Black Ginger

Kaempferia parviflora (of the family Zingiberaceae) is a medicinal herb from Thailand that has purported usage as an aphrodisiac as well as general health promotion and stimulation.^[2] Other usages touted towards this herb include anti-depressive, anti-peptic ulcer, anti-inflammatory, anti-mutagenic and anti-allergic; it is sometimes referred to as Kra chai Dum or just as a Thai Ginseng^[1] (although taxonomically unrelated to Panax Ginseng).^[3] It is also sometimes referred to as 'Black Turmeric' due to sharing similar morphology to Curcuma Longa (source of dietary Turmeric), but these two compounds do not have similar bioactives and Kaempferia Parviflora does not have a curcumin content.^[4] It should be noted that sources of confusion here is Curcuma Parviflora, another herb with a similar name to both^[5] and Kra chai (rather than Kra Chai Dum) being used to refer to Boesenbergia rotunda.^[6]

Kaempferia parviflora is Thai Ginseng, and commonly called Black Turmeric (since the root is purplish-black underneath the outer layer) although not related to the common spice Turmeric

• The three 'main' methoxyflavonoids 5,7-dimethoxyflavone (DMF) at 0.289%, 5,7,4'-trimethoxyflavone (TMF) at 0.0101% and 3,5,7,3',4'-pentamethoxyflavone (PMF)^[2][7] and a variety of other polymethoxyflavonoids^[8]
• 5-hydroxy-3,7-dimethoxyflavone at 0.0252%; a methoxyflavone that appears to be well reseached but is not one of the 'primary' three^[7]
• Kaempferiaosides A and B with similar glycosides^[9] as well as Kaempferiaosides C and D (flav-3-en-3-ol glycosides) as well as E and F (acetophenone glycosides)^[3]
• Techtochrysin (Methoxy derivative of Chrysin) at 0.131% dry weight^[7]
• 7,4′-dimethylapigenin at 0.0453%, trimethylapigenin at 1.29% (methylated derivatives ofo Apigenin)^[7]
• Tetramethylluteolin at 0.0312% (derivative of Luteolin)^[7]
• 3,7,4′-trimethylkaempferol at 0.0719% and tetramethylkaempferol at 0.0070% (derivatives of Kaempferol)^[7]
• Tilianine (Methanolic fragment)^[9]
• Ayanin at 0.0111%^[7]
• Retusine at 0.0215%^[7]
• Pentamethylquercetin at 0.391% (Methylated derivative of Quercetin)^[7]
• Sesquiterpenoids 4αα-acetoxycadina-2,9-diene-1,8-dione and 1αα,3αα,4ββ-trihydroxy-9-cadinen-8-one^[10]
• (2R,3R)-(−)-aromadendrin trimethyl ether (ethanol acetate fragment)^[9]
• Tamarixetin 3-O-rutinoside (Methanolic fragment)^[9]
• Syringetin 3-O-rutinoside (Methanolic fragment)^[9]
• 2,4,6-trihydroxyacetophenone 2,4-di-O-β-D-glucopyranoside^[9]
• Adenosine^[9]
• L-phenylalanine^[9]
• A thermostable lectin (sugar-binding protein) in the rhizome at 0.45%^[11]

Due to the high methoxyflavone content, this plant has a respectable anti-oxidant profile in vitro.^[12] Some of the above methoxyflavones also exist in glycoside form.^[13]

In general, the 'Kaempferosides' appear to be unique to Kaempferia Parviflora but are not seen as the active ingredients. The methoxyflavones (flavones with methoxy groups attached to them) are seen as the main compounds, with the three known as DMF, TMF, and PMF being most commonly researched. This plant also appears to take standard bioflavonoid compounds and add either methoxy or methyl groups to their structures

In testing oral pharmacokinetics of an ethanolic extract of Kaempferia parviflora given at 250mg/kg (9.44, 9.75, and 10.58 mg/kg of PMF, TMF, and DMF) with another group of rats given injections of the same dose (to assess bioavailability), the following parameters were achieved.^[2]

