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The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting β-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.
Ayahuasca, also known by the names Daime, Yajé, Natema, and Vegetal, is a psychotropic plant tea used by shamans throughout the Amazon Basin in traditional medicine, rites of passage, and magico-religious practices (Schultes and Hofmann, 1982; Dobkin de Rios, 1984). This ancient pattern of use has given way to a more widespread and frequent consumption by members of a number of modern Brazilian-based syncretic religious groups, mainly the Santo Daime and the Uniao do Vegetal, which have incorporated the use of the beverage in their rituals (Dobkin de Rios, 1996). In recent years, groups of followers of these Brazilian religions have become established in the United States and in several European countries, including Germany, Great Britain, Holland, France, and Spain (Anonymous, 2000). As a larger number of people have come into contact with ayahuasca, the tea has begun to attract the attention of biomedical researchers (Callaway et al., 1999; Riba et al., 2001b).
Ayahuasca is obtained by infusing the pounded stems of the malpighiaceous vine Banisteriopsis caapi either alone or, more frequently, in combination with the leaves of Psychotria viridis (rubiaceae) in Brazil, Peru, and Ecuador or Diplopterys cabrerana (malpighiaceae), used mainly in Ecuador and Colombia (Schultes and Hofmann, 1980; McKenna et al., 1984). P. viridis and D. cabrerana are rich in the psychedelic indole N,N-dimethyltryptamine (DMT; Rivier and Lindgren, 1972; Schultes and Hofmann, 1980), whereas B. caapi contains substantial amounts of β-carboline alkaloids, mainly harmine and tetrahydroharmine (THH), and to a lesser extent harmaline and traces of harmol and harmalol (Rivier and Lindgren, 1972; McKenna et al., 1984).
DMT is structurally related to the neurotransmitter serotonin and, like better-characterized psychedelics such as LSD and mescaline, binds to 5-hydroxytryptamine 2A receptors in the central nervous system (CNS), where it acts as an agonist (Pierce and Peroutka, 1989; Smith et al., 1998). Studies in humans have shown that when administered parenterally, DMT provokes dramatic modifications in perception, the sense of self and reality that can be very intense but relatively short in duration (Strassman et al., 1994). The drug also exerts marked autonomic effects elevating blood pressure, heart rate, and rectal temperature, and causes mydriasis (Strassman and Qualls, 1994). Unlike the vast majority of known psychedelic phenethylamines, tryptamines, and ergolines, DMT is orally inactive (Ott, 1999), apparently due to metabolism by monoamine oxidase (MAO; Suzuki et al., 1981). Interestingly, harmine and harmaline, and, to a lesser extent, THH, are potent MAO inhibitors (Buckholtz and Boggan, 1977; McKenna et al., 1984). In 1968, Agurell and coworkers (cited in Ott, 1999, p. 172) postulated that the interaction between β-carbolines and DMT in ayahuasca "might result in specific pharmacological effects". It is now a widely accepted hypothesis that following ayahuasca ingestion, MAO inhibition brought about by harmine, given that it is more potent than THH and is present in the tea in larger amounts than harmaline (McKenna et al., 1984), prevents the enzymatic degradation of DMT, allowing its absorption. It has also been speculated that β-carbolines may contribute to the overall central effects of ayahuasca by blocking brain MAO and weakly inhibiting serotonin reuptake, which combined would lead to enhanced neurotransmitter levels and modulate the effects of DMT (Callaway et al., 1999).
In the present paper we report a double-blind placebo-controlled crossover clinical trial conducted with ayahuasca, in which subjective and cardiovascular effects, and alkaloid pharmacokinetics were assessed in a group of healthy volunteers experienced in psychedelic drug use. Additionally, urine monoamine metabolites were studied to measure in vivo the MAO-inhibitory effects of ayahuasca. In this respect, the neurotransmitters norepinephrine, epinephrine, and dopamine are physiologically degraded by MAO and catechol-O-methyltransferase (COMT) to produce deaminated and methylated metabolites, respectively. Serotonin, on the other hand, is exclusively metabolized by MAO to produce a deaminated compound. In vivo and in vitro studies have shown that when MAO is pharmacologically inhibited, the levels of MAO-dependent deaminated metabolites decrease and those of COMT-dependent methylated metabolites increase. In humans, MAO inhibitors decrease, after acute administration, the urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), the deaminated metabolites of norepinephrine/epinephrine, dopamine, and serotonin, respectively, while increasing that of metanephrine and normetanephrine, the methylated metabolites of epinephrine and norepinephrine, respectively (Pletscher, 1966; Koulu et al., 1989). Monoamine metabolites have both a CNS and a non-CNS origin, and their assessment in urine does not give information regarding the organ in which MAO was inhibited. Nevertheless, this approach can identify dose-response relationships after drug administration and allows for the study of the time course of MAO inhibition.
Materials and Methods
A total of 18 volunteers (15 males and 3 females) with experience in psychedelic drug use were recruited by word of mouth. Eligibility criteria required prior use of psychedelics on at least five occasions without sequelae derived thereof, i.e., psychedelic-related disorders as described in the DSM-III-R. Participants had used psychedelics from six to hundreds of times. The most commonly used psychedelic was LSD (17 of 18), followed by psilocybian mushrooms (15 of 18) and ketamine (10 of 18). The least commonly used were peyote (3 of 18), Salvia divinorum (3 of 18), mescaline (2 of 18), Amanita muscaria (2 of 18), and Datura stramonium (1 of 18). Although prior exposure to ayahuasca was not required for participation, two of the volunteers had ingested this tea before inclusion. Besides psychedelics, volunteers had consumed cannabis (18 of 18), cocaine (17 of 18), and MDMA (17 of 18). Volunteers were in good health, confirmed by medical history, laboratory tests, ECG, and urinalysis. Prior to physical examination, volunteers were interviewed by a psychiatrist (structured interview for DSM-III-R) and completed the trait-anxiety scale from the State-Trait Anxiety Inventory (Spielberger et al., 1970). Exclusion criteria included current or previous history of psychiatric disorder and/or family history of Axis-I psychiatric disorder in first degree relatives, alcohol or other substance dependence, and high scores on trait anxiety (over 1 standard deviation above normative mean). Participants had a mean age of 25.7 years (range 19–38), mean weight 66.47 kg (range 50.7–79.5), and mean height 175.11 cm (range 158–188). The study was conducted in accordance with the Declarations of Helsinki and Tokyo concerning experimentation on humans, and was approved by the hospital's ethics committee and the Spanish Ministry of Health. The volunteers received detailed information on the nature of ayahuasca, and the general psychological effects of psychedelics and their possible adverse effects, as reported in the psychiatric literature. All volunteers gave their written informed consent to participate.
