Founder
May 3rd, 2005, 04:26 PM
5-HTP and Hoodia for Weight Loss and Appetite Control
by Nandi
5-HT (Serotonin)
Serotonin (5-HT) has been closely linked with satiety, the sense of being full after a meal, beginning with the research of JE Blundell in the 1970’s (1,2). Serotonergic drugs such as D-fenfluramine and the selective serotonin reuptake inhibitors (SSRI) fluoxitene and sertraline have also been shown to dramatically reduce food intake and induce weight loss in both animals and humans (3). To summarize the research to date, when 5-HT or its precursors the amino acid tryptophan, or 5-hydroxytryptophan (5-HTP) are administered to animals or humans, food intake, eating rate and meal size are all significantly reduced. Conversely, chemically blocking the synthesis of neuronal 5-HT or destroying 5-HT neurons in animals increases food intake.
At present 14 different subtypes of 5-HT receptors have been identified. The ones most closely associated with appetite regulation appear to be the presynaptic 5-HT(1A) and the postsynaptic 5-HT(1D) and 5-HT(2C) receptors (3). Interestingly, Tecott and coworkers successfully produced a breed of mice lacking functional 5-HT(2C) receptors (4). These knockout mice exhibited hyperphagia (overeating) and were markedly obese. However, extrapolating the obesity seen in these mice to humans is complicated by the fact the obesity is associated with decreased beta 3-AR gene expression (5). The role of the beta 3 adrenoreceptor in human obesity has yet to be fully elucidated.
Human studies employing selective 5-HT agonists confirm that agonism of 5-HT(2C) and 5-HT(1D) receptors produces reductions in food intake, hunger, and body weight consistent with a satiety inducing action. The 5-HT(1D) agonist sumatriptan has also been shown to reduce food intake, especially high fat food, in lean women (6). Moreover, the research described in (6) also shows that agonism of the 5-HT(1D) receptor elevates growth hormone in both men and women, and in men, lowers prolactin.
There is considerable evidence that 5-HT may selectively suppress consumption of fats, as mentioned above in the case of sumatriptan (7). To summarize, there are considerable data supporting the concept that 5-HT exerts both a general inhibitory effect on food intake by modulating hunger and satiety, and also has a selective suppressive effect on dietary fat consumption.
The mechanism behind the appetite suppressing effects of 5-HT may be antagonism of the hunger inducing peptide neuropeptide Y (NPY). Studies have shown that the administration of a 5-HT antagonist increased NPY synthesis in the hypothalamus. Conversely, the SSRI fluoxitene reduced hypothalamic NPY levels and secretion (8). Additionally, the serotonin releaser and reuptake inhibitor D-fenfluramine reversed NPY induced feeding (9). When 5-HT agonists are injected into the portion of the brain known as the hypothalamic paraventricular nucleus (PVN) immediately prior to PVN administration of neuropeptide Y, the normal induction of feeding seen after NPY administration is blocked (10). All these data support a mutually antagonistic relationship between 5-HT and NPY.
Besides the antiobesity effects of 5-HTP described above, the supplement is widely used as a precursor to serotonin to treat depression. Studies have shown that 5-HTP appears to be superior to placebo for the treatment of depression (11).
5-HTP sold over the counter is extracted from the Griffonia seed. The seeds come from an African tree grown mostly in Ghana and the Ivory Coast. 5-HTP can also be made synthetically in the laboratory. The final product is the same as the one made by the body. Only a small (3 to 7) percent of the griffonia seed is made of 5-HTP, therefore, consuming griffonia seeds is not an efficient way of getting 5-HTP.
Quoting Ray Sahelian, M.D., author of the popular treatise on 5-HTP use, 5-HTP: Nature’s Serotonin Solution, “It’s difficult to say what the best time to take 5-HTP is since it varies among individuals. It depends whether 5-HTP is being used for sleep, in that case it is taken in the evening; for anxiety or low mood, 5-HTP can be taken any time of day; or weight loss, in which case it is taken on an empty stomach an hour or two before a meal. 5-HTP is absorbed better taken on an empty stomach. There has not been enough research done with 5-HTP to know the ideal dosages and timing. Also, there is significant individual variability to the response to 5-HTP. Hence, each person may need to find out for themselves the lowest dose that works well, and the ideal timing, whether early in the day, midday or evening.”
