Glucosamine

Glucosamine (2-amino-2-deoxy-β-d-glucopyranose) is an aminosugar (sugar molecule with a nitrogen) naturally occurring in the human body and in shellfish.^[1][2] It is present in most body tissues, with high concentrations in joint and cartilage, and is a structural component of Keratin Sulfate (a disaccharide of which Glucosamine sulfate is one of the monosaccharides) and Hyaluronic acid, which is a repeated chain of glucuronic acid and N-acetylglucosamine.^[1]

Glucosamine appears to be a highly popular alternative medicine for knee osteoarthritis (47% of persons confirming usage of alternative medicine with 59% of these users using Glucosamine and 54% using Chondroitin)^[3] and highly used in general, with one survey noting that 5% of the US population used glucosamine supplementation with up to 7 and 9% of elderly women and men, respectively.^[4]

Similar in structure to Hyaluronic acid (Glucuronic acid and N-Acetylglucosamine) os Chondroitin (Glucuronic acid and N-Acetylgalactosamine chains).

In many countries, the amount of Glucosamine found in dietary supplements appears to be unreliable and may be lower than reported.^[5] This was theorized^[2] to be either intentional or from accidental dilution of the active components (glucosamine and, at time, chondroitin) with potassium hydrochloride, an additive which stabilizes glucosamine crystals in supplements.

It was noted^[2] that the combination of lower than reported label doses paired with lower tested concentrations of Glucosamine could have made research artefacts in studies using doses of Glucosamine in the lower therapeutic range (as the benefits of Glucosamine appear to be dose-dependent and may not reach statistical significance if underdosed).^[6][7][8][9]

Historically, the labelling of Glucosamine supplementation has not been wholly accurate when assessing one manufacturer over another; brand and reliable providers may be more important when it comes to selecting Glucosamine supplementation

Glucosamine Hydrochloride (HCl) is a Glucosamine molecule bound to Hydrochloric acid, which upon reaching the intestines is hydrolyzed to form free Glucosamine.^[2][10] Glucosamine HCl is the most basic form of glucosamine supplementation and has been used in some large scale trials such as GAIT^[11] although its usage in this trial has been criticized as at least one meta-analysis that divided glucosamine into HCl and another form (sulfate) failed to find a significant benefit associated with supplemental HCl.^[12]

It has been noted^[13] that of overarching bodies that recommend glucosamine for the treatment of hip and/or knee osteoarthritis that neither the Osteoarthritis Research Society International (OARSI^[14][15]) nor the European League Against Rheumatism (EULAR^[16][17]) recommend the usage of Glucosamine HCl, but suggest the sulfated version instead (although it should be noted that some bodies, such as UK National Institute for Health and Clinical Excellence^[13] and American College of Rheumatology^[18] do not support Glucosamine as a viable treatment and that OARSI has recommended discontinuation of use of any Glucosamine supplement after 6 months if no visible benefit occurs).

Glucosamine Hydrochloride is the reference form of Glucosamine due to its simplicity, but appears to be a subpar version and is not as well recommended as other forms; many trials using HCl report null (no significant) results, and usage of another form of glucosamine (sulfated) is recommended

As mentioned previously, although the boards capable of recommending glucosamine are split in whether to use it or not those that do support its usage (EULAR^[16][17] and OARSI^[14][15]) recommend the sulfate form. The aforementioned meta-analysis that failed to find a significant benefit associated with HCl did find an effect with sulfate.^[12]

Both glucosamine HCl and sulfate are hydrolyzed to form free glucosamine in the intestinal tract of humans following oral ingestion,^[2][10] yet sulfate appears to have an apparent intestinal bioavailability of around 90%^[19] relative to free Glucosamine's bioavailability of around 26%.^[20]

Glucosamine sulfate, relative to Glucosamine per se, appears to be better absorbed for unknown reasons

The half-life of one hour^[21] and bodily AUC (related to tissue deposition) of 28 hours^[22] are enhanced to 56 hours with Glucosamine sulfate.^[23][24]

Excretion rates (urinary) between HCl and sulfate are similar^[25] despite sulfate being noted to reach 6-fold higher levels in plasma than HCl following oral administration.^[2]

Relative to Glucosamine Hydrochloride, Sulfate appears to result in higher tissue concentrations and circulating levels. Trials using Glucosamine Sulfate tend to have more promising results than those using HCl

Sulfate per se may confer some benefit in this regard, and has been noted as being crucial for providing a negative ion for proteoglycans to trap water in a cartilage matrix.^[26] This mechanism is more of an in vitro one and thought to only be practically relevant during sulfer deficiencies.^[27]

The Sulfate group may be an independent factor in joint health, although this is currently at the hypothesis stage and not scientifically validated to a large degree

Glucosamine sulfate can be formed into a salt crystal solution, with a 2:1:2:2 stoichiometric ratio of Glucosamine:Sulfate:Chloride:Sodium.^[28] This is considered a once-a-day formulation rather than thrice daily dosing, and was used in the GUIDE trail,^[28] and is patented by Rottapharma of Germany^[29] and sometimes simply referred to as the 'Rotta formulation' due to this. The once-daily supplementation of the crystal salts of glucosamine appears to be validated^[30] and reach higher circulating levels when compared to glucosamine HCl.^[11] When comparing the salt form using sodium against an equivalent one with potassium as substitute, there may not be any significant differences.^[31]

This formulation of glucosamine has been validated in numerous trials, although there is consistent (not omnipresent) potential conflicts of interest with Rottapharma.^[12][32][33] A Cochrane meta-analysis^[34] noted that the efficacy of glucosamine on reducing pain in osteoarthritis was higher with the Rotta formulation and improving symptoms of osteoarthritis (assessed by the Lequesne Index) relative to studies not using this formulation despite similar overall oral doses and sample sizes. These studies were not all in consensus (positive^{[35][36][37][38][39][24][40]} and null results merely trending towards significance^[41][39]). This particular meta-analysis^[34] did not conduct a publication bias analysis, three meta-analysis conducted either revealed presence of publication bias with glucosamine overall (5 trials^[42]) or no significant evidence of publication bias (15 trials each^[12][43]).

Considered the best form of supplemental glucosamine and unique in the sense it require a single dose daily rather than the recommended thrice daily dosing, although evidence to support this form tends to be intimately linked with the patent holder (Rottapharma) and potential conflicts of interest

As assessed by funnel plots in meta-analyses, there appears to be insufficient evidence to suggest the presence of significant publication bias

Glucosamine tends to have somewhat limited absorption in the intestines, although it has previously been claimed to have 100% bioavailability (when measuring apparent absorption). It has been said that the bioavailability is approximately 26%^[19] although this number may be incorrect as the 14^C label rather than the intact 14^C GlcN-labelled molecule was measured (critiqued here^[44]).