To administer ayahuasca in accurate dosings and masked in a double-blind, double-dummy design, a 9.6-liter batch of Brazilian Daime was subjected to a freeze-drying process that yielded 611 g of powder, which was subsequently homogenized and analyzed. The DMT content was determined by HPLC, as described by Callaway et al. (1996), and the β-carbolines were determined according to a modified version of the method described therein. One gram of freeze-dried material contained 8.33 mg of DMT, 14.13 mg of harmine, 0.96 mg of harmaline, and 11.36 mg of THH, which corresponded to the following alkaloid concentrations in the original tea: DMT, 0.53 mg/ml; harmine, 0.90 mg/ml; harmaline, 0.06 mg/ml; and THH, 0.72 mg/ml. The ayahuasca doses administered to the volunteers in the present study were chosen based on tolerability and subjective effect data gathered in a previous study (Riba et al., 2001b). The low and the high dose contained, per kilogram of body weight: 0.6/0.85 mg of DMT, 1.0/1.4 mg of harmine, 0.07/0.09 mg of harmaline, and 0.82/1.16 mg of THH. The average (range) alkaloid content in milligrams administered in each dose (low dose/high dose) was: 39.8 (30.4–47.9)/57.4 (43.7–67.7) for DMT, 67.4 (51.6–81.2)/95.8 (74.2–114.8) for harmine, 4.6 (3.5–5.5)/6.5 (5.0–7.8) for harmaline, and 54.2 (41.5–65.3)/77.0 (59.6–92.3) for THH. The calculated individual dose for each volunteer was administered by combining 00 gelatin capsules containing different amounts of freeze-dried ayahuasca, i.e., 0.5 g, 0.25 g, or 0.125 g, and placebo capsules containing 0.75 g of lactose. Placebo capsules were added when necessary, so that all volunteers took the same number of capsules on each experimental day. It is interesting to note that although the amount of DMT administered with the present low dose was similar to that administered in the only other published study on the human pharmacology of ayahuasca (Callaway et al., 1999), the amounts of β-carbolines administered in this work were much lower. This was due to the different alkaloid proportions present in the tea samples used in each study. Thus, the average amounts (range) in milligrams administered by Callaway et al. (1999) were: 35.5 (28.8–43.2) for DMT, 252.3 (204.0–306.0) for harmine, 29.7 (24.0–36.0) for harmaline, and 158.8 (128.4–196.6) for THH.
Study Design
Each volunteer participated in four experimental sessions at least 1 week apart. Volunteers were informed that on each experimental day they would randomly receive a single oral dose of encapsulated freeze-dried ayahuasca (one low and one high dose), a placebo, and a random repetition of one of the three mentioned treatments. In actual fact, they all received a placebo on the first experimental day in a single-blind fashion, followed by one of the three treatments from days 2 to 4 in a double-blind balanced fashion, according to a randomization table. The first nonrandomized placebo was administered to familiarize the volunteers with the experimental setting and to minimize the stress associated with the experimental interventions. Volunteers were requested to abstain from any medication or illicit drug use 2 weeks before the beginning of the experimental sessions until the completion of the study. Volunteers also abstained from alcohol, tobacco, and caffeinated drinks 24 h before each experimental day. Urinalysis for illicit drug use was performed for each experimental session. The volunteers were admitted to the research unit on four separate experimental days. Upon arrival at 8:00 AM under fasting conditions, a cannula was inserted in the cubital vein of their right arm for drawing blood samples, and capsules were administered at approximately 10:00 AM with 250 ml of tap water. Throughout the experimental session, the volunteers remained seated in a comfortable reclining chair in a quiet, dimly lit room. At 4 h after administration of the capsules, when the most prominent subjective effects associated with the drug had disappeared, the volunteers had a meal. The last experimental time point was at 8 h, and volunteers were discharged approximately 9 h after administration.
Study Methods
Subjective Effect Measures. The subjective effects elicited by ayahuasca were measured by means of visual analog scales (VAS) and self-report questionnaires. VAS were 100-mm horizontal lines with the following labels: "any effect," indicating any effect, either physical or psychological, that the volunteer attributed to the administered drug; "good effects," indicating any effect the volunteer valued as good; "liking," reflecting that the volunteer liked the effects of the administered substance; "drunken," indicating any dizziness or lightheadedness; "stimulated," indicating any increases in thought speed and/or content, or any increases in associations and/or insights; "visions," indicating modifications in visual perception, including any variations in object shape, brightness, or color and any illusion, abstract or elaborate, seen with either eyes closed or open; and "high," which reflected any positive psychological effect the volunteer attributed to the drug. Except for the "visions" item, the other VAS items administered had been used in human studies by other researchers assessing the subjective effects of a variety of psychoactive drugs (Farré et al., 1993, 1998; Camí et al., 2000). The volunteers were requested to answer the VAS immediately before administration (baseline) and at 15, 30, 45, 60, and 75 min, and 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 h after administration.