With respect to dosing, 50 - 100 mg is a popular dosage for curbing appetite and alleviating mild depression. Some people may require higher doses, some lower to achieve the desired effect. As a sleep aid, higher doses may be required.
Hoodia Gordonii
While there are extensive weight loss data relating to 5-HT, as outlined above, there are much fewer data relating to the anorectic effects of the active ingredient (14-OH,12-tigloyl pregnane steroidal glycoside, or P57 for short ) found in the South African succulent (not cactus, as is commonly stated) Hoodia Gordonii. The plant is localized to the Kalahari desert region of South Africa. Modern research on this plant and P57 stems from ethnobotanical studies of San Bushmen who ingest the plant to stave off hunger. In a study published last year (2004), researcher were able to elucidate the potential mechanism behind the satiety inducing effects of P57 (12). Direct intracerebroventricular injection of P57 in rats increased the ATP content of hypothalamic neurons by 50 – 150%. This was accompanied by a 40 –60% reduction in 24 hour food intake.
We know that ATP serves as the body’s universal energy currency, providing the energy needed to carry out the metabolic processes associated with life. ATP is formed from the breakdown and subsequent oxidation of foodstuffs. The hypothalamus evidently is sensitive to ATP levels in the body, with high ATP levels corresponding to the fed state, and low ATP being associated with fasting (12).
These results are in accord with other research involving levels of AMPK (adenosine 5’-monophosphate-activated protein kinase) in the hypothalamus. AMPK is a kinase (an enzyme capable of phosphorylating its substrate) that is sensitive to the ratio of AMP to ATP. ATP is comprised of an adenosine molecule bonded to three phosphates; each phosphate bond contains energy, especially the third bond. By breaking the two phosphate bonds and reducing ATP to AMP cells can get the energy to carry out their various processes: ATP -> AMP + 2P + energy. So a high AMP/ATP ratio is a signal that energy stores are being depleted. Conversely, a high content of ATP relative to AMP is a signal that energy stores are high. The job of AMPK is to shut down energy (ATP) consuming processes such as biosynthesis, and activate energy producing processes such as fatty acid oxidation that generate ATP. This will replenish ATP, and raise the ATP to AMP ratio, eventually deactivating AMPK when the cell is replenished with the energy (ATP) it needs.
Andersson et.al. showed recently that AMPK levels in the hypothalamus control food intake in animals (13). Leptin, which is known to reduce food intake, decreased hypothalamic AMPK activity when administered to laboratory animals. Ghrelen, a hormone with the opposite effect as leptin increases food intake. When injected, ghrelen caused an increase in food intake along with an increase in AMPK activity in the hypothalamus. AICAR, or 5-amino-4-imidazole carboxamide riboside, mimics the action of AMP on AMPK, increasing AMPK activity. When AICAR was administered to the animals, food intake increased significantly, as did AMPK activity. All this evidence suggests that low levels of hypothalamic AMPK activity decrease food intake, whereas high levels of AMPK activity increase food intake. This certainly makes sense from what we have learned thus far about the role of AMPK as a metabolic switch. When energy is depleted and AMP levels high relative to ATP, AMPK is activated and might be expected to signal the animal to eat.
So we see that two lines of research lead to the same conclusion; namely that the hypothalamus is sensitive to ATP levels, with high ATP content initiating the signaling for satiety, and low ATP levels inducing hunger. Whether Hoodia is involved in regulating AMPK signaling is unclear, as there have been no direct measurements of AMPK activity after Hoodia administration. However, the observation that Hoodia elevates hypothalamic ATP, and that high ATP relative to AMP reduces the activity of AMPK, is highly suggestive of a model whereby Hoodia controls food intake by regulating AMPK levels in the hypothalamus.
To date only one human study of the effects of P57 has been carried out. The study was undertaken by the company Phytopharm, which holds the patent on P57. A press release by Phytopharm summarizes the outcome of the trial:
“Phytopharm plc (PYM: London Stock Exchange) (“Phytopharm”) announces today the successful completion of the third and final stage of its proof of principle clinical study of P57. The objectives of this stage of the study included the evaluation of the safety, tolerability, pharmacokinetic profile and effect on calorie intake of P57. This is a patented product which is under development as an appetite suppressant for the treatment of obesity and related conditions.