5,7-dimethoxyflavone (DMF) had a C_max of 0.78+/-0.11ug/mL at a T_max of 0.76+/-0.4 hours with an AUC of 7.01+/-1.37h/ug/mL and a half-life of 5.85+/-1.72 hours; the overall bioavailability was determined to be 2.1%.^[2] 5,7,4'-trimethoxyflavone (TMF) had a C_max of 0.88+/-0.11ug/mL at a T_max of 0.85+/-0.40 hours with an AUC of 6.96+/-1.11h/ug/mL and a half-life of 5.04+/-1.10 hours; the bioavailability was 1.75%.^[2] 3,5,7,3',4'-pentamethoxyflavone (PMF) had a C_max of 0.55+/-0.05ug/mL at a T_max of 1.71+/-0.36 hours with an AUC of 3.65+/-0.63h/ug/mL and a half-life of 3.12+/-1.34 hours; the bioavailability was 3.32%.^[2]

The methoxyflavanoids appear to be poorly yet quickly absorbed with a relatively long half-life

The three main methoxyflavones were found in tissues of rats after an acute bolus of 750mg/kg reaching the brain, testes, liver, kidney, and lung.^[2]

All three main methoxyflavones had a similar degree of fecal excretion, with PMF and TMF having a high urinary excretion relative to DMF.^[2]

Kaempferia parviflora extract can, in vitro alter CYP1A1 (induction; non-competitive), CYP1A2 (induction; mixed competitive), CYP2B (induction; competitive), and CYP2E1 (induction; uncompetitive) without affecting CYP3A enzymes.^[14]

The rhizome extract appears to also inhibit the Xanthine Oxidase enzyme to a degree of 38% at 500mcg/mL concentration (underperforming the active control of Allopurinol at 10uM inhibiting 44%).^[4] Isolated methoxyflavones were tested on Xanthine Oxidase, and most showed weak inhibitory potential aside from 3',4',5,7-tetramethoxyflavone (36% at 400uM) and PMF (54% at 400uM), both still underperforming Allopurinol.^[4]

After an acute bolus of 750mg/kg Kaempferia parviflora (9.44, 9.75, and 10.58 mg/kg of PMF, TMF, and DMF), PMF reached the brain with a C_max of 0.26+/-0.10ug/g and a T_max of 3.14+/-1.07 hours giving an overall neural AUC of 0.76+/-0.13ug/g/h,^[2] TMF reached the brain with a C_max of 1.43+/-0.58ug/g and a T_max of 3.43+/-0.98 hours giving an overall neural AUC of 2.50+/-0.37ug/g/h,^[2] and DMF reached the brain with a C_max of 0.96+/-0.37ug/g and a T_max of 3.14+/-1.07 hours giving an overall neural AUC of 1.91+/-0.56ug/g/h.^[2]

Oral administration of Thai Ginseng is able to increase methoxyflavone concentrations in the brain, but slightly due to poor bioavailability

Several compounds from Kaempferia Parviflora have been tested for acetylcholinesterase inhibitory potential at a concentration of 0.1mg/mL (appears to be well above what DMF, TMF, and PMF have been recorded to be in the brain) and noted that Acetylcholinesterase is inhibited weakly by DMF and TMF in the range of 42.6-47.1%.^[15] Other compounds were either less effective or wholly ineffective.^[15]

butyrylcholinesterase is inhibited most potently by DMF (84.6+/-1.3%) which neared the inhibitory potential of Galantamine as active control (95.5+/-1.4%); other notable inhibitions were TMF (46.2+/-1.4%) and 5-hydroxy-7,4'-dimethoxyflavone (22.8+/-0.1%).^[15]

Possesses cholinergic properties, but is unlikely to be practically significant due to the concentrations required (unless bioavailability is otherwise enhanced)