Self-report questionnaires included the Hallucinogen Rating Scale (HRS) and the Addiction Research Center Inventory (ARCI). The HRS (Strassman et al., 1994) measures psychedelic-induced subjective effects and includes six scales: Somaesthesia, reflecting somatic effects; Affect, sensitive to emotional and affective responses; Volition, indicating the volunteer's capacity to willfully interact with his/her "self" and/or the environment; Cognition, describing modifications in thought processes or content; Perception, measuring visual, auditory, gustatory, and olfactory experiences; and, finally, Intensity, which reflects the strength of the overall experience. In the present study, a Spanish adaptation of the questionnaire was used (Riba et al., 2001a). The range of scores for all HRS scales is 0 to 4. The short version of the ARCI (Martin et al., 1971) consists of five scales or groups: MBG, morphine-benzedrine group, measuring euphoria and positive mood; PCAG, pentobarbital-chlorpromazine-alcohol group, measuring sedation; LSD, lysergic acid diethylamide scale, measuring somatic-dysphoric effects; BG, the benzedrine group, measuring intellectual energy and efficiency; and the A scale, an empirically derived scale measuring amphetamine-like effects. Both the A and BG scales are sensitive to psychostimulants. The range of scores is 0 to 16 for MBG, –4 to 11 for PCAG, –4 to 10 for LSD, –4 to 9 for BG, and 0 to 11 for A. The questionnaire had been translated into Spanish and validated by Lamas et al. (1994). Volunteers answered the ARCI immediately before drug administration and 4 h after drug intake, whereas the HRS was only answered at 4 h postadministration.
Cardiovascular Measures. Systolic and diastolic blood pressure and heart rate were measured with the volunteer seated, immediately before administration (baseline), and at 15, 30, 45, 60, 75, 90, 120, 150, 180, 210, and 240 min after intake using a sphygmomanometer cuff (Dinamap; Critikon, Tampa, FL) placed around the volunteer's left arm. No measurements were made after 240 min, the time point when subjects had their meal and after which they were allowed to move and leave the room.
Urine Samples. Urine was collected in fractions of 0 to 8 h, 8 to 16 h, and 16 to 24 h in plastic containers with 3 ml of 6 N HCl and kept in the refrigerator during the 0- to 24-h collection period. Volunteers took home the two plastic containers corresponding to the 8- to 16-h and 16- to 24-h periods. Volume of each fraction was recorded and pH was adjusted to 2 to 4 with 6 N HCl, and two 50-ml aliquots were frozen at –20°C and stored at –80°C until analysis. The following monoamine metabolites, VMA, HVA, 5-HIAA, metanephrine, and normetanephrine were quantified by means of HPLC with coulometric detection following previously validated procedures (Soldin and Hill, 1980; Parker et al., 1986; Gamache et al., 1993). The limit of quantification was 3 mg/l for VMA, HVA, and 5-HIAA, 0.05 mg/l for metanephrine, and 0.10 mg/l for normetanephrine.
Blood Samples. Blood samples (10-ml EDTA tubes) were drawn at baseline, 30, 60, 90, 120, and 150 min, and 3, 4, 6, 8, and 24 h after administration for analysis of DMT, harmine, harmaline, and THH concentrations in plasma and those of the O-demethylated metabolites harmol and harmalol. Samples were centrifuged at 2000 rpm for 10 min at 4°C and plasma was immediately frozen at –20°C. The frozen plasma samples were stored at –80°C until analysis. DMT was quantified by gas chromatography with nitrogen-phosphorus detection and the β-carbolines by means of HPLC with fluorescence detection following previously reported methods (Yritia et al., 2002). The limit of quantification was 1.6 ng/ml for DMT, 0.5 ng/ml for harmine, 0.3 ng/ml for harmaline, 1.0 ng/ml for THH, and 0.3 ng/ml for harmol and harmalol. The intraday and interday coefficients of variation were lower than 10.9% and 13.4%, respectively, for all determined compounds.
Pharmacokinetic Analysis
After quantification of the different compounds in plasma, the following pharmacokinetic parameters were calculated using a noncompartmental approach by means of WinNonlin software (version 3.0; Pharsight, Mountain View, CA): maximum concentration (Cmax), time taken to reach the maximum concentration (Tmax), and area under the concentration-time curve from 0 to 8 h (AUC0–8h), calculated by means of the trapezoidal rule. AUC was extrapolated to infinity (AUC0-∞) by addition of the residual area calculated by the last plasma concentration/terminal elimination rate constant. Terminal half-life (t½λz = ln 2/λz) was obtained by linear regression analysis of the terminal log-linear portion of the plasma-concentration curve. Clearance (CL/F) was determined as dose/AUC0-∞. Apparent volume of distribution (Vz/F) was calculated as dose/(λz · AUC0-∞). The AUC0-∞ normalized by dose (AUC0-∞/D) was also calculated. All data are expressed as mean ± S.D. except for Tmax, where median and range are given.
Prior to statistical analysis, ARCI scores were transformed to differences from preadministration values, and the following parameters were calculated for VAS items: peak effect (maximum absolute change from baseline values), time taken to reach the maximum effect (tmax), and the 8-h area under the curve (AUC0–8h) of effect versus time calculated by the trapezoidal rule. For cardiovascular variables, peak effect (maximum absolute change from baseline values) and the 4-h area under the curve (AUC0–4h) of effect versus time were calculated. The obtained parameters, transformed ARCI scores, and raw HRS scores were analyzed by means of a one-way repeated measures ANOVA with drug (placebo, ayahuasca low dose, ayahuasca high dose) as factor. When a significant effect was observed, post hoc comparisons were performed using Tukey's multiple comparisons test. The time course of subjective effects was explored using repeated measures two-way ANOVAs with drug and time (13 time points) as factors. When a drug by time interaction was significant, multiple comparisons were performed at each time point by means of Tukey's test.
Monoamine metabolite levels in urine were analyzed by means of a one-way repeated measures ANOVA with drug (placebo, ayahuasca low dose, ayahuasca high dose) as factor. When a significant effect was observed, post hoc comparisons were performed using Tukey's test. The time course of effects was explored using repeated measures two-way ANOVAs with drug and time (three time points) as factors. Pharmacokinetic parameter comparisons between doses were performed by means of Student's t test, except for Tmax, which was compared by means of a nonparametric Wilcoxon test.
To explore possible differences in the time-to-peak of DMT plasma concentrations and time-to-peak of subjective effects (for each of the administered VAS), nonparametric Wilcoxon tests were performed comparing Tmax for DMT and tmax for each VAS. These tests were performed for data obtained after each of the two administered ayahuasca doses. In all tests performed, differences were considered statistically significant for p values lower than 0.05.