This stage of the study used a double-blind, randomized, placebo-controlled design. Nineteen overweight but otherwise healthy male volunteers were randomly allocated to receive either P57 or placebo twice daily for 15 days. Eighteen subjects completed the study (nine subjects in each of the P57 and placebo groups). Assessments recorded during the study included daily calorie intake, body weight and body fat content. The primary endpoint compared the average daily calorie intake between the groups for the last three days of dosing. Blood samples were also obtained for routine analysis of safety parameters and pharmacokinetic profiling of this orally administered agent.
Preliminary data indicate that there was a statistically significant reduction in the average daily calorie intake of the P57 group compared with the placebo group (p= 0.014). Preliminary data also indicate a statistically significant reduction in body fat content in the P57 group compared with the placebo group at the completion of dosing (p=0.035). No serious adverse effects were experienced by any of the subjects, and the safety data are consistent with a satisfactory overall safety profile. The pharmacokinetic data confirm that the systemic exposure to biologically active constituents of P57 was consistent with the observed clinical effects.” (14).
The reader should bear in mind that the research carried out by Phytopharm was not performed by independent researchers, but rather by a company with a financial interest in P57. Moreover, the data are preliminary and the research has yet to be published in a credible peer- reviewed scientific journal.
With respect to dosing of Hoodia itself (not the active ingredient P57), most people are taking 400-500 mg three times daily (or a total of 1.2-1.5 g daily). This regimen is purely empirical, with no research available to justify it. Lacking controlled studies of the consumption of the plant itself, it may very well be that smaller doses are equally efficacious. On the other hand, there may be a dose response relation in which higher doses are more effective at reducing hunger.
References:
1. Blundell JE, Latham CJ, Leshem MB. Biphasic action of a 5-hydroxytryptamine inhibitor on fenfluramine-induced anorexia. J Pharm Pharmacol. 1973 Jun;25(6):492-4.
2. Blundell JE. Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obes. 1977;1(1):15-42.
3. Blundell, JE, Halford, JCG. Serotonin and appetite regulation: implications for the pharmacological treatment of obesity. CNS Drugs 1998, 9: 473-95
4. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature. 1995 Apr 6;374(6522):542-6.
5. Nonogaki K, Memon RA, Grunfeld C, Feingold KR, Tecott LH. Altered gene expressions involved in energy expenditure in 5-HT(2C) receptor mutant mice. Biochem Biophys Res Commun. 2002 Jul 12;295(2):249-54.
6. Boeles S, Williams C, Campling GM, Goodall EM, Cowen PJ. Sumatriptan decreases food intake and increases plasma growth hormone in healthy women. Psychopharmacology (Berl). 1997 Jan;129(2):179-82.
7. Blundell JE, Lawton CL, Halford JC. Serotonin, eating behavior, and fat intake. Obes Res. 1995 Nov;3 Suppl 4:471S-476S. \
8. Dryden S, Frankish HM, Wang Q, Pickavance L, Williams G. The serotonergic agent fluoxetine reduces neuropeptide Y levels and neuropeptide Y secretion in the hypothalamus of lean and obese rats. Neuroscience. 1996 May;72(2):557-66
9. Grignaschi G, Sironi F, Samanin R. The 5-HT1B receptor mediates the effect of d-fenfluramine on eating caused by intra-hypothalamic injection of neuropeptide Y. Eur J Pharmacol. 1995 Feb 14;274(1-3):221-4.
10. Currie PJ, Coiro CD, Niyomchai T, Lira A, Farahmand F. Hypothalamic paraventricular 5-hydroxytryptamine: receptor-specific inhibition of NPY-stimulated eating and energy metabolism. Pharmacol Biochem Behav. 2002 Apr;71(4):709-16.
11. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.