One study in obese (TSOD) and lean (TSNO) mice given 1% or 3% of their feed as Kaempferia Parviflora for 8 weeks noted that supplementation at either dose was able to preserve reaction latency to a pain test but only in the obese group; the authors hypothesized that TSOD obese mice developed diabetic neuropathy and that Kaempferia Parviflora attenuated these changes.^[16] The only human study to assess pain was a human study measuring the Rate of Perceived Exertion (RPE) on an exercise test, and found no effect with an acute bolus of 1.35g.^[1]

One study in sexually mature rats given 70mg/kg bodyweight Kaempferia parviflora daily noted that supplementation was able to increase mounting frequency and reduce ejaculatory latency (indicative of aphrodisiac effects) and was nonsignificantly additive with exercise; post ejaculatory latency was seemingly unaffected.^[17] This has been replciated elsewhere, but the hexane and aqueous extracts were ineffective at decreasing mounting and ejaculatory latency.^[6] Interestingly, one study using a higher dose (240mg/kg) noted inhibitory effects on aphrodisia in rats^[18] and one using 1g/kg noted no significant differences between groups.^[19]

Some evidence that 70mg/kg in rats (human dose of 11.2mg/kg ethanolic extract) is an aphrodisiac, while higher doses may be adverse; the increase in sexuality does not appear to be too remarkable in magnitude

In primary cultured rat cortical cells treated with high levels of glutamate (sufficient to bring controls 100% viability to 0%), 5‐Hydroxy‐3,7,3′,4′‐tetramethoxyflavone was found to be protective in a concentration dependent manner from 0.1uM (13.4+/-0.5% survival) to 10uM (63.4+/-1.4% survival).^[20] This was less protective than the active controls of CNQX and MK‐801, but of similar potency to Amino‐5‐phosphonovaleric acid (APV).^[20] Other methoxyflavones were either ineffective (TMF and 5‐Hydroxy‐3,7‐dimethoxyflavone) or less protective.

Moderate neuroprotection from one compound; practical relevance of oral supplementation unknown

A study in anaesthesized rats injected with 12.5 or 100mg/kg Kaempferia parviflora was shown to increase cGMP content of cardiac tissue at the higher dose (to a lesser degree than the active control of 4mg/kg Sidenafil) with no effect at 12.5mg/kg, and this via a NOS-cGMP pathway (abolished by L-NAME, an inhibitor of NOS).^[21] Concentrations of 100mcg/mL have been found to protect cardiac contracility after Ischemic injury, possibly secondary to anti-oxidant effects.^[22]

Flavanoids in Kaempferia parviflora can exert endothelium-dependent relaxation properties via a NO-cGMP pathway and inhibiting calcium-induced contractility,^[23][22] which may be due to the DMF content which works via the endothelium and work via multiple pathways (NO-cGMP and COX) but mostly calcium influx inhibition and facilitating potassium efflux.^[24]

Antioxidant effects are also attributed to methoxyflavones which have shown benefit in diabetic rats (high oxidant stress in endothelium) at an oral intake of 100mg/kg bodyweight;^[25] in this study which confirmed a DMF content, the supplemental Kaempferia almost normalized superoxide production (and indirectly preserved nitric oxide levels) in diabetic mice without influencing control mice.^[25]

A study in type I diabetic rats tested the efficacy of Kaempferia Parviflora in attenuating endothelial stress failed to notice any reduction in fasting blood glucose over 4 weeks of supplementation with 100mg/kg.^[25]

1% Kaempferia parviflora in the diet of obese rats has been associated with a reduced feed intake, which although present at 2 weeks (nonsignificant at 20.5% decrease) it appears to extend over a prolonged period of time (being significant at 18% reduction at 8 weeks); 0.3% of the diet was ineffective, and this was determined to not be taste aversion (same effects via gavage).^[26] One other study in obese mice using 1% and 3% failed to note these effects, however.^[16]