Subjective Effects. Subjective effects results are shown in Tables 1 and 2 and Figs. 1 and 2. Ayahuasca administration induced significant increases in all six HRS scales, both after the low and the high dose, except for Volition, which showed statistically significant differences from placebo only after the 0.85 mg of DMT/kg dose. The ARCI questionnaire showed statistically significant dose-dependent increases after ayahuasca in measures of stimulatory effects (A scale), euphoria (MBG scale), and somatic symptoms (LSD scale). Scores on the BG and PCAG scales were not significantly different from placebo.
Scorings on all seven VAS items showed significant drug effects (peak values and AUC) and significant drug by time interactions. Initial effects appeared between 30 and 45 min, reflected as rises in the VAS any effect item, and were followed by a prominent increase at around 60 min, as indicated by steep rises in all seven VAS items. In general terms, the maximum scorings were observed between 90 and 120 min after drug administration. A gradual return to baseline levels followed thereafter and was complete at 360 min. Regarding effect magnitude, the largest scores were obtained for the VAS any effect, liking, and high, followed by VAS good effects, visions, and stimulated items. The least modified VAS after ayahuasca administration was the drunken item.
More qualitative information on the nature of the effects brought about by ayahuasca is provided in Table 2, which lists the most frequently reported positive responses to specific items of the HRS questionnaire.
Cardiovascular Effects.Mean values for systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) over time are presented in Fig. 3, and results of the statistical analysis performed are shown in Table 1.
Ayahuasca administration produced only moderate elevations of cardiovascular parameters. Statistically significant changes relative to placebo were only found for DBP, both for peak values and AUC. The largest difference in DBP between the low dose and placebo was 9 mm Hg and occurred at 75 min after dosing. Between the high dose and placebo, differences of 10 and 9 mm Hg were observed at 15 and 75 min, respectively. A maximal increase of 7 mm Hg from baseline values was observed at 60 min for the low dose. After the high dose, a maximal increase of 9 mm Hg was observed at 15 min. For SBP, the largest differences with placebo were observed at 75 min and corresponded to 4 and 6 mm Hg increases for the low and high dose, respectively. Similarly, the maximal increase in SBP relative to baseline values was observed at 75 min and corresponded to 6 and 8 mm Hg for the low and high dose, respectively. Finally, HR showed the largest differences with placebo at 60 min and corresponded to 5 and 4 beats/min increases for the low and the high ayahuasca doses, respectively. The maximal increase from baseline values observed for HR was 4 beats/min and occurred at 60 min after administration of both the low and high ayahuasca doses.
Only two volunteers showed SBP values equal to or above 140 mm Hg at any time point: volunteer 1 at 75 and 90 min (140 mm Hg) after receiving the low dose, and at 60 (146 mm Hg) and 75 min (140 mm Hg) after receiving the high dose; and volunteer 6 as early as 15 min after administration of the high ayahuasca dose (146 mm Hg). Two volunteers showed DBP above 90 mm Hg: volunteer 1 at 30 min (93 mm Hg) after the low dose, and at 15 min (96 mm Hg) after the high dose; and volunteer 15 at 120 and 150 min (95 and 92 mm Hg, respectively) after administration of the high dose. Regarding HR, volunteer 1 also showed values above 100 beats/min (101 beats/min) at 60 min after the high dose.
Urine Monoamine Metabolites. Urine samples were successfully collected for 15 of the 18 volunteers enrolled in the study, and results are given for this subgroup only. Statistical analyses showed a significant effect of drug only for normetanephrine. No significant drug by time interaction was found for any of the metabolites studied. In view of this, the total monoamine metabolite amounts excreted during the 0- to 24-h period after placebo and the two ayahuasca doses are presented in Table 3. As shown therein, rather than the expected decreases in deaminated metabolites (VMA, HVA, 5-HIAA), drug administration increased the excretion of these compounds nonsignificantly. Similarly, levels of the O-methylated metabolites metanephrine and normetanephrine increased with dose, although only the latter showed statistically significant differences with placebo.
Pharmacokinetics. The time course of plasma concentrations and the calculated pharmacokinetic parameters for DMT, harmaline, THH, harmol, and harmalol are shown in Fig. 4 and Table 4. The graphs correspond to 15 of the total 18 participants enrolled in the study. To avoid the miscalculation of pharmacokinetic parameters, data from three volunteers were excluded from the analysis due to vomiting occurring after administration of the low dose (volunteer 6) and the high dose (volunteers 4 and 18). An additional subject (volunteer 12) was excluded from the calculation of harmalol parameters. Plasma levels for this volunteer after the high dose showed a plateau between 6 and 24 h, precluding parameter assessment.
As shown in Table 4, Cmax and AUC values increased with dose for all measured compounds. DMT showed a Tmax of 1.5 h (median) after both the low and high doses. Nevertheless, the upper end of the range of Tmax values increased with dose, and the Wilcoxon test indicated a statistically significant difference between doses. A larger Tmax after the high ayahuasca dose is evident also in the DMT concentration-time curve included in Fig. 4. Both harmaline and THH plasma concentrations peaked later than DMT, and their Tmax values were larger after the high relative to the low ayahuasca dose. An unexpected finding was the absence of measurable harmine plasma levels except for a few time points in 4 of 18 volunteers, precluding the calculation of pharmacokinetic parameters for this alkaloid.
Interestingly, all volunteers showed measurable levels of harmol, the O-demethylated analog of harmine. Plasma concentrations showed dose-dependent increases and peaked at 1.5 and 2 h after the low and high doses, respectively. Harmalol, the O-demethylated analog of harmaline, could also be quantified. Maximum concentrations were attained later than for harmaline, with Tmax observed at 2.5 and 2.75 h after the low and high dose, respectively.
The AUC normalized by dose was calculated for each parent alkaloid, and these values were compared between doses by means of a paired Student's t test. A statistically significant difference was found for DMT, suggesting a possible nonproportional increase of plasma levels between doses. In line with this possibility, mean Vz/F and CL/F values calculated for DMT decreased with dose. These decreases were statistically significant for Vz/F and showed a tendency for CL/F (t(14) = 1.94, p = 0.073).