12. MacLean DB, Luo LG. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside. Brain Res. 2004 Sep 10;1020(1-2):1-11.
13. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004 Mar 26;279(13):12005-8
14. http://www.phytopharm.co.uk/hoodia_faq.html
by Nandi
5-HT (Serotonin)
Serotonin (5-HT) has been closely linked with satiety, the sense of being full after a meal, beginning with the research of JE Blundell in the 1970’s (1,2). Serotonergic drugs such as D-fenfluramine and the selective serotonin reuptake inhibitors (SSRI) fluoxitene and sertraline have also been shown to dramatically reduce food intake and induce weight loss in both animals and humans (3). To summarize the research to date, when 5-HT or its precursors the amino acid tryptophan, or 5-hydroxytryptophan (5-HTP) are administered to animals or humans, food intake, eating rate and meal size are all significantly reduced. Conversely, chemically blocking the synthesis of neuronal 5-HT or destroying 5-HT neurons in animals increases food intake.
At present 14 different subtypes of 5-HT receptors have been identified. The ones most closely associated with appetite regulation appear to be the presynaptic 5-HT(1A) and the postsynaptic 5-HT(1D) and 5-HT(2C) receptors (3). Interestingly, Tecott and coworkers successfully produced a breed of mice lacking functional 5-HT(2C) receptors (4). These knockout mice exhibited hyperphagia (overeating) and were markedly obese. However, extrapolating the obesity seen in these mice to humans is complicated by the fact the obesity is associated with decreased beta 3-AR gene expression (5). The role of the beta 3 adrenoreceptor in human obesity has yet to be fully elucidated.
Human studies employing selective 5-HT agonists confirm that agonism of 5-HT(2C) and 5-HT(1D) receptors produces reductions in food intake, hunger, and body weight consistent with a satiety inducing action. The 5-HT(1D) agonist sumatriptan has also been shown to reduce food intake, especially high fat food, in lean women (6). Moreover, the research described in (6) also shows that agonism of the 5-HT(1D) receptor elevates growth hormone in both men and women, and in men, lowers prolactin.
There is considerable evidence that 5-HT may selectively suppress consumption of fats, as mentioned above in the case of sumatriptan (7). To summarize, there are considerable data supporting the concept that 5-HT exerts both a general inhibitory effect on food intake by modulating hunger and satiety, and also has a selective suppressive effect on dietary fat consumption.
The mechanism behind the appetite suppressing effects of 5-HT may be antagonism of the hunger inducing peptide neuropeptide Y (NPY). Studies have shown that the administration of a 5-HT antagonist increased NPY synthesis in the hypothalamus. Conversely, the SSRI fluoxitene reduced hypothalamic NPY levels and secretion (8). Additionally, the serotonin releaser and reuptake inhibitor D-fenfluramine reversed NPY induced feeding (9). When 5-HT agonists are injected into the portion of the brain known as the hypothalamic paraventricular nucleus (PVN) immediately prior to PVN administration of neuropeptide Y, the normal induction of feeding seen after NPY administration is blocked (10). All these data support a mutually antagonistic relationship between 5-HT and NPY.
Besides the antiobesity effects of 5-HTP described above, the supplement is widely used as a precursor to serotonin to treat depression. Studies have shown that 5-HTP appears to be superior to placebo for the treatment of depression (11).
5-HTP sold over the counter is extracted from the Griffonia seed. The seeds come from an African tree grown mostly in Ghana and the Ivory Coast. 5-HTP can also be made synthetically in the laboratory. The final product is the same as the one made by the body. Only a small (3 to 7) percent of the griffonia seed is made of 5-HTP, therefore, consuming griffonia seeds is not an efficient way of getting 5-HTP.
Quoting Ray Sahelian, M.D., author of the popular treatise on 5-HTP use, 5-HTP: Nature’s Serotonin Solution, “It’s difficult to say what the best time to take 5-HTP is since it varies among individuals. It depends whether 5-HTP is being used for sleep, in that case it is taken in the evening; for anxiety or low mood, 5-HTP can be taken any time of day; or weight loss, in which case it is taken on an empty stomach an hour or two before a meal. 5-HTP is absorbed better taken on an empty stomach. There has not been enough research done with 5-HTP to know the ideal dosages and timing. Also, there is significant individual variability to the response to 5-HTP. Hence, each person may need to find out for themselves the lowest dose that works well, and the ideal timing, whether early in the day, midday or evening.”