There is no active transport of glucosamine in the small intestine,^[45][22] which may be related to its structural similarity to glucose causing it to have affinity for glucose transporters but subsequently blocking them.^[46][47][45] Glucosamine is a poor substrate for the glucose transporter with its K_0.5 value being greater than 100mM.^[48]

There does not appear to be active transport of glucosamine in the intestine, meaning most absorption would be secondary to paracellular absorption; the exact bioavailability is unknown

Apparent absorption (a ratio of oral ingestion versus how much fecal metabolite is left) appears to be complete (100%), although this may be due to intestinal microflora metabolizing glucosamine.^[49][50] Human and animal Bifidobacteria appears to metabolize glucosamine^[51] as can some Bacteroides spp.^[52]

Some sources claim that there is 100% bioavailability as no significant glucosamine is detected in the feces of animals and humans ingesting oral glucosamine, but this may be a false negative due to intestinal microflora metabolizing glucosamine

In general, absorption of glucosamine in the intestines following ingestion of a standard (1,500mg) dosage of glucosamine tends to result in circulating levels of approximately 3-8µmol/L.^{[53][54][55][56]} Doubling the oral dose to 3,000mg (as sulfate) does not appear to double serum levels^[30] and at least one trial using 7540mg glucosamine sulfate has failed to detect serum levels about 15µmol/L when measured over 180 minutes.^[22]

At least one study has noted that, in a sample of 18 persons, one person failed to experience a spike in glucosamine following supplementation and that serum concentrations were fairly unreliable (1.9-11.5µmol/L) and that the first detectable serum presence varied from 15-90 minutes and T_max values varied from 90-150 minutes.^[55] This study also noted that prior to supplementation, serum glucosamine is below 0.5µmol/L in humans.^[55]

Glucosamine is detectable in the blood following oral administration, and the range of 3-8µmol/L is commonly cited for the approximate circulating levels. The amount of glucosamine that enters the serum, and the time of which it does, appears to be unreliable

When glucosamine has been tested for its interactions with CYP2C9 and CYP2C19, an interaction was not found in otherwise healthy subjects.^[57]

Glucosamine was initially thought the be a building block (substrate) for collagen synthesis, as collagen is highly composed of N-acetylglucosamine in chains of both Keratin and Hyaluronic acid.^[1] In vitro, glucosamine has been found to be taken up into chondrocytes (cartilage cells)^[58] and this increased proteoglycan synthesis was independent of any genomic actions^[59] and independent of antiinflammatory biomarkers.^[60]

The importance of the notion that Glucosamine acts as a building block for joints has been cast in doubt by numerous review articles^[13] as the maximal detected serum level (11.5µmol/L) plausibly contributes to less than 2% of total galactosamine synthesis in cartilage.^[55] In part due to the other mechanisms of action (both collagen synthesis and reducing the rate of collagen degradation) being more plausible and gaining evidence.

Glucosamine was initially thought to act as a substrate of collagen in a similar manner to how dietary protein is a substrate for muscle tissue (as it naturally occurs in the body with high levels in cartilage and synovial fluid); this theory is not too well supported, and lately has been cast in doubt

Another mechanism thought to underlie the benefit of glucosamine supplementation has been through stimulating cartilage synthesis (independent of acting as a substrate), which appears to occur reliably in vitro.^[61] It has been noted^[62] that in vitro studies range from 50-5,000µM in concentration, but that circulating levels of Glucosamine detected in the serum of people following standard dosing regiments tends to be in the range of 3-8µmol/L (with some of the highest detectable serum levels being 12µmol/L).^{[55][34][63][62][26]} Additionally, looking at 1mmol/L of glucosamine in vitro (approximately 83-fold the highest detectable serum concentration) has failed to influence collagen synthesis in chondrocytes.^[64]

Of trials that attempt to measure serum biomarkers of collagen synthesis (CPII) there appears to be no significant effect of Glucosamine treatment.^[65][66][67]

Collagen synthesis technically occurs when a cell is treated with high Glucosamine concentrations, but this does not appear to be practically relevant following oral consumption in humans due to too low a dose reaching the blood

Glucosamine may inhibit Interleukin-1 (IL-1; a mediator of the immune system) induced gene effects, which are known to exacerbate the degradation of collagen in arthritic tissue.^[68] Downstream of inhibiting IL-1 signalling, reduced MMP secretion is noted^[69][70] and less induction of the COX2 enzyme which exacerbates inflammation in cartilage.^[71][72]

Inhibition of interleukin-induced collagen breakdown would ultimately result in a lower rate of collagen degradation, and studies measuring CPX-II (biomarker of collagen breakdown) note that this biomarker is either significantly reduced^[65][66] or trends towards being reduced.^[67]

It is more likely that the mechanism of Glucosamine hindering the rate of collagen degradation via interfering with inflammatory signalling underlies the effects observed with Glucosamine, rather than the previously held theory of Glucosamine acting as a substrate

These mechanisms are more in line with interventions with oral Glucosamine supplementation, as Glucosamine has never been implicating in reversing pathological changes of Osteoarthritis but merely slowing down the progression thereof (Osteoarthritis being a disease state of excessive collagen degradation)

In 250 persons with degenerative lower back pain and chronic osteoarthritis in this joint, Glucosamine Sulfate supplementation at 1500mg for 6 months failed to reduce back pain either at the 6 month period of at follow-up 6 months after the trial ended.^[73] From this study, a subgroup of 45 persons with confirmed Vertebral body marrow changes or high intensity zones (vertabrae findings on MRIs^[74] thought to be related to back pain^[75][76]) were investigated and no significant influence on these MRI biomarkers was observed.^[77]

In general, a systemic review on supplements for the purpose of spinal regeneration found insufficient evidence to recommend glucosamine (or two other main joint supplements, chondroitin and MSM) in improving spinal dysfunction.^[78] This meta-analysis could only find one study on glucosamine in isolation for the spine (unpublished from Rottapharm, and did not get subject to peer review and was excluded from analysis) and two studies^[79][80] confoudned with the inclusion of other compounds and contradictory in their conclusions (effective^[79] and ineffective^[80] combination therapies).

