Glucosamine is a molecule that is part of a major biomolecular group called glycosaminoglycans.  This category of large complexes exist as negatively charged carbohydrate chains that are usually associated with proteins. What makes glycosaminoglycans essential for joint function is their ability to bind large amounts of water, which produces a gel-like extracellular matrix. A web of ground substance made of glycosaminoglycans is interspersed with insoluble protein fibers, making up the connective tissues found in joint cavities and other locations throughout the body. Varying amounts of the ground substance containing tissue fluid, along with the given amount of fibrous proteins, denotes connective tissue types; either collagen, reticular, or elastic fibres.
Glucosamine is a basic building block of the carbohydrate portion of glycosaminoglycans. The unbranched heteropolysaccahride is made up of a repeating string of an amino sugar joined to an acidic sugar. Glucosamine, as its name implies, is the amino sugar. It also functions to stimulate proteoglycan synthesis, inhibit proteoglycan catabolsim, and works to incorporate sulfur into cartilage.  When cartilage is damaged experimentally, glucosamine rebuilds it.
Glucosamine sulfate is the most popular form of glucosamine taken as a nutritional supplement. Some researchers have even suggested that the sulfated form appears to have a particular affinity for cartilage and other joint tissues.  However, Glucosamine hydrochloride has provided for similar efficacy, and may be a more relevant choice as it is not stablized with sodium chloride. The hydrochloride form offers a more concentrated source of glucosamine, as there is no need to stabilize glucosamine hydrochloride with salt.
Glucosamine is made in the body from glucose and the amino acid glutamine. Therefore an adequate supply of glutamine is necessary.  Food sources containing high concentrations of glutamine include raw parsley and spinach. Glucosamine itself, is found in the largest amounts in cartilage tissue. Cartilage-containing products are available and include those harvested from shark and bovine sources. Glucosamine may also found in extracts produced from the tough outer covering of shellfish, which is made up of chitin. 
Glucosamine is most commonly known as an effective treatment for osteoarthritis. A large trial of 1208 subjects conducted in numerous medical centers across Portugal studied the effects of 1500 mg of oral glucosamine sulfate daily, for treatments of arthroses of shoulder/elbow, knee, vertebral column, tibio-tarsal joints, and hips.  Treatment periods lasted an average of 50 days. The results concluded that pain symptoms, at rest and with activity, improved. Active and passive mobility also increased and continued steadily throughout the treatment. In addition, these noted effects lasted for 6 - 12 weeks after glucosamine was discontinued.
Numerous studies have compared the efficacy of glucosamine sulfate to that of the popular over-the-counter anti-inflammatory medication, ibuprofen. [6-8] An early trial was conducted upon 40 patients with osteoarthritis of the knee received 500 milligrams of glucosamine sulfate orally three times daily, or 1.2 grams per day of ibuprofen for eight weeks. The results showed that even though both pain relief and the rate of improvement was faster in the ibuprofen group during the first two weeks, by the eighth week glucosamine sulfate was the dominant treatment showing significantly greater efficacy. 
Another trial of 178 subjects with knee osteoarthritis demonstrated improved effectiveness of glucosamine sulfate over ibuprofen, using the same doses as the previous study, but for a duration of only 4 weeks.  Furthermore, there was a lower incidence of adverse effects and no drug-related drop-outs in the glucosamine group. When glucosamine was compared to piroxicam in a large randomized trial of patients with osteoarthritis of the knee, it also showed improved efficacy over this drug therapy with no reported side effects. 
Glucosamine has also been administered as an intramuscular or intravenous therapy for osteoarthritis as well. An early double-blind controlled study of 30 subjects with chronic degenerative arthritis was conducted using daily injections of 400 milligrams of glucosamine sulfate or piperazine plus chlorbutanol, followed by oral maintenance therapy (500 milligrams three times daily of glucosamine sulfate) or placebo.  The results showed that symptom scores were significantly improved in the glucosamine group versus control, with no adverse effects reported. Another placebo-controlled study of 155 patients with knee osteoarthritis given 400mg of glucosamine sulfate two times per week by intramuscular injection showed similar results; again, with the absence of adverse effects. 
In addition to addressing physical symptoms, glucosamine therapy for osteoarthritis has demonstrated improvements in tissue pathology. Scanning electron microscopy revealed a picture resembling healthy cartilage in patients given glucosamine sulfate for 30 days, while patients taking placebo showed the typical picture of damage caused osteoarthrosis. 
A recent in vitro study demonstrated that glucosamine (>0.01 mM) dose-dependently suppressed platelet aggregation in response to ADP (a known stimulant of platelet aggregation).  In addition, glutamine also inhibited the release of granule constituents, thromboxane A2 production, calcium mobilization and phosphorylation of Syk, possibly via the inhibition of ADP-binding to the receptors. The authors concluded that glucosamine could be expected as a novel anti-platelet agent for thrombotic disorders, due to its suppressive actions on platelets.