With respect to dosing, 50 - 100 mg is a popular dosage for curbing appetite and alleviating mild depression. Some people may require higher doses, some lower to achieve the desired effect. As a sleep aid, higher doses may be required.
Hoodia Gordonii
While there are extensive weight loss data relating to 5-HT, as outlined above, there are much fewer data relating to the anorectic effects of the active ingredient (14-OH,12-tigloyl pregnane steroidal glycoside, or P57 for short ) found in the South African succulent (not cactus, as is commonly stated) Hoodia Gordonii. The plant is localized to the Kalahari desert region of South Africa. Modern research on this plant and P57 stems from ethnobotanical studies of San Bushmen who ingest the plant to stave off hunger. In a study published last year (2004), researcher were able to elucidate the potential mechanism behind the satiety inducing effects of P57 (12). Direct intracerebroventricular injection of P57 in rats increased the ATP content of hypothalamic neurons by 50 – 150%. This was accompanied by a 40 –60% reduction in 24 hour food intake.
We know that ATP serves as the body’s universal energy currency, providing the energy needed to carry out the metabolic processes associated with life. ATP is formed from the breakdown and subsequent oxidation of foodstuffs. The hypothalamus evidently is sensitive to ATP levels in the body, with high ATP levels corresponding to the fed state, and low ATP being associated with fasting (12).
These results are in accord with other research involving levels of AMPK (adenosine 5’-monophosphate-activated protein kinase) in the hypothalamus. AMPK is a kinase (an enzyme capable of phosphorylating its substrate) that is sensitive to the ratio of AMP to ATP. ATP is comprised of an adenosine molecule bonded to three phosphates; each phosphate bond contains energy, especially the third bond. By breaking the two phosphate bonds and reducing ATP to AMP cells can get the energy to carry out their various processes: ATP -> AMP + 2P + energy. So a high AMP/ATP ratio is a signal that energy stores are being depleted. Conversely, a high content of ATP relative to AMP is a signal that energy stores are high. The job of AMPK is to shut down energy (ATP) consuming processes such as biosynthesis, and activate energy producing processes such as fatty acid oxidation that generate ATP. This will replenish ATP, and raise the ATP to AMP ratio, eventually deactivating AMPK when the cell is replenished with the energy (ATP) it needs.
Andersson et.al. showed recently that AMPK levels in the hypothalamus control food intake in animals (13). Leptin, which is known to reduce food intake, decreased hypothalamic AMPK activity when administered to laboratory animals. Ghrelen, a hormone with the opposite effect as leptin increases food intake. When injected, ghrelen caused an increase in food intake along with an increase in AMPK activity in the hypothalamus. AICAR, or 5-amino-4-imidazole carboxamide riboside, mimics the action of AMP on AMPK, increasing AMPK activity. When AICAR was administered to the animals, food intake increased significantly, as did AMPK activity. All this evidence suggests that low levels of hypothalamic AMPK activity decrease food intake, whereas high levels of AMPK activity increase food intake. This certainly makes sense from what we have learned thus far about the role of AMPK as a metabolic switch. When energy is depleted and AMP levels high relative to ATP, AMPK is activated and might be expected to signal the animal to eat.
So we see that two lines of research lead to the same conclusion; namely that the hypothalamus is sensitive to ATP levels, with high ATP content initiating the signaling for satiety, and low ATP levels inducing hunger. Whether Hoodia is involved in regulating AMPK signaling is unclear, as there have been no direct measurements of AMPK activity after Hoodia administration. However, the observation that Hoodia elevates hypothalamic ATP, and that high ATP relative to AMP reduces the activity of AMPK, is highly suggestive of a model whereby Hoodia controls food intake by regulating AMPK levels in the hypothalamus.
To date only one human study of the effects of P57 has been carried out. The study was undertaken by the company Phytopharm, which holds the patent on P57. A press release by Phytopharm summarizes the outcome of the trial:
“Phytopharm plc (PYM: London Stock Exchange) (“Phytopharm”) announces today the successful completion of the third and final stage of its proof of principle clinical study of P57. The objectives of this stage of the study included the evaluation of the safety, tolerability, pharmacokinetic profile and effect on calorie intake of P57. This is a patented product which is under development as an appetite suppressant for the treatment of obesity and related conditions.