Insufficient evidence to support a beneficial effect of glucosamine on the spine, and the limited evidence that exists not being highly supportive of this notion either

One open-labelled trial using Glucosamine noted that usage of Glucosamine was associated with 80% of persons reporting less joint noise^[81] and another pilot study has concluded a reduction in pain associated with combination therapy of Glucosamine Hydrochloride (1500mg) and Chondroitin Sulfate (1200mg) for a period of 12 weeks.^[82] Furthermore, one trial has noted that Glucosamine Sulfate (1500mg) performed equally to Ibuprofen (1200mg) over a period of 3 months in persons with jaw osteoarthritis (no placebo control).^[83]

A study conducted in persons with osteoarthritis of the temporomandibular joints (jaw) noted that 6 weeks supplementation of 1,200mg Glucosamine sulfate failed to outperform placebo in reducing pain.^[84] This study reported that the primary treatment goal was a 25% reduction in pain as assessed by VAS, and noted that although there was a significant reduction in pain associated with glucosamine relative to its own baseline values that this significance did not carry over when compared to the placebo group (which had an insignificant reduction in pain relative to its own baseline).^[84] This study was short in duration (6 weeks) although the only other blinded study to assess jaw osteoarthritis was confounded with the inclusion of Chondroitin Sulfate.^[82]

Possible benefits in reducing jaw pain and improving jaw functionality in persons with osteoarthritis of the jaw, but insufficient evidence exists to make conclusions on its efficacy

Glucosamine appears to be one of the more popular supplements overall for athletes, due to its interactions with joint health^[85] and is used also by athletes (or active persons) with osteoarthritis alongside NSAIDs.^[86][87]

A study conducted in bicycle racers has noted that Glucosamine at 1,500-3,000mg daily was able to reduce circulating CTX‑II (biomarker for collagen degradation^[88]) without significantly influencing CPII (biomarker of collagen synthesis), BAP, nor NTx (biomarkers of bone formation and resorption, respectively).^[65] The observed effect on CTX-II appeared to be dose-dependent.^[65] In soccer players using similar methodology (1,500-3,000mg daily for 3 months in university level athletes) has also confirmed a reduction of CTX-II without significantly affecting other parameters (C2C, CPII, NTx).^[66] The reduction in CTX-II began to normalize after supplement cessation (although did not completely 3 months after supplement cessation) and was again dose-dependent.^[66]

Multiple studies have noted that glucosamine supplementation, in a dose-dependent manner with most effects at 3g, modify a serum biomarker thought to be indicative of less collagen breakdown. Collagen synthesis does not appear to be significantly affected, and this has been observed in high impact (soccer) and low impact (bicycling) sports

Finally, one study in 106 male athletes with an acute knee injury using either placebo or 1,500mg Glucosamine for 28 days following injury failed to significantly reduce pain or size of the injured knee; only on day 28, but no measurement prior, was there an observable enhancement of knee mobility (9% more range of flexion and 7.1% increase range of tension) in the Glucosamine group relative to placebo.^[89]

One study investigating injury rehabilitation with Glucosamine, and although there were noticeable benefits they took a while to occur and were minor in magnitude

One trial known as GUIDE (Glucosamine Unum In Die (Once a day) Efficacy Trial) sponsored by Rottapharm (was involved with study conductance but not publication, although the lead author has been involved with Rottapharm previously^[28]) using Acetominophen at 3,000mg as a reference drug (preference for osteoarthritis^[18][17]) noted that, in 228 persons with confirmed moderate-severe knee osteoarthritis given 1,500mg of Glucosamine sulfate daily for 6 months noted that, according to the Lequesne index,^[90] glucosamine was associated with a 3.1 point reduction in symptoms which outperformed placebo (1.9) and acetominophen (2.7).^[28] Both glucosamine (39.6%) and acetominophen (33.3%) had more responders than placebo (21.2%) as assessed by OARSI responder criteria (55% pain reduction on WOMAC or moderate improvement on 2/3 subscales of WOMAC).^[90] Glucosamine improved WOMAC function and total scores (improvement in pain was not statistically significance) and outperformed placebo overall; acetominphen also outperformed placebo overall, and the difference between acetominophen and glucosamine on WOMAC total was not significantly different.^[28]

The GUIDE trial noted significant protective effects associated with a particular salt of glucosamine sulfate which outperformed the reference drug for osteoarthritis (Acetominophen). The trial appeared to be well conducted and structured, but has been criticized due to a high possibility for industry influence from Rottapharm

One particularly large trial known as GAIT (Glucosamine/chondroitin Arthritis Intervention Trial^[11]) of 1583 persons with radioscopically confirmed osteoarthritis given 1,500mg Glucosamine (Hydrochloride) and/or 1,200mg Chondroitin for 6 months (200mg Celecoxib as active control) and assessed by the rate of response to treatment (deemed as a 20% decrease in WOMAC score) noted that no treatment (including Celecoxib) was able to significantly outperform placebo when looking at all persons, and that only combination therapy with Glucosamine and Chondroitin was significantly protective when subgroups were restricted to moderate-to-severe osteoarthritis (with the other three interventions trending to significance).^[11] This study did confirm the purity of the supplementation, and noted that while all monotherapies failed to perform significantly the effect size of Celecoxib appeared to outperform both Glucosamine and Chondroitin.^[11]

This study has spurred a deal of commentary^[91] which is mostly positive^[92][93][94] although some of which remark on the huge placebo effect (60% of placebo experienced a 20% reduction in pain symptoms, with this commentary (duplicated)^[95][96] attacking the citations to support 'other trials have noted such a reduction with the placebo effect' for not being an accurate representation of the trial at hand^[97][98]). The GAIT trial has also been criticized for its usage of glucosamine HCl rather than glucosamine sulfate.

