinal cancer: a
review.
Xin Z, Jiang S, Jiang P. J Pineal Res. 2015 May;58(4):375-87.

 “The ability of melatonin to inhibit gastrointestinal cancer is substantial.”

 “In this review, we first clarify the relationship between the disruption of
the melatonin rhythm and gastrointestinal cancer.”
 “The mechanisms through which melatonin exerts its anti-
gastrointestinal cancer actions are explained, including inhibition of
proliferation, invasion, metastasis, and angiogenesis, and promotion of
apoptosis and cancer immunity.”
 “We discuss the drug synergy effects and the role of melatonin receptors
involved in the growth-inhibitory effects on gastrointestinal cancer.
 “The information compiled here serves as a comprehensive reference for
the anti-gastrointestinal cancer actions of melatonin that have been
identified to date.”
Melatonin uses in oncology: breast cancer prevention
and reduction of the side effects of chemotherapy
and radiation.
Sanchez-Barcelo EJ, Mediavilla MD, Expert Opin Investig Drugs. 2012 Jun;21(6):819-31.

 “Because of its SERM (selective estrogen receptor modulators) and

SEEM (selective estrogen enzyme modulators) properties, and its
virtual absence of contraindications, melatonin could be an
excellent adjuvant with the drugs currently used for
breast cancer prevention (antiestrogens and antiaromatases).”
 “The antioxidant actions also make melatonin a suitable treatment
to reduce oxidative stress associated with chemotherapy, especially
with anthracyclines, and radiotherapy.”
 Melatonin’s anti-estrogenic properties are especially useful for breast
cancer prevention in cases of obesity, steroid hormone treatment or
chronodisruption by exposure to light at night.
Protective and sensitive effects of melatonin combined
with adriamycin on ER+ (estrogen receptor) breast cancer.
Ma C, Li LX, Zhang Y, Xiang C, Eur J Gynaecol Oncol. 2015;36(2):197-202.

 ER+ breast cancer rat model was established and then rats were randomly divided
into five different groups as follows: control group, Diss group, adriamycin (ADM)
group, MLT group, and MLT combined with adriamycin (M+A) group.
 Tumor weights were significantly lighter in M+A group than those in ADM group (p <
0.05). Under optical and electro-microscopy, tumor cell apoptosis was obviously
increased in MLT group, and tumor cell injury was more severe in M+A group than
that in ADM group.
 Decreased E-cadherin expression in cancer cells increases proliferation, invasion,
and/or metastasis. Expression of E-cadherin was higher in MLT group and M+A
group than that in other groups.
 MLT group had the highest one month survival rate (100%), there was the poorest
life quality in ADM group, but the best life quality in MLT.
 “MLT could enhance the sensitivity of tumor to ADM in vivo and improve patient's
life quality.”
Physiological and pharmacological concentrations
of melatonin protect against cisplatin-induced acute
renal injury. J. Pineal Res. 2002 Oct;33(3):161-6.

 Acute tubular necrosis is a major side effect of cisplatin

 “Melatonin is a direct free radical scavenger and indirect antioxidant.”
 “We investigated the effects of melatonin on cisplatin-induced changes
of renal malondialdehyde (MDA), a lipid peroxidation product, and blood
urea nitrogen (BUN) and serum creatine (Cr). The morphological changes in
kidney were also examined using light microscopy.”
 Melatonin administration either before or after CDDP injection caused
significant decreases in MDA.
 The morphological damage to the kidney induced by cisplatin was reversed
by melatonin.
 “The results show that pharmacological and physiological
concentrations of melatonin reduce cisplatin-induced renal injury.”
Melatonin as a radioprotective agent: a review.
Vijayalaxmi, Reiter RJ, et al. Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):639-53.

 Melatonin is both a direct and indirect free radical scavenger.

 The radical scavenging ability of melatonin works via electron
donation to detoxify hydroxyl radical.
 Ionizing radiation results in the production of hydroxyl radical.
 “The results from many in vitro and in vivo investigations have
confirmed that melatonin protects mammalian cells from the
toxic effects of ionizing radiation.”
 Furthermore, several clinical reports indicate that melatonin
administration, either alone or in combination with
traditional radiotherapy, results in a favorable efficacy:toxicity
ratio during the treatment of human cancers.
Melatonin for Prevention of Breast Radiation Dermatitis: A
Phase II, Prospective, Double-Blind Randomized Trial.
Ben-David MA, Elkayam R, et al. Isr Med Assoc J. 2016 Mar-Apr;18(3-4):188-92.

 Radiation-induced dermatitis is commonly seen

during radiotherapy for breast cancer.
 randomized, placebo-controlled double-blind study, patients
randomly allocated to topical cream twice daily use
during radiation treatment and 2 weeks following the end
of radiotherapy.
 Grade 1-2 acute radiation dermatitis was 59% vs. 90% in
the melatonin group.
 “Patients treated with melatonin-containing emulsion experienced
significantly reduced radiation dermatitis compared to patients
receiving placebo.”
Dosing

 Only red lights in the bedroom.

 Prevention: 180 mg about 30 minutes before
bedtime.
 Treatment: 60 mg 3-6x/day
 300mg two hours before PET/CT
 Melatonin Max – 60 mg pure capsules
(www.scientifichealthsolutions.com)
 Melatonin powder – www.purebulk.com
 Zero contraindications