This stage of the study used a double-blind, randomized, placebo-controlled design. Nineteen overweight but otherwise healthy male volunteers were randomly allocated to receive either P57 or placebo twice daily for 15 days. Eighteen subjects completed the study (nine subjects in each of the P57 and placebo groups). Assessments recorded during the study included daily calorie intake, body weight and body fat content. The primary endpoint compared the average daily calorie intake between the groups for the last three days of dosing. Blood samples were also obtained for routine analysis of safety parameters and pharmacokinetic profiling of this orally administered agent.
Preliminary data indicate that there was a statistically significant reduction in the average daily calorie intake of the P57 group compared with the placebo group (p= 0.014). Preliminary data also indicate a statistically significant reduction in body fat content in the P57 group compared with the placebo group at the completion of dosing (p=0.035). No serious adverse effects were experienced by any of the subjects, and the safety data are consistent with a satisfactory overall safety profile. The pharmacokinetic data confirm that the systemic exposure to biologically active constituents of P57 was consistent with the observed clinical effects.” (14).
The reader should bear in mind that the research carried out by Phytopharm was not performed by independent researchers, but rather by a company with a financial interest in P57. Moreover, the data are preliminary and the research has yet to be published in a credible peer- reviewed scientific journal.
With respect to dosing of Hoodia itself (not the active ingredient P57), most people are taking 400-500 mg three times daily (or a total of 1.2-1.5 g daily). This regimen is purely empirical, with no research available to justify it. Lacking controlled studies of the consumption of the plant itself, it may very well be that smaller doses are equally efficacious. On the other hand, there may be a dose response relation in which higher doses are more effective at reducing hunger.
References:
1. Blundell JE, Latham CJ, Leshem MB. Biphasic action of a 5-hydroxytryptamine inhibitor on fenfluramine-induced anorexia. J Pharm Pharmacol. 1973 Jun;25(6):492-4.
2. Blundell JE. Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obes. 1977;1(1):15-42.
3. Blundell, JE, Halford, JCG. Serotonin and appetite regulation: implications for the pharmacological treatment of obesity. CNS Drugs 1998, 9: 473-95
4. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature. 1995 Apr 6;374(6522):542-6.
5. Nonogaki K, Memon RA, Grunfeld C, Feingold KR, Tecott LH. Altered gene expressions involved in energy expenditure in 5-HT(2C) receptor mutant mice. Biochem Biophys Res Commun. 2002 Jul 12;295(2):249-54.
6. Boeles S, Williams C, Campling GM, Goodall EM, Cowen PJ. Sumatriptan decreases food intake and increases plasma growth hormone in healthy women. Psychopharmacology (Berl). 1997 Jan;129(2):179-82.
7. Blundell JE, Lawton CL, Halford JC. Serotonin, eating behavior, and fat intake. Obes Res. 1995 Nov;3 Suppl 4:471S-476S. \
8. Dryden S, Frankish HM, Wang Q, Pickavance L, Williams G. The serotonergic agent fluoxetine reduces neuropeptide Y levels and neuropeptide Y secretion in the hypothalamus of lean and obese rats. Neuroscience. 1996 May;72(2):557-66
9. Grignaschi G, Sironi F, Samanin R. The 5-HT1B receptor mediates the effect of d-fenfluramine on eating caused by intra-hypothalamic injection of neuropeptide Y. Eur J Pharmacol. 1995 Feb 14;274(1-3):221-4.
10. Currie PJ, Coiro CD, Niyomchai T, Lira A, Farahmand F. Hypothalamic paraventricular 5-hydroxytryptamine: receptor-specific inhibition of NPY-stimulated eating and energy metabolism. Pharmacol Biochem Behav. 2002 Apr;71(4):709-16.
11. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.
12. MacLean DB, Luo LG. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside. Brain Res. 2004 Sep 10;1020(1-2):1-11.
13. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004 Mar 26;279(13):12005-8
14. http://www.phytopharm.co.uk/hoodia_faq.html