The largest trial did replicated efficacy of Glucosamine and osteoarthritis, but when looking at all participants this effect was not significant. It appeared to be significant only when looking at the subgroup with worse baseline pain and symptoms, and a high placebo response may have obscured results a bit

Due to the vast amount of meta-analyses on the topic of Glucosamine, they will be addressed individually. For these topics, the inclusion critera are factors involved in considered which studies to assess while the exclusion criteria are factors involved in considered which studies one will intentionally exclude from the analysis. Results of a meta-analysis vary depending on inclusion and exclusion criteria. Additionally, the closer a 95% CI gets to 0.00 the less the potency of the effects are; crossing the 0.00 mark and having a range that reaches both positive and negative values (ex. -0.02 to 0.10) means the results are not statistically significant

One meta-analysis of studies from 1980-2006 including only randomized, double-blind, placebo-controlled trials of the knee or hip (oral or injection studies) excluding studies that also used Chondroitin supplementation alongside Glucosamine^[12] was able to find 15 studies to meet its criteria, all of which are cited here (^{[99][100][36][101][11][102][40][41][103][104][24][105][39]} with one unpublished study by Rovati et al. 1999 unable to be cited). This study did not control for form of glucosamine supplementation and allowed both sulfate and hydrochloride, but most studies used the standard 1,500mg daily (two used lower doses via injections)

This meta-analysis assessed the hetereogeneity of studies (how significantly they varied) and industry influence. It found that overall there was a positive effect of treatment of rather small magnitude (effect size of 0.35 overall, 95% CI of 0.14-0.56) with independent trials noting a CI of 0.05-0.16 and those associated with potential conflicts of interest noting a CI of 0.47-0.55.^[12] This meta-analysis failed to find evidence for publication bias (Funnel plot) and when assessing only trials using Glucosamine sulfate the effect size was increased to 0.44 (95% CI of 0.18-0.79); at both times when results were pooled the authors made note that this may not be advisable due to the hetereogeneity.

This meta-analysis was criticized^[32] and when its own statistical analysis was conducted and restricted to the three most well conducted trials^[28][39][24] that no significant hetereogeneity was present. The author later notes that this hetereogeneity was present in most meta-analyses conducted (and thus placing causation on industry involvement was misleading) and criticized the inclusion of glucosamine hydrochloride, a form commonly seen as less effective.^[32]

There does appear to be a division between studies that are conducted independently (tend to show promise, but less promising) and studies conducted by potential conflicts of interest (still positive, but more so). It is not certain if these differences are due to the design of the study or due to not publishing poor results, with both being plausible hypotheses but the meta-analysis failing to find evidence of the latter (publication bias)

A meta-analysis (JAMA^[42] on studies between 1966-1999) of published or unpublished double-blind, randomized, placebo-controlled that excluded studies below 4 weeks in length but included all manners of Glucosamine (injections, hydrochloride, and sulfate) that assessed trials by both the reported outcomes as well as standards put forth by the Osteoarthritis research society^[106] found 17 trials that met inclusion criteria although two were excluded due to not providing enough data to be included in meta-analysis (one not being found online^[107]).

It should be noted that this meta-analysis on 15 remaining trials were on both Glucosamine^{[41][36][102][40]} (two not found online) with the remaining being on Chondroitin supplementation. For the glucosamine trials, an effect size of 0.44 was detected with a 95% CI of 0.24-0.64, for pain reduction an effect size of 0.51 (95% CI of 0.05-0.96) and according to the Lequesne index improvements on osteoarthritis reached an effect size of 0.41 (95% CI of 0.14-0.69).^[42]

In a quality assessment by two independent researchers, the quality of individual trails was 35.5+/-12% (with 100% used as ideal reference) and a funnel plot revealed some evidence of publicity bias.^[42] This meta-analysis is somewhat limited on its analysis for glucosamine due to the low quantity of studies assessed.

This meta-analysis looked at minimal studies on glucosamine (as it assessed both glucosamine and chondroitin separately, with only 5 trials meeting the criteria for glucosamine) and found a positive effect on symptoms of knee/hip osteoarthritis but found poor individual study quality and some evidence of publication bias

A later Journal of American Medical Association (JAMA) meta-analysis^[43] of studies between 1980-2002 investigating oral supplementation of glucosamine or chondroitin with no limitations on study inclusion beyond being randomized, double-blind, placebo-controlled, parallel-group, and prospective trials and being more than 4 weeks in length assessing persons with hip or knee osteoarthritis (and studies that had sufficient data for inclusion in meta-analysis).^[43] The resulting search yielded 15 studies for meta-analysis, and 7 studies using glucosamine as Sulfate (Rovati 1997 not found online)^{[105][104][24][39][36][40]} assessing 1020 patients. This is one of the few meta-analyses conducted to not find hetereogeneity in the assessed studies, and reported an effect size of 0.41 (95% CI of 0.21-0.60).

The authors attempted to convert the effect size into more practical units, and concluded that the ability of Glucosamine sulfate to reduce the rate of joint narrowin in osteoarthrisi was around 0.27mm (95% CI of 0.13-0.41mm) associated with 1,500mg glucosamine sulfate for 3 years.^[43] Glucosamine sulfate at this dose was associated with improvments in osteoarthritic symptoms (articular pain, stiffness, and function assessed by WOMAC) of 0.30 (95% CI, 0.11-0.49) but could not find sufficient evidence to calculate an effect size for pain reduction.

This meta-analysis^[43] noted that a funnel plot analysis showed a trend towards asymmetry (P=0.08) and suggested that this may be due to smaller sample studies conferring a larger effect size; mentioning that publication bias is not the only source of funnel plot asymmetry^[108] and that the test has limited statistical power unless significant bias is present.^[109]

A subsequent meta-analysis published in JAMA found significant homogeny between glucosamine trials and a significantly larger effect size of treatment with trials investigating only glucosamine sulfate. Publication bias was not detected at a statistically significant level and deemed to not be relevant to the analysis

A Cochrane meta-analysis in 2001^[110] and updated in 2005^[34] conducted three separate analyses; overall, trials with adequate allocation concealment, and those limited to the Rotta preparation (Glucosamine sulfate as salts).

The meta-analysis, in the overall sense, assessed 20 studies overall (19 published) and although blinding was a prerequisite a placebo control was not (3 trials being comparative between glucosamine and only an NSAID drug^{[111][112][113]}). Studies comparing oral glucosamine to placebo are listed here^{[114][100][104][24][40][105][37][115][103][101][36][39]} and those using injections here.^{[102][35][41]} One study included was investigating the effects of milk protein on osteoarthritis and used Glucosamine as a reference drug.^[116]

Overall, the 20 trials (collective sample of 2570) assessed noted a significant reduction in pain by 28% and improvement in functionality as assessed by the Lequesne Index of 21%, although the benefit appeared to be hetereogeneous; WOMAC ratings of pain, stiffness, and function failed to reach statistical significance. When restricting the trials to only those that had adequate allocation concealment (description of methods to ensure blinding of the protocol) there were no significant effects overall.^[34]

When restricting trials (n=10) to those using the Rotta preparation, the reduction in pain as assessed by the Lequesne Index was approximately double that of the effect size noted overall with similar improvements in functionality via the Lequesne Index; WOMAC again failed to show significant benefit associated with glucosamine.^[34] In studies where the Rotta preparation was compared against a reference NSAID drug, the four trials were evenly divided in either outperfoming NSAID reference drug or being equally effective.^[34]

The common summary states that glucosamine sulfate may improve pain on a scale of 0 to 100 by 13 points.^[34] This Cochrane analysis did not conducted an analysis of possible bias.