In support of a parallel evolution of DMT plasma levels and subjective effects, no significant differences were found between DMT Tmax values and any of the seven VAS tmax values at any of the two administered ayahuasca doses.
The psychotropic effects of ayahuasca could be demonstrated in a group of experienced psychedelic users who, in their vast majority, had reported no prior exposure to the tea. Oral administration of the freeze-dried material induced feelings of increased activation (ARCI-A, VAS-stimulated), euphoria and well being (ARCI-MBG, VAS-high, VAS-liking, VAS-good effects), and somatic effects (ARCI-LSD), in addition to perceptual modifications (HRS-Perception, VAS-visions) and changes in thought content (HRS-Cognition) and increased emotional lability (HRS-Affect). Increases in VAS-high have been observed after a great variety of drugs including MDMA (Camí et al., 2000), cocaine (Farré et al., 1993), and the sedative flunitrazepam (Farré et al., 1998). The VAS-stimulated item reflects more specifically the effects of psychostimulants such as amphetamine and MDMA (Camí et al., 2000). Increases in VAS-drunken, which was the least modified VAS item by ayahuasca, have been observed mainly after sedatives, such as flunitrazepam (Farré et al., 1998), and alcohol (Farré et al., 1993), but also after 125 mg of MDMA (Camí et al., 2000). Regarding the HRS, our findings are in line with results by other researchers who have demonstrated statistically significant increases in all HRS scales after the administration of various psychedelics, such as i.v. DMT and oral psilocybin (Strassman et al., 1994; Gouzoulis-Mayfrank et al., 1999). However, ayahuasca differed from these drugs in the time course of effects. The overall duration was longer than that of i.v. DMT, but shorter than that of mescaline or LSD (Strassman, 1994). Finally, regarding the ARCI questionnaire, increases in the ARCI-A, ARCI-BG, and ARCI-MBG scales are a common feature of psychostimulants (Martin et al., 1971; Lamas et al., 1994). However, in contrast, with drugs like amphetamine, methamphetamine, ephedrine, and methylphenidate (Martin et al., 1971), ayahuasca did not induce significant increases in the ARCI-BG scale, a measure of subjectively perceived improvement in intellectual efficiency. The coexistence of drug-induced stimulation with a wide range of modifications in the sensorium places ayahuasca among the psychedelics, a drug class which shares arousing properties with psychostimulants (Brawley and Duffield, 1972).
The present results on the subjective effects induced by ayahuasca in a clinical research setting replicate those obtained in a preliminary study involving a smaller sample of volunteers with prior experience with ayahuasca, and with a single-blind nonrandomized design (Riba et al., 2001b). In the previous study, statistically significant increases were observed in all HRS items, except volition, and in the ARCIMBG, ARCI-LSD, and ARCI-A scales. In the present study, however, scores on these measures at the 0.6 and 0.85 mg of DMT/kg doses tended to be lower than those obtained after 0.5 and 0.75 mg of DMT/kg doses, respectively. Several factors such as sample size, study design, and prior exposure to ayahuasca could account for these differences. Scores on the HRS items at the present low dose were also lower than those reported by Grob et al. (1996), except for the somaesthesia and perception items, after the administration of an equivalent ayahuasca dose, in terms of DMT content, to a group of experienced long-term ritual users. Nevertheless, scores on all HRS items after the present high dose were higher than those reported by these researchers. Compared with i.v. DMT as described by Strassman et al. (1994), ayahuasca evokes effects of milder intensity, which show a slower onset and a longer overall duration. Scorings on the six HRS scales after the present high dose fell between those reported after 0.1 and 0.2 mg/kg i.v. DMT.
In our previous study on ayahuasca (Riba et al., 2001b), we failed to observe statistically significant modifications of cardiovascular parameters in a five-subject sample. In the present work, only modifications in DBP reached statistical significance. Increases in DBP, SBP, and HR were milder than those reported for other more prototypical sympathomimetics, such as amphetamine or MDMA, at doses showing psychotropic properties (Mas et al., 1999; de la Torre et al., 2000). DBP increases from baseline values after both ayahuasca doses were somewhat lower than the elevations from baseline values reported by Callaway et al. (1999) after an ayahuasca dose containing 0.48 mg of DMT/kg but larger amounts of β-carbolines.
The time course of DMT plasma concentrations closely paralleled that of subjective effects. The steep rise in DMT plasma levels observed at 1 h coincided with an analogous rise in VAS scores, and peak DMT concentrations and peak effects were obtained between 1.5 and 2 h. In the present study, quantifiable plasma levels were observed for DMT and THH. Tmax values for DMT and THH were similar to those reported by Callaway et al. (1999). However, Cmax values for DMT and THH in the present study were lower than expected, even after taking into account the smaller amounts administered in the case of THH. This could be due to a lower alkaloid bioavailability from the lyophilizate compared with the aqueous solution administered by Callaway et al. (1999). The calculated Vz/F values are similar in both studies, but Callaway et al. (1999) reported higher t1/2 and lower CL/F values. In the case of DMT, these differences may be associated with the lower levels of harmala alkaloids present in our ayahuasca and the consequent lower degree of MAO inhibition. In addition to these interstudy differences, it is interesting to note that the normalized AUC calculated for DMT in the present study showed a statistically significant increase between the low and the high ayahuasca doses. This is suggestive of a nonlinear increment of DMT levels following the administration of increasing doses of ayahuasca. Considering that both Vz/F and CL/F decreased in a similar proportion between doses, these data could be interpreted as indicating a greater DMT bioavailability following the high dose, probably related to the higher amounts of harmala alkaloids ingested, leading to more effective MAO inhibition.