In vitro, Kaempferia Parviflora appears to have pancreatic lipase inhibitory properties with an IC₅₀ of 487μg/mL in regards to the whole plant; isolated constituents with inhibitory potential include 5-hydroxy-3,7-dimethoxyflavone (IC₅₀ 291μg/mL), 5-hydroxy-3,7,4′-tri-methoxyflavone (IC₅₀ 536μg/mL), 5-hydroxy-7,4′-dimethoxyflavone (IC₅₀ 220μg/mL), and 5-hydroxy-7-methoxyflavone (IC₅₀ 291μg/mL).^[26]

An in vitro study with preadipocytes during their differentiation phase appear to beneficially influence adipocyte differentiation without being ligands for PPARγ, as assessed by 1-3uM of methoxyflavones increasing triglyceride assumulation and lipid droplet staining.^[8] This appeared to mostly be due to 3,5,7,4′-tetramethoxyflavone and 3,5,7,3′,4′-pentamethoxyflavone, and despite not being a PPARγ agonist they induced activity of C/EBPβ and C/EBPδ.^[8]

In TSOD mice (metabolic syndrome model), 1% Kaempferia parviflora was able to slightly decrease liver triglyceride and cholesterol content without significantly affecting serum concentrations; a reduction in body weight was apparent over 8 weeks in TSOD mice given either 0.3% or 1% K.Parviflora although the control (TNOS) mice were still lighter.^[26] Dose dependent benefits to weight loss have been noted with 1% and 3% in another study using the same mouse model (TSOD) and again showed no significant effect in lean control mice.^[16]

Slight unremarkable anti-obese effects

In a study on untrained males given 1.35g of Kaempferia Parviflora 90 minutes before a Repeated Wingate test and time to exhaustion (65% VO2 max) failed to find any improvment on either test or in the rate of percieved exertion.^[1]

One intervention using either 25mg or 90mg Kaempferia parviflora (2.1% DMF, 3.1% TMF, 2.3% PMF) for 8 weeks in persons over 60 who were otherwise healthy noted that the 90mg group experienced improvements in the 30-second chair stand test (11% improvement) and the 6-minute walk test (5%) with the 25mg group not being statistically significant.^[27] Improvements did not occur in the grip tests or tandem (gait) tests, and the benefits were attributed to an improvement in oxidative markers.^[27]

25mg and 90mg Kaempferia parviflora daily for 8 weeks was able to increase levels of superoxide dismutase (SOD) in otherwise healthy adults over 60 without influencing Catalse of Glutathione peroxidase, and only affecting lipid peroxidation slightly at the higher dose of 90mg.^[27]

The chloroform extract of Kaempferia parviflora appeared to be the most anti-inflammatory in macrophages (assessed via suppressing iNOS expression in response to the proinflammatory LPS stimuli) with an IC₅₀ between 8.1-8.4μg/ml; anti-inflammatory properties were shared by many methoxyflavones, but the most potent ones appeared to be 5,7-dimethoxyflavone, trimethylapigenin, and tetramethylluteolin with IC₅₀ values of 18μM or 5.1μg/mL, 15μM or 4.6μg/mL, and 26μM or 8.7μg/mL respectively.^[7] When compared to the reference compound of Parthenolide (active component of Feverfew with an IC₅₀ of 0.31μg/mL and 1.1μM) they underperformed.^[7] The mechanism of these three anti-inflammatory methoxyflavones appears to be mixed on ERK and JNK (inhibition) with tetramethylluteolin being a SYK inhibitor. This suppression of iNOS has been noted elsewhere, alongside a small suppression of COX-2 mRNA, where PGE₂ production can be inhibited with an IC₅₀ value of 9.2μg/mL (ethanolic extract)^[28] mostly due to 5-hydroxy-3,7,3',4'-tetramethoxyflavone.^[29]

General anti-inflammatory effects against macrophage activation from inflammatory stimuli