There is no established Recommended Dietary Allowance (RDA) for glucosamine. Doses of glucosamine sulfate for osteoarthritis that have been reported in study range from 500 milligrams of oral supplementation, three times daily; to 400 milligrams, administered twice per week via intramuscular injection. Generally, it takes approximately three weeks to one month to observe clinical effects. Maximum effect is noticed by months two and three of supplementation.
When taking glucosamine sulfate following articular injury, generally double the oral dose is indicated for the first two months; followed by the regular dose for maintenance therapy.  A transdermal delivery system is currently being investigated to improve patient compliance. 
Patients with peptic ulcers should take glucosamine sulfate with food, while those taking diuretics may need to increase their dosage to compensate for the reduced effectiveness of glucosamine when taking these drugs.
Glucosamine is not an essential nutrient. As it can be made in the body, a true deficiency state has never been reported. Glucosamine sulfate is considered a therapeutic substance. However, as some people age their body’s ability to produce adequate amounts of glucosamine declines. Supplementation can be quite beneficial.
Glucosamine is generally considered a safe therapeutic substance when taken in recommended doses. The majority of studies reveal the absence of adverse effects in patients taking glucosamine sulfate, although side effects were noted in a large multi-centre trials, including; gastrointestinal discomfort, drowsiness, skin reactions, and headache.  These complaints were later found to be related to pre-existing gastrointestinal disorders and concomitant diuretic treatment.
A significant review of the safety of glucosamine was published in 2005.  The study found that altered glucose metabolism can be associated with the parenteral administration of large doses of glucosamine. However, the oral administration of large dosed glucosamine-containing supplements does not adversely affect glucose metabolism.
Clinical trial data for 3063 human subjects showed that fasting plasma glucose values decreased slightly for subjects after treatments with oral glucosamine; for approximately 66 weeks. Side effects were minimal, and no serious or fatal effects were documented with glucosamine versus placebo or other non-steroidal anti-inflammatory drugs (NSAIDs). The authors conclude that glucosamine is safe under its current condition of use and its supplementation does not affect glucose metabolism.
The LD50 of oral glucosamine in animals is approximately 8000 mg/kg with no adverse effects at 2700 mg/kg with continued administration over a 12 month period. 
1. Champe PC and Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. JB Lippincott Company, Philadelphia, PA, 1987:81.
2. Murray M and Pizzorno J. Encyclopedia of Natural Medicine, 2nd Ed. Prima Publishing, Rocklin, CA 1998:698.
3. AANP. Nature’s Pharmacy- Your Guide to Healing Foods, Herbs, Supplements and Homeopathic Remedies. Publications International Ltd., Lincolnwood, IL 2001;274.
4. Balch PA. Prescription for Nutritional Healing: The A-Z Guide to Supplements, 2nd Ed. Penguin Putnam, Inc. New York, NY 2002;172-173.
5. Tapadinhas MJ et al. Oral glucosamine sulphate in the management of arthrosis: a report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3:157-168.
6. Vaz AL. Double blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthritis of the knee in outpatients. Curr Med Res Opin 1982;8:145-149.
7. Qiu GX et al. Efficacy and safety of glucosamaine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforsch 1998;48:469-474.
8. Muller-Fabbender H et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarth and Cart 1994;2:61-69.
9. Rovat Et al. A large randomized placebo-controled double-blind study of glucosamine sulfate vs. piroxicam and vs their assocaitiion on the kinetics of the symptomatic effect in knee osteoarthirits. Osteoarthritis Cartilage 1994;2(Suppl 1):56.
10. D’Ambrosio E et al. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmtherapeutica 1981;2:504-508.
11. Reichelt A et al. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomized, placebo-controlled, double-blind study. Arzneimittelforsch 1994;48:469-474.
12. Drovanti A et al. Therapeutic activity of oral glucosamine sulfate in osteoarthritis: a placebo-controlled double-blind investigation. Clin Ther 1980;3:260-272.
13. Hua J et al. Glucosamine, a naturally occurring amino monosaccharide, suppresses the ADP-mediated platelet activation in humans. Inflamm Res 2004;53(12):680-8.
14. Mantle D, Wilkins RM, Preedy V. A novel therapeutic strategy for Ehlers-Danlos syndrome based on nutritional supplements. Med Hypotheses. 2005;64(2):279-83.
15. Musnick D. Sports Medicine Class Notes. Bastyr Univeristy, Kenmore, WA 2003.
16. Kanwischer M et al. Evaluation of the physicochemical stability and skin permeation of glucosamine sulfate. Drug Dev Ind Pharm 2005;31(1):91-7.
17. Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol 2005;43(2):187-201.