This Cochrane analysis is fairly strong in the sense that it investigated all trials and then divided trials based on different criteria. The Rotta preparation appeared to outperform the overall analysis (inclusive of Rotta, glucosamine sulfate and glucosamine hydrochloride), and a difference between the two rating scales used (WOMAC and Lequesne Index) appeared to exist.

The most recent (2010) meta-analysis^[117] with the primary outcomes of measuring pain as well as the progression of knee joint narrowing was able to find 10 trials with minimum samples of 200 (collective sample of 3803) to fit its inclusion criteria; one trial not found online and another being solely on chondroitin.^{[6][9][28][101][39][11][40][24]} Most trials used glucosamine sulfate, although one^[101] requires a switch to glucosamine hydrochloride part way through the study and another merely using hydrochloride.^[11]

Glucosamine was associated with a reduction in pain on a VAS measurement (10cm visual scale) with an effect size of −0.4cm (95% CI of −0.7 to −0.1cm) which did not appear to be significantly different than combination therapy between glucosamine and chondroitin. The meta-analysis noted that they would consider a 0.9cm as clinically significant, and due to the CI of glucosamine being below this predetermined end-point treatment was considered to be statisically significant but not clinically relevant.^[117] A similar trend was noted for joint narrowing, where a small benefit was noted with glucosamine supplementation (−0.2 mm with a 95% CI of −0.3 to 0.0mm) but was not clinically relevant.^[117]

This study noted that although there was a reduction in pain with glucosamine supplementation it did not reach a level where it would be considered to be clinically relevant. In effect, the conclusions are that glucosamine works but not the degree where it would make a good therapeutic intervention for people with hip/knee osteoarthritis

Overall there is undoubtedly a benefit associated with glucosamine sulfate supplementation in delaying the progression of hip/knee osteoarthritis and providing some analgesic (pain relieving) effects although the amount of benefit is questionable. Short term (less than 4 month) studies are highly mixed due to being too short in time, whereas trials over 4 months show promise statisically but probably not to a clinically relevant degree; trials around 3 years in length show a great deal of promise but are confounded with industry influence somewhat (due to a patent on the most effective formulation)

Glucosamine sulfate has repeatedly outperfomed glucosamine HCl in these interventions for unknown reasons, and meta-analyses that include hydrochloride seem to reduce the overall effect size seen with glucosamine per se. The dose of 1,500mg is by far the most commonly used, and whenever comparative studies are done it seems that Glucosamine sulfate is similarly effective as NSAID drugs (Ibuprofen mostly, sometimes Piroxicam or Celecoxib)

In persons with knee osteoarthritis assigned to either Glucosamine (1500mg) or NSAID (1200mg Ibuprofen) and then paired with resistance training of the legs for 12 weeks, both treatment groups as well as placebo experienced similar increases in muscle cross-sectional area and that power improvements were similar between all groups; Ibuprofen experienced a greater strength gain than placebo while Glucosamine and placebo both increased satellite cells more than Ibuprofen (Glucosamine not outperforming placebo) and both treatments reduced workout related pain relative to placebo.^[118]

May reduce pain secondary to physical exercise in persons with osteoarthritis (may not apply to otherwise healthy persons), but does not appear to significantly influence muscle growth or power/strength gains during training

Glucosamine is thought to be involved with glucose metabolism due to its high structural similarity to glucose (differing by merely a carbon exchanged for a nitrogen).^[44] It is investigated in its interactions with glucose metabolism in part due to this, and given the rates of glucosamine usage (5% with 2006 data^[119]) and diabetes prevalence in the US (between 11.7-15.6 persons per 1000 persons over 45 years of age with 2010 data^[120]) it can be estimated that perhaps over 400,000 elderly persons with diabetes and 2.7m persons with pre-diabetes may be exposed to glucosamine supplementation.^[44]

The addition of an N-acetylglucosamine molecule (O-linked β bond) to hydroxyl groups of serine and threonine moieties is a reversible strctural modification of proteins known as N-Glucosamine Acetylation (shorthand of GlcNAcylation^[121][122]). This structural modification is a naturally occuring modification of membrane proteins (nuclear and cytosolic) with some involvement in processes from cell cycle progression and transcription to signal transduction and metabolism.^[123][124]

N-acetylglucosamine, biologically speaking, is involved in structurally and mechanistically modifying proteins and transporters (similar to how free radicals or nitrogen can modify proteins). This is not inherently a good or bad mechanism, just a regulatory one using N-acetylglucosamine as a means to an end

The process of excessive GlcNAcylation from various underlying causes has been linked to poor glucose metabolism, specifically glucose toxicity and hyperglycemia-induced insulin resistance.^[125][126] In vitro using cell cultures, glucosamine can be used to experimentally induce insulin resistance in a reversible manner^[127] with maximal efficacy at 50mM (adipocytes).^[128]

In regards to hexosamine biosynthesis, 2-5% of cellular glucose enters hexosamine biosynthesis to ultimately form uridine diphosphate-N-acetylglucosamine (which donates N-acetylglucosamine molecules during the process of GlcNAcylation).^[129][127] In vitro studies suggest that Uridine diphosphate-N-acetylglucosamine is increased with increasing concentrations of glucosamine^[130] and may subsequently cause oxidative stress to the endoplasmic reticulum^[131] or otherwise interfere with insulin signalling independent of the receptor (possibly related to Akt).^[132][133] Other proteins that have been detected to have possible relevance^[121] include IRS-1,^[129] Fox01,^[134] and CRTC2/TORC2 (hepatic gluconeogenesis).^[135]

Glucosamine, in these settings, does not interfere with GLUT4 mRNA nor the insulin receptor^[136][128] (although previous studies appear to be confounded with a depletion of intracellular ATP in vitro,^[137] controlling for ATP does not appear to change the insulin resistance as outcome^[138][136]). However, GLUT4 translocation to the cell surface appears to be hindered in both myocytes^[139][140] and adipocytes.^[138]

In general, the cellular state of excessive N-acetylglucosamine donation to proteins appeared to be highly related to diabetic pathology and glucosamine can temporarily induce insulin resistance in isolated cells at sufficient concentrations. Increasing glucosamine concentration in a cell increases the amount of N-acetylglucosamine donation that occurs for as long as glucosamine is elevated, but appears reversible