Some methoxyflavones appear to be anti-allergic, as one in vitro study in RBL-2H3 Mast Cells noted that degranulation (a hallmark of allergic responses) was attenuated most potently by 5-hydroxy-3,7,3',4'-tetramethoxyflavone with an IC₅₀ of 8uM followed by 5-hydroxy-7-methoxyflavone (20.6uM) and 5-hydroxy-7,4'-dimethoxyflavone (26uM).^[30] The overall rhizome ethanolic extract (concentrated methoxyflavones) had an IC₅₀ of 10.9ug/mL,^[30] and it appears to be the most anti-allergic of the Zingiberaceae family according to one study.^[31]

Possible anti-allergic effects of unknown practical potency

The ethanolic extract of Kaempferia parviflora has been tested in an animal model of carrageenan-induced paw edema (biomarker of acute inflammation) and various extracts at 150mg/kg appeared to inhibit paw edema in the range of 6.01-25.31% with the active control of 10mg/kg Indomethacin inhibiting 10.75%.^[28]

In castrated male rats given 1,000mg/kg Kaempferia parviflora daily for 5 days, an increase of serum testosterone occurred independent of any changes in LH, Progresterone, or FSH and to the degree of 66% higher than control.^[32] Another study in adult male rats (not castrated) also failed to note significant changes to LH and FSH, while testosterone trended to be nonsignificantly reduced; oddly, this study noted an increase in the weight of the prostate but not levator ani (mixed results on androgenicity indpendent of serum testosterone).^[19]

A later study in sexually mature rats measuring the weight of the levator ani muscle (hypertrophy of this muscle correlated with overall androgenicity) found no significant improvemenet with supplementation at 70mg/kg, while exercise increased the weight slightly; this latter study did not measure serum testosterone.^[33] A lack of influence on the levator ani has been noted elsewhere at 70mg/kg.^[6]

3,5,7,3',4'-pentamethoxyflavone (PMF) at 0.3mM was able to relax pre-contracted human cavernosal strips from 100% contraction to 1.63+/-0.62%, and this was not inhibited with a cGMP inhibitor (ODQ), potassium channel blocker (TEA), nor an ATP channel blocker (glybenclamide);^[34] In a test of PDE5 inhibition, PMF failed to augment glyceryl trinitrate-induced relaxation while Viagra was effective.^[34] These results suggest the relaxing effects of PMF on the penis tissue are not mediated by NO, cGMP, nor potassium channels (common mechanisms of action for other drugs) and is unlikely to be a Rho-Kinase inhibitor, but appears to be a calcium channel inhibitor but may act by other (currently unknown) mechanisms.^[34]

Other constituents of Kaempferia parviflora appear to be PDE5 inhibitors (similar to Viagra and Horny Goat Weed's Icariin).^[33] When the extract was tested by itself at 50ug/mL, Kaempferia parviflora rhizome was able to inhibit 62.63+/-7.17% of PDE5 inhibitory value (out of 41 tested herbs, only Caesalpinia sappan stem (60.23+/-1.81%), Senna surattensis leaf (65.08+/-0.78%), Acacia auriculaeformis leaf (73.66+/-4.87%) and Boesenbergia rotunda rhizome (40.86+/-3.94%) were similar); K.Parviflora had an IC₅₀ of 12.24+/-0.99ug/mL with the ethanolic extract.^[33] Isolated compounds and their individual PDE5 IC₅₀ values are 10.64+/-2.09ug/mL (DMF), 37.38+/-1.15ug/mL (2,7,4'-trimethoxyflavone), 16.32+/-1.93ug/mL (3,5,7-trimethoxyflavone), and 30.41+/-2.34ug/mL (PMF); all underperforming relative to Viagra.^[33]

Has a variety of mechanisms which indicate that Thai Ginseng is pro-erectile, but the practical significance of these pro-erectile effects have not been recorded in vivo (the one aphrodisiac study did not measure effects on the Penile Erection Index; PEI)