Another relevant difference from the study by Callaway et al. (1999) is the lack of measurable concentrations of harmine in plasma and the presence of significant levels of harmol and harmalol. Differences in ayahuasca harmine content alone cannot entirely explain the absence of this alkaloid in plasma, considering that THH was present in the lyophilizate in amounts similar to those of harmine and was later measurable in plasma. Thus, harmine was either not absorbed in the gastrointestinal tract or was extensively degraded by first-pass metabolism before reaching systemic circulation. The presence of harmol in plasma would support the second hypothesis. Harmol glucuronide and harmol sulfate have been described as the main urine metabolites of harmine following its i.v. administration in humans (Slotkin et al., 1970). A very recent study has found cytochrome P450 to catalyze the O-demethylation of harmine and harmaline, and has identified CYP2D6 and CYP1A1 as the major isoenzymes involved in the process (Yu et al., 2003). Nevertheless, we cannot conclude that harmine was completely metabolized to render harmol, because very small amounts of harmol and harmalol have been detected in B. caapi and ayahuasca (Rivier and Lindgren, 1972; McKenna et al., 1984). Thus, it cannot be entirely ruled out that at least part of the amounts found in plasma could have been ingested with the tea.
The low plasma levels found for harmine in the present study could explain the absence of a clear-cut MAO inhibitor effect on the urinary excretion of monoamine metabolites. The acute administration of a MAO-A inhibitor induces a decrease in the levels of oxidized deaminated monoamine metabolites and an increase in the levels of COMT-dependent methylated compounds (Pletscher, 1966; Koulu et al., 1989). Whereas in the present study normetanephrine, a methylated breakdown product of norepinephrine, showed statistically significant increases after dosing with ayahuasca, the levels of the deaminated metabolites measured, i.e., VMA, HVA, and 5-HIAA, did not show decreases but, rather, were nonsignificantly increased. It is thus unclear whether the observed neurotransmitter metabolite profile was secondary to MAO inhibition. An alternative explanation would be an increase in norepinephrine release induced by DMT, which would fit well the observed sympathomimetic properties of this compound. However, this assumption is not supported by the limited available evidence from related compounds. Results obtained in two studies involving LSD administration to humans found no drug effects on monoamine metabolite excretion (Hollister and Moore, 1967; Messiha and Grof, 1973), and to our knowledge, no data are available on the effects of parenteral DMT on these measures. In any case, MAO inhibition by ayahuasca alkaloids effectively facilitated the access of DMT to systemic circulation but may have been insufficiently potent or insufficiently prolonged to modify the profile of deaminated monoamine metabolites in the 8-h urine collection periods used.
To conclude, the present findings indicate that following ayahuasca administration to humans, measurable DMT plasma levels are obtained together with distinct psychedelic effects. Psychoactivity is attained with negligible levels of circulating harmine. These results and the lack of a clear-cut systemic MAO inhibitor effect are suggestive of a harmine-DMT interaction predominantly taking place in the gastrointestinal tract and possibly in the liver. Harmine effects at a peripheral level would appear to suffice to prevent first-pass metabolism of DMT and allow its access to the CNS in amounts able to evoke psychotropic effects.
We express gratitude to José María Fábregas, Félix González, and Esther Martínez for their support in the initial stages of the research project. We are also indebted to CEFLURIS in Brazil, who kindly provided the ayahuasca (Daime) used in the present study. We also acknowledge the support of James C. Callaway, Department of Pharmaceutical Chemistry, University of Kuopio, Finland, for quantifying the DMT in ayahuasca; María Montero, who conducted the psychiatric interviews with the volunteers; Josep Maria Queraltó, Biochemistry Department, Hospital de Sant Pau, Barcelona, for quantifying urine monoamine metabolites; and Sylvie Cotxet, David Martínez, and Llúcia Benito for collaboration in data collection, and Pablo Ayesta for editing the figures.
DOI: 10.1124/jpet.103.049882.
ABBREVIATIONS: DMT, N,N-dimethyltryptamine; THH, tetrahydroharmine; LSD, d-lysergic acid diethylamide; CNS, central nervous system; MAO, monoamine oxidase; COMT, catechol-O-methyltransferase; VMA, vanillylmandelic acid; HVA, homovanillic acid; 5-HIAA, 5-hydroxyindoleacetic acid; MDMA, methylenedioxymethamphetamine; HPLC, high-performance liquid chromatography; VAS, visual analog scale(s); HRS, Hallucinogen Rating Scale; ARCI, Addiction Research Center Inventory; MBG, morphine-benzedrine group; PCAG, pentobarbital-chlorpromazine-alcohol group; BG, benzedrine group; AUC, area under the concentration-time curve; CL/F, total plasma clearance; Vz/F, apparent volume of distribution; ANOVA, analysis of variance; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate.
- Received February 3, 2003.
- Accepted March 13, 2003.
- The American Society for Pharmacology and Experimental Therapeutics


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Lobbyists representing National Air Cargo, 2008:
Lobbying Firm Hired | Amount | Subsidiary (Lobbied For) | Lobbyist |
Akin, Gump et al | $120,000 | National Air Cargo |
Goode, Chris Simmons, John M Vaart, Ryan |
Commonwealth Consulting | $0 | National Air Cargo |
Green, Jeffery Lehman, Christopher M |
*Each quarterly filing is treated as a separate report.
Feel free to distribute or cite this material, but please credit the Center for Responsive Politics. For permission to reprint for commercial uses, such as textbooks, contact the Center: firstname.lastname@example.com

subset: commoncrawl


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Recipe that looks amazing. I don't know if it was you or me, but things just didn't work out. I could have had something that looked like you but tasted, like, ten times better for under five bucks.
My dad told me this might happen. I should have listened to him.
Maybe things will be better between us after some time apart. Wait for me in the fridge.


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Watch artisans at work as they demonstrate their talents in our six observation studios. Studios serve as the artisans' business center, as well as a focal point for guests to speak to artisans about their processes.


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The little fantasy of meteor streams that shoot on the nails.
I love to look up the sky as it gets colder.
Happy Halloween and wish you a lovely weekend!!
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Gorgeous nail art!
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Welcome to
The Saturday Showcase
- Publisher: Fused Publishing (12 Nov 2013)
Let's go back in time and see how Cordelia began...
Every person has emotional wounds, internal scars, and at one time or another, witnessed an event they wished they'd never saw.
These things change us irrevocably
For Cordelia Kelly, growing up at the mercy of her Dark Empathic father caused her to tear in two when she was sixteen. As she tried to save her mother from his brutal attacks, she unknowingly unleashed her inner duality and now struggles under the weight of who she truly is, and what she's capable of.