The mechanism in question appears to be via disturbing GLUT4 translocation, although the underlying mechanism prior to this is not fully elucidated

In ex vivo models of intestinal tissue, high concentrations of D-Glucosamine have been noted to interfere with glucose absorption via competitively inhibiting glucose transporters (due to their similar structures having affinity for the same transports).^[46][45][47]

An infusion of glucosamine (3.5mg/kg/min) intravenously to rats was been known to disturb glucose homeostasis (nonsignificantly over 120 minutes) yet caused a significant reduction in insulin secretion in response to high blood glucose (the 315% increase in insulin seen in control was reduced to 46%); this was thought to be due to interfering with pancreatic β-cell function as arginine-stimulated insulin secretion was also hindered.^[141] This dosage (3.5mg/kg/min) has been shown previously to be the peak of insulin resistance induced by glucosamine (as 6.5mg/kg/min was no more effective)^[142] and 0.805mg/kg/min^[143] as well as a 200mg acute bolus (human equivalent of 32mg).^[144]

Injections of 0.1mg/kg/min have shown a significant reduction of glucose disposal rates of 17.2+/-7.3%, and the ED₅₀ of disturbing glucose disposal was thought to be at or below this concentration.^[142]

Infusions of high doses of Glucosamine are able to disturb glucose homeostasis in research animals, which is likely related to the structural similarity of glucose and glucosamine. Although not as potent, lower concentrations of glucosamine infusions (possible achievable by oral ingestion) have been noted to impair insulin secretion to a degree

When looking at studies in humans using intravenous injections, 1.6-5.0µmol/min/kg of Glucosamine (resulting in serum concentrations of 570-1150µmol/L) has reported a slight but significant worsening of glucose tolerance (approximately 10% at 1150µmol/L) as assessed by a glucose tolerance test.^[145] It has been noted^[44] that this plasma concentration is higher than that achieved by oral glucosamine supplementation, which reaches plasma levels of 3-8µmol/L.^{[56][146][55]}

Intravenous administration of glucosamine appears to induce insulin resistance in humans, but to a lesser degree than that observed in rat studies and requires a high circulating concentration of glucosamine

One study in otherwise healthy persons with no abnormal glucose abnormality using 500mg Glucosamine thrice a day (1500mg daily) for 6 weeks noted a rise in serum insulin and a significant reduction in insulin sensitivity (HOMA-IR rising from 2.8 to 3.2; 14% increase); this study noted that 71% of subjects experienced an increase in insulin resistance, and that those with worse insulin sensitivity at baseline were more likely to experienc a worsening of symptoms.^[147] This trend has been noted elsewhere, where although there was an overall nonsignificant effect that the increase in insulin resistance was significant when analyzing only those with undiagnosed high blood glucose in response to an oral glucose tolerance test.^[56]

Conversely, one large (uncontrolled) trial of 1208 persons (92 of which reported having diabetes) using 6-8 week supplementation periods of 1500mg glucosamine sulfate has failed to find a significant impairment of insulin sensitivity when analyzing the subset of persons with diabetes.^[148] Another study in diabetics has failed to find an effect, although this study was short (2 weeks) and of limited persons (12 persons)^[149] but was replicated with a trial of 1,500 glucosamine sulfate and 1,200mg chondroitin sulfate over 90 days which failed to find any significant alteration of biomarkers (although HbA1c trended to increase by 0.05% in the glucosamine group, this faile to reach significance).^[150] Additionally, the GAIT trial^[11] reported HbA1c changes in the diabetic cohort of the study and did not report any significant changes over the trial period.

For studies not assessing those with impaired glucose metaolism, one study in lean and obese subjects using 500mg of Glucosamine thrice a day (1,500mg daily) for 6 weeks failed to find evidence for a worsening of insulin resistance, with no observable effect associated with Glucosamine relative to placebo as assessed by hyperinsulinemic-isoglycemic glucose clamp (independent research)^[151] which was replicated in another study over 4 weeks in a similar cohort of persons and oral doses of glucosamine sulfate.^[152]

Other studies including healthy persons have failed to find an increase in insulin resistance following 3000mg and 6000mg of acute glucosamine supplementation given a glucose tolerance test^[153] and that the standard dose of 1,500mg glucosamine sulfate for 12 weeks has failed to significantly alter serum glucose or insulin (with a trend to reduce glucose in the glucosamine group).^[154]

Finally, in a systemic review on the interactions of supplementation glucosamine and serum glucose in humans^[44] several studies were noted that measured serum glucose (although not a primary outcome of treatment) which failed to find any evidence of insulin resistance associated with supplemental glucosamine.^{[38][35][37][155][105][40][111][156][36]} This review has also noted that, when looking at long term evidence, that there is no evidence for supplemental periods under 3 years using the standard 1,500mg glucosamine sulfate doses for worsening insulin resistance.^[44]

Although there is some sparse evidence for worsening glucose parameters in pre-diabetic subsets, the majority of the evidence suggests that there is no adverse effect of supplemental glucosamine on insulin resistance in either healthy or pre-diabetic subjects

Kashin-Beck disease (KBD) is a degenerative bone disease^[157] characterized by a degradation of cartilage similar in pathology to osteoarthritis.^[158] Due to the similarities between KBD and Osteoarthritis pathology, the usage of Glucosamine in treatment of KBD has been investigated.

One study using combination therapy of Glucosamine (HCl) and Chondroitin sulfate at 1440mg and 1200mg repsectively in 251 adults with KBD noted that after 6 months of treatment combination therapy was significantly more effective than placebo at reducing pain associated with the disease (assessed by WOMAC) with 23.4% of persons reporting more than 20% reduction of symptoms and 15.7% reporting more than 50% reduction of symptoms (stiffness, pain, and mobility).^[159] This study makes note of another (Zhang et al. 2010) with similar results, although it cannot be located online, and a third study using combination therapy of Glucosamine and Chondroitin has also confirmed benefit to KBD symptoms when measuring joint space (a narrowing of joint space seen in KBD as well as osteoarthritis) where 77.4% of the treatment group had a narrowing of less than 0.1mm while 20% of the placebo has such a small decline (conversely, a narrowing between 0.2-0.3mm was present in 37.1% of placebo yet only 6.7% of treatment).^[160]