Following oral ingestion of 750mg/kg ethanolic extract of Kaempferia parviflora (9.44, 9.75, and 10.58 mg/kg of PMF, TMF, and DMF) PMF reached with a C_max of 0.50+/-0.31ug/g at a T_max of 2.36+/-1.25 hours giving an AUC of 1.01+/-0.24ug/g/h,^[2] DMF reached with a C_max of 0.91+/-0.44ug/g at a T_max of 2.86+/-1.07 hours giving an AUC of 1.90+/-0.62ug/g/h,^[2] and TMF reached with a C_max of 1.10+/-0.43ug/g at a T_max of 3.14+/-1.07 hours giving an AUC of 1.96+/-0.67ug/g/h.^[2]

One study in rats given 70mg/kg bodyweight of the herb noted an increase in the weight of the seminal vesicles, epididymus, and levator ani muscles when paired with exercise; these results were more likely induced by exercise, as changes in the supplementation only group were minimal.^[17] This same oral dose was found to not significantly increase testicular weight when ethanolic, hexane, and water extracts were all tested despite the ethanolic group conferring aphrodisiac properties.^[6] An increase in blood flow through the spermatic artery was noted with this extract independent of changes in blood pressure or heart rate, which was deemed an acute effect.^[6]

Following oral ingestion of 750mg/kg ethanolic extract of Kaempferia parviflora (9.44, 9.75, and 10.58 mg/kg of PMF, TMF, and DMF) PMF reached with a C_max of 3.10+/-1.78ug/g at a T_max of 3.43+/-0.98 hours giving an AUC of 9.07+/-1.37ug/g/h,^[2] DMF reached with a C_max of 3.85+/-1.45ug/g at a T_max of 2.57+/-1.10 hours giving an AUC of 8.60+/-1.97ug/g/h,^[2] and TMF reached with a C_max of 3.01+/-1.49ug/g at a T_max of 2.64+/-1.38 hours giving an AUC of 7.83+/-0.33ug/g/h.^[2]

The three main methoxyflavones have been detected in the rat liver following oral administration

In a preliminary test of protection of liver cells against D-GalN-induced toxicity, 5,3′-dihydroxy-3,7,4'-trimethoxyflavone appeared to be more effective than Silybin (a constituent of Milk Thistle) in protecting the cells, with an IC₅₀ of 18.4μM relative to Silybin's 38.8μM.^[9]

Following oral ingestion of 750mg/kg ethanolic extract of Kaempferia parviflora (9.44, 9.75, and 10.58 mg/kg of PMF, TMF, and DMF) PMF reached with a C_max of 1.00+/-0.39ug/g at a T_max of 3.43+/-0.98 hours giving an AUC of 2.03+/-0.67ug/g/h,^[2] DMF reached with a C_max of 1.33+/-0.49ug/g at a T_max of 3.43+/-0.98 hours giving an AUC of 2.51+/-0.68ug/g/h,^[2] and TMF reached with a C_max of 1.64+/-0.59ug/g at a T_max of 3.43+/-0.98 hours giving an AUC of 3.01+/-0.85ug/g/h.^[2]

Following oral ingestion of 750mg/kg ethanolic extract of Kaempferia parviflora (9.44, 9.75, and 10.58 mg/kg of PMF, TMF, and DMF) PMF reached with a C_max of 2.23+/-1.13ug/g at a T_max of 0.08+/-0.17 hours giving an AUC of 1.60+/-0.37ug/g/h,^[2] DMF reached with a C_max of 2.00+/-1.20ug/g at a T_max of 1.20+/-0.19 hours giving an AUC of 2.17+/-0.31ug/g/h,^[2] and TMF reached with a C_max of 1.41+/-0.58ug/g at a T_max of 1.76+/-0.19 hours giving an AUC of 1.88+/-0.35ug/g/h.^[2]