This is the beginning.
Torn in Two is a 24 page short story delving into the teenage mind of Cordelia Kelly. The story can stand alone, but is better read after Duality.
Every person has emotional wounds, internal scars, and at one time or another, witnessed an event they wished they'd never saw.
These things change us irrevocably
For Cordelia Kelly, growing up at the mercy of her Dark Empathic father caused her to tear in two when she was sixteen. As she tried to save her mother from his brutal attacks, she unknowingly unleashed her inner duality and now struggles under the weight of who she truly is, and what she's capable of.
This is the beginning.
Torn in Two is a 24 page short story delving into the teenage mind of Cordelia Kelly. The story can stand alone, but is better read after Duality.
Character Interview with Cordelia Kelly
Could you tell us
when and where you were born?
I was born in 1861 in
Connecticut. I recently just told a story about what happened to me when I was
sixteen, in Torn in Two. You should
check it out, it's rather painful to talk about.
Tell us a little
about yourself, your family, any brothers or sisters etc...
I'm an only child and
I spent most of my childhood alone. I tried to go to school once, but feeling
the despair and poverty amongst the other children nearly drowned me. I was homeschooled
by my mother and grandmother after my horrific experience. They'd wanted to
teach me from the start, but I was determined to be a normal child.
Do you have any
special gifts, if so what are they and how did you come to possess such amazing
We hail from the
Empathic race. Both of my parents are of Royal lineage. A first, you might say.
God created light empaths to aid in human suffering. We filter out their darker
emotions and leave them with a sense of well being and peace. Lucifer created
the dark empaths in retaliation, their sole purpose is to create havoc, devour
the happiness of humans, and dance in darkness.
In addition to
feeling the emotions of humans and intuitively knowing what they're thinking,
well, I can't read minds, I get more of an impression, I have some elemental
powers that have manifested over the years. I wield fire from my right side,
and ice from my left side.
What is your
favourite tv show/book/movie/song?
I love any music that
moves me and suits my mood. I like listening to classical music when my head
becomes too cluttered with noise. For reading I prefer
J.D. Robb books, and I adore the kick ass snarky attitude of Kate Daniels.
What is your
favourite drink?
I'm an ice coffee
junkie, though I really enjoy herbal teas as well. Black, no cream, sugar, or
other additives. For alcohol, I prefer
white wine.
What is your
favourite type of food?
Chocolate. Oh, that
wasn't an option? Fine. I like mashed potatoes.
What's your most
pivotal life defining moment?
Meeting Sol in a
decrepit barroom. He turned my world from upside down, to right side up.
In less than ten
words describe yourself.
I'm a simple, yet
complex woman.
Are you a night owl,
if so, why?
Delia is prefers the
night, I prefer the daytime. However, both have their good points. And no, I'm
not a multiple personality, before you ask. I was born to two very different
parents and I am unique. Dual-natured. I am half light empath, and half dark
empath. I fought the darker side of my nature for almost my entire life, but
since meeting Sol I've learned to embrace who I really am.
Do you have any
hobbies or pastimes?
I practice Yoga and I
like candlepin bowling.
If you could go
anywhere in the world, where would it be?
Scandinavia. I'd love
to take in the air, the mountains, and the atmosphere.
Tell us one thing
that no-one knows about you.
That's a tough
question. I harbour so many secrets.
Who's your ideal date
and where would you go?
Who? Sol of course.
Where would we go... let's see. With Sol, I'd go anywhere, but I think my ideal
date is curled up on the couch with a glass of wine while watching a movie, and
laying between his legs with my head on his chest.
Do you kiss on the
first date or treat them mean and keep them keen?
Depends on the man. I
kissed Sol the first time we met.
How would you
describe your personal style?
I like comfortable
clothes with pretty patterns and natural fibres. I'm a wool fanatic.
If you could choose
one accessory that defines you, what would it be?
Mascara. You can hide
anything behind armour.
What's your preferred
pet, cat or dog or other?
I'm not an animal
person, at least, not any longer. Don't get me wrong, I adore them, but I can't
be responsible for their lively hood.
If you could pass one
Law, what would it be and why?
Human law? Those who
hurt children don't get to live.
What's your fondest
memory growing up?
I don't have any.
If you had a choice,
would you:
A. sleep under the stars
B. sleep in a gypsy caravan
C. check into a 5* hotel
I would sleep under the stars.
Are you a nature
lover or city slicker?
Both have their pros
and cons. I love to visit the city, but there are too many emotions and there
is no escape. I don't know many empaths who could tolerate living in the city,
well, unless of course you were a dark empath feeding on the negativity. I'm a
nature lover and country girl at heart. Not country, country, but I like not
having neighbours close by, owning land, and living in a log cabin, probably
somewhere in Connecticut.
I don't currently own
a log cabin, but it's on my wish list.
If you saw a giant
black hairy spider crawling up the bed towards you, would you:
A. Scream like a
girl and run like hell
B. lay paralysed
and pray for rescue
C. adopt it as
your new pet
I'm not a huge fan of spiders. I'd probably lay paralysed
and hope it jumps off the bed onto the floor so I don't have to squash it. I
tend to live and let live, but if that thing attacked me, I'd probably scream
and toss the blankets off while I jumped and ran out of the room. I know, Not
very respectable.
What's your favourite
My favorite color is
red. Second favorite is royal blue.
If you could go back
to any point in history and change one event, what would it be and why?
I wouldn't. Things
happen for a reason.
What are your plans
for the future?
I prefer to live in
the moment. The future isn't guaranteed.
Who out of everyone
you've ever met, has had the most influence on your life?
My grandmother, and
What is your
favourite time of year and why?
I like Thanksgiving
and Christmas. I love eating Thanksgiving meals, and I really enjoy the hunt
for the perfect gift for someone I care about.
If you could fly,
what would your mode of transport be:
A. Wings
B. Broomstick
C. Magick
I'd want to teleport. That
would be so awesome. Like in Harry Potter. But If I had to choose, I'd want
What is the most
embarrassing thing that has ever happened to you?
I can't tell you, a
girl's gotta have some secrets.
Book Blurb:
She is, the most interesting Empath in the world...