One other double-blind study has noted that twice daily supplementation of 750mg Glucosamine sulphate (1,500mg daily) for 6 weeks was associated with reduced pain symptoms and improved functionality in adults with KBD, and that the active controls of diclofenac sodium 50mg twice a day (100mg total) and naproxen 300mg twice a day (600mg total) performed equally.^[161]

There appears to be evidence to support the notion that Glucosamine supplementation improves mobility and reduces pain in persons with Kashin-Beck's Disease, which has similar pathology to Osteoarthritis

Ayurveda is a branch of Indian medicine involving interventions with herbs or natural components in a seemingly pharmaceutical manner; considered a traditional medicine, some herbs are currently being validated scientifically in the West and their potency compared to reference standards

One study using combination therapy of Tinospora cordifolia and Ginger (not located online, reported on in this systemic review^[162]) noted that there were no significant differences between Glucosamine control and Ayurvedic intervention on an intent-to-treat analysis on pain (weight bearing) and WOMAC (knee function). Addition of both Emblica officinalis and Boswellia Serrata to the aforementioned formulation (2,000mg total) against 2,000mg Glucosamine daily still performed equally to 2,000mg Glucosamine sulfate, and also performed equally to 200mg Celecoxib.^[163]

Some evidence that Ayurvedic formulations are equally effective as Glucosamine sulfate and some reference drugs, although a potential complication of these studies is the usage of combination therapy (rather than a single isolated compound, making determination of the active ingredient(s) more difficult)

In persons after traumatic elbow injury given Traditional Chinese Medicine (Liuwei Dihuang Decoction, Chushi Tongbi Decoction, or Zuogui Decoction depending on symptoms) versus combination reference therapy (Glucosamine hydrochloride paired with Celecoxib and intramuscular injections of sodium hyaluronate and Triamcinolone Acetonaide Acetate) for 6 months did not note any significant differences between joint range of motion, pain, or biomarkers of daily activity.^[164] This study, however, is highly confounded as both groups used multiple herbs and/or interventions making it difficult to assess the efficacy of any single ingredient, with the TCM interventions being composed of 6, 10, and 8 herbs respectively.^[164]

One study (funding from a producer of Glucosamine but conducted independently) noted that 1,500mg of Glucosamine sulfate taken once daily was approximately equivalent to 3,000mg of Acetominophen over the period of 6 months with both outperforming placebo.^[28]

500mg Glucosamine thrice a day (1,500mg total) for a period of 3 months in hospitalized persons with osteoarthritis, when compared to 400mg Ibuprofen thrice a day (1,200mg daily) noted that while there was no significant difference in pain reduction as assessed by Lequesne's index at the end of the trial that Ibuprofen has quicker effects (being more significant at one week).^[112]

200mg Celecoxib has been once shown to be equally effective as 2,000mg Glucosamine over a period of 6 months in persons with knee osteoarthritis.^[163]

A 24 month study using Glucosamine Sulfate (1,500mg daily), chondroitin Sulfate (1,200mg), their combination or Celecoxib (200mg) with radiographic-confirmed knee osteoarthritis noted that while both Glucosamine Sulfate and Celecoxib trended to reduce WOMAC, no treatment reached statistical significance.^[8]

A study in persons with knee osteoarthritis given either 1,500mg Glucosamine Sulfate once daily or 10g of enzymatically hydrolyzed collagen (single dose) for 90 days noted that Hydrolyzed collagen outperformed Glucosamine Sulfate as assessed by Quadruple VAS and SF-36 questionnaire;^[165] this study was not funded by a producer of either supplement (despite using the brand name product Colatech®), but has a limitation in that the formulation of Glucosamine Sulfate used was not specified to be a salt (currently the only approved form to be supported for once daily usage, with all other forms requiring thrice daily).^[165]

Chondroitin is a common joint health supplement sold alongside glucosamine commonly said to be synergistic. In vitro, the combination of glucosamine and chondroitin in bovine chondrocytes, tenocytes, and ligament at 5 μg/ml glucosamine (23 μM) and 4μg/ml chondroitin sulfate (0.25 μM) was able to induce collagen synthesis in all cell types with more efficacy in ligament (69%) relative to chondrocytes (56%) and tenocytes (22%).^[166] Other studies using higher concentrations have noted synergistic stimulation of collagen synthesis^[167] and are synergistic in inhibiting collagen breakdown.^[168]

In vitro, the two appear to be synergystic in inducing collagen synthesis

A study comparing the circulating levels of glucosamine following administration of either glucosamine (as hydrochloride) alone at 1,500mg or in combination with 1,200mg chondroitin noted that in both healthy subjects taking the drugs once or in subjects with knee pain taking their respective drugs for three months that the overall exposure of the body to glucosamine appeared to be greater when it was taken alone;^[169] the peak exposure (C_max) and overall exposure (AUC) to glucosamine from combination therapy was 63% and 78% that of glucosamine alone in acute usage while AUC in prolonged usage was 58% that of glucosamine alone with chronic usage.^[169]

Exposure to glucosamine may be less when used alongside chondroitin sulfate according to one study

A study which compared the efficacy of Glucosamine (1,500mg) against Chondroitin (1,200mg) and their combination noted that Glucosamine trended to outperform both Chondroitin in isolation as well as combination therapy, although no intervention reached statistical significance; this study also noted the failure of 200mg Celecoxib as active control in persons with knee osteoarthritis.^[8] Additionally, in meta-analyses comparing the overall protective effects of glucosamine against chondroitin and against combination treatment (Glucosamine plus chondroitin) do not support the notion that they are synergistic in reducing the symptoms of osteoarthritis when assessed by osteoarthritis rating scales (WOMAC and Lequesne Index),^[42][43] although a secondary analysis from a larger scale trial (GAIT,^[8] testing both glucosamine as hydrochloride and chondroitin) found that chondroitin may have a practical additive benefit of reducing joint swelling.^[170]

Intervention research does not currently support the notion that glucosamine and chondroitin are synergistic for reducing pain and symptoms of osteoarthritis (with most benefit coming from glucosamine intervention alone) although there may be a practical benefit of reduce joint swelling with chondroitin

Methylsufonylmethane (MSM) is a joint health supplement, sometimes seen as one of the major ones following both glucosamine and chondroitin.^[171][172] Glucosamine and MSM are sometimes used together due to both being involved with joint health and osteoarthritis, while the inclusion of sulfur groups in MSM is though to make up for the lack of sulfur in glucosamine HCl (sulfur of which is possible an indepenent factor in joint health^[173]). This combination is called 'Glucosamine MSM'.^[174]

In thirty obese women with knee osteoarthritis who began an exercise regimen, a combination supplement of glucosamine (1,500mg HCL), chondroitin (1,200mg sulfate), and MSM (900mg) noted that while there was no significant influence on any health biomarker or the perception of pain (SF-36 and VAS rating scales) between groups the combination therapy appeared to have a greater functional aerobic capacity ().^[175] This study is less then adequate due to also comparing high protein to a high carbohydrate diet (whittling the sample of 30 down to 7-8 in any single group) and having the supplement further confounded with Zinc (45mg), Rutin (15mg), Boswellia Serrata (300mg), and 180mg white willow bark.^[175] Another study that is equally confounded (Glucosamine and chondroitin paired with MSM, Guava, and Vitamin D) has been conducted and notes a benefit with combination therapy.^[176]

One better conducted study using both a glucosamine (1,500mg; form not stated) and MSM (1,500mg) group as well as their combination alongside a fourth group given placebo noted that in persons with knee osteoarthritis over 12 weeks of supplementation all three interventions were effective in reducing pain and swelling, with combination therapy was just as effective in reducing pain (Lequesne Index).^[100] Only on one parameter, joint swelling, was combination therapy more effective than monotherapties.^[100]

Sometimes used together, but there is insufficient evidence to support a synergistic interactions between MSM and glucosamine. The limited evidence suggests that combination therapy is somewhat subadditive (a 1 + 1 = between 1-2 relationship, where additive is 1 + 1 = 2 and synergistic is 1 + 1 = more than 2)

In persons with mild to moderate knee osteoarthritis given either Glucosamine (Sulfate) at 1,500mg daily either in isolation or paired with an NSAID drug (Ibuprofen or Piroxicam) noted that while Glucosamine was effective in reducing pain at 12 weeks relative to baseline that combination therapy outperfomed Glucosamine in isolation.^[177]

Quercetin is a bioflavonoid that has been suspected of alleviating arthritic pain secondary to interactions with the immune system^[178][179] and is thought to alleviate damage to cartilage secondary to this and its antioxidant properties (oxidation has been noted to higher degrees in arthritic cartilage^[180] and is correlated with the extent of damage^[181]).

An oral supplement of Quercetin glycosides (3-{4-O-α-glucosyl}1-6-O-β-glucosides derived from Styphnolobium japonicum) alongside both Glucosamine and Chondroitin appears to outperform placebo in regards to pain reduction in persons with osteoarthritis^[182][67] and a trend to reduce urinary CTX-II (indicative of reduced cartilage breakdown) has been noted.^[67]

Quercetin has been tested alongside Glucosamine and Chondroitin in regards to reducing the symptoms of arthritis, but insufficient evidence exists to support the notion that it is significantly better than simply Glucosamine and Chondroitin (theoretically is, has not been demonstrated)

Fish Oil is mostly a combination of two fatty acids known as Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA).

One study comparing 1,500mg glucosamine sulfate against the combination of glucosamine sulfate with fish oil (1332mg total with 600mg omega-3 fatty acids) noted that there was no significant difference in primary outcome (a 20% reduction in pain via WOMAC) but when the criteria were bumped up (80% pain reduction at the end of 26 weeks) it was noted that combination therapy was slightly but significantly more effective than Glucosamine alone.^[183]

There is some evidence that the benefits of Glucosamine and Fish oil on joint pain associated with osteoarthritis may be additive

D-pinitol (3-O-methyl-chiro-inositol) is a small molecule similar to Inositol which appears to be recommended for its anti-diabetic properties, and it inherently has minor anti-inflammatory properties. Oral ingestion of 20mg/kg D-pinitol and 25mg/kg glucosamine both exert minor anti-inflammatory effects, but the combination appears to be synergistic in a Cotton pellet granuloma test but not carrageenan-induced paw edema;^[184] despite the synergism, the combination failed to outperform the reference drug of 100mg/kg aminopyrine.^[184]

Synergistic with D-pinitol, but even the combination fails to outperform the reference drug

Boswellia serrata is an ayurvedic herb that also appears to have anti-osteoarthritic properties.

A study using either glucosamine or boswellia serrata at 250mg/kg or their combination at 125mg/kg each (to total 250mg/kg) oral ingestion to rats appeared to support anti-arthritic synergism (although the acute inflammatory response was unaltered).^[185] The anti-arthritic synergism over the course of 13 days seemed comparable to 100mg/kg Ibuprofen.^[185]

Synergistic with glucosamine, but even after synergism is accounted for it fails to outperform the reference drug

Although not a nutrient, physical exercise appears to also be a recommendation to persons with knee and/or hip osteoarthritis to alleviate pain symptoms.^[186]

One small trial in sedentary persons deemed low active who were given 1,500mg Glucosamine sulphate daily for 6 weeks and then given a walking program of at least 3000 steps daily noted that there appeared to be improvements from both walking and Glucosamine; increasing steps to 6000 failed to enhance the pain reduction, and there was no control group not given a walking program.^[187]

Doses of up to 2000mg a day have been deemed most likely safe for long-term side effects in a risk assessment^[188] while multiple meta-analysis' conducted on the usage of Glucosamine (usually as Sulphate) at doses of up to 1,500mg (with or without the inclusion of up to 1,200mg Chondroitin Sulphate) note that these doses are not associated with side-effects that are more prevalent than placebo treatment.^{[42][117][34][43]} In regards to position statements on Glucosamine by the Osteoarthritis Research Society International (OARSI^[14][15]), the European League Against Rheumatism (EULAR^[16][17]) the American College of Rheumatology^[18] and the UK National Institute for Health and Clinical Excellence^[13] Glucosamine is generally recognized as a safe nutritional intervention (the positions seem split on the efficacy thereof, but safety appears to be consensus).

Glucosamine supplementation at or around the most commonly used dosage of 1,500mg appears to be quite a safe supplemental intervention as assessd by previous human trials and toxicological studies

Acute liver injury has been associated with supplemental Glucosamine, where the observed spike in serum liver enzymes (indicative of hepatotoxicity) was lowered after supplement cessation; causation could not be placed on the Glucosamine molecule.^[189] Another case study in a male experiencing autoimmune hepatitis placed probably causation on the ingested Glucosamine and Chondroiton supplement, and the autoimmune hepatitis was treatable.^[190]

There have been case studies on Glucosamine and liver complications, which have placed probably causation on the supplement used (without analyzing the structure of the supplement). The possibility of additives to the supplement cannot be ruled out