My name is Cordelia Kelly and I'm an empath. I know what you're thinking. In fact, I know what you're feeling, too. I could use your emotions against you or free you from their constraints. My choice, really, and depends on my mood. You see, I filter both light and dark emotions from humans, but which I chose depends on which side of me is in charge.
I'm not normal. I am the line walker and restorer of balance. A Royal. Think black sheep with red hair - not the blonde bombshell princess. I'm an aberration and unique. Not fully light, nor fully dark. Not accepted by anyone, but wanted by everyone. Mostly for their own amusements or nefarious purposes.
Cordelia Kelly Novels in reading order + Buy Links:
Duality (Cordelia Kelly#1)
Torn in Two (Cordelia Kelly #1.5)
Night of the Wolf (Cordelia Kelly World #1.7 - Snowed In Anthology coming December 10th)
Author Bio:
I write with emotion, occasionally a temper, and I let my words flow free. I dabble in paranormal, contemporary romance, erotic fiction and darker urban fantasy. I fly by the crotch of my panties when writing, though I do try to keep a notebook handy for my many scribbled ideas, plot twists, and characters.
Want to stay up to date on my work? Join my Code Blue newsletter http://eepurl.com/DV9rH
I've been writing for as long as I can remember. I wrote my first story when I was in seventh grade--A first person account of an entire summer. I went through a massive teen angst poetry phase, and I have notebooks and binders filled with prose.
Ceithin and Aurelia from Fractured Moon showed up in my head. They yapped incessantly, demanding I sit and tell their story. After a month or two of being woken up with harsh whispers, I started writing. They haven't stopped, and in fact, brought friends. Now my head is filled with stories, scenes, snippets and crazy people. Cue Law and Order music here: dun, dun. These are their stories.
Oh, and hey... I'm a Virgo..
Author Links:
All Novels by ER Pierce:
Available on Amazon, Barnes and Noble, Smashwords, and All
Romance Ebooks
(Cordelia Kelly #1)
in Two (Cordelia Kelly #1.5)
of the Wolf (Cordelia Kelly #1.7) (December 10,
2013) Snowed in Anthology
Moon (Steel #1)
Time (Marriage #1)
Hot Lunch Series: (Eating Out, Hot or Cold, Table for Two)
My-Sir Series: (The Contract, Lock and Key, One Night
of Control)
of Pain and Illusions
Well that's it for my blogging week, I'm back on Tuesday with a Book Blog Tour, join me if you can and I'll be emailing the winners of my Give-away in the next couple of days, so keep an eye on your email just in case you win one of those gorgeous bookmarks, bracelets and phone charm sets!
Have a truly divine weekend


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Port Ludlow, WA 98365Email: firstname.lastname@example.com
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Gheorghescu Lucian, RomaniaThe rajputana Sheraton at Jaipur and the Jaypee Palace were excellent but The Park in Delhi, wasn't in the same level, the public spaces like corridor were dirty.
Excellent experience guided and suggested by an excellent tour conductor. Thanks a lot.
Hotel Rajputana Palace Jaipur
The Rajputana Palace Sheraton is a palace converted into hotel, offering a range of services in a truly regal ambience. The perfect blend of tradition and modernity can be witnessed here. The hotel therefore has become the first choice of all the business and leisure travellers.
The hotel Rajputana Palace in Jaipur is located on the Palace Road. It is 14 kms from Jaipur's domestic airport and half a kilometre from the city centre.
The Welcomgroup Rajputana Palace Sheraton offers 216 rooms, including 17 suites. The 70 Executive Club rooms are a unique concept in accommodation, pioneering a tradition in corporate hospitality and setting a premium ondiscreet efficiency and business-related services. The room privileges for the guests thereof include the use of Executive Lounge facilities, Complimentary Breakfast, Complimentary Club Hour etc.
The Rajputana Palace caters to the taste of connoisseurs. The Rajputana Palace Sheraton comes out with the finest recipes in Indian and International cuisine. Chandravanshi Pavilion open round-the-clock is a charming restaurant renowned especially for the celebrated Dum Pukht cuisine. Peshwari leads the North West Frontier in barbecued specialties and baked Indian breads prepared at the restaurant's display kitchen. Jal Mahal is a splendid venue for Indian, Continental, Chinese and Rajasthani delicacies. Sheesh Mahal christened as the "Palace of Mirrors", is indeed the finest bar in the town, overlooking the Jai Singh Bagh courtyard.
Conference and Banquet Facilities
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The Suryavanshi Mahal, the main banquet hall, can accommodate more than 500 people at a time. It can also be divided into several flexible conference areas. The verdant Jaisingh Bagh (Pool side) is perfect for parties and receptions. The six Royal Chowks (Courtyards), named after the six princely states of Rajasthan - Jodhpur, Bikaner, Boondi, Kota, Bharatpur and Karauli. Also the open-air courtyard with live outdoor entertainment form the ideal venues for theme parties.
Recreational Facilities
The Rajputana Palace Sheraton has a swimming pool and a jogging track. It also has Kaalbelia, the discotheque that chills you out after a hectic schedule. Spectrum, the home theatre may also be enjoyed. Shatranj is the indoor games' room. The Playpen is a children's room/crèche. Marwari Bazaar is the shopping arcade, which offers the finest of Rajasthani souvenirs. You can also avail the services of the health club and the beauty parlor.
Name: | Rajputana Palace Jaipur |
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Podcast: Juan Enriquez: Beyond the crisis, mindboggling science and the arrival of Homo evolutis
View Podcast Online? Yeshttp://www.ted.com/index.php/talks/juan_enriquez_shares_mindboggling_new_science.htmlPodcast length: 18minutes 50 SecondsPodcast DescriptionJuan Enriquez' humourous talk from TED 2009, meandering through the state of the economy, developments in stem cells, tissue cloning and robotics - and how they are all connected. Very funny, very poignant. It will not say anything you do not already know, if you have kept up with transhumanist work, but serves as a nice, low barrier introduction. Presenter BiographiesJuan EnriquezA broad thinker who studies the intersection of science, business and society, Juan Enriquez has a talent for bridging disciplines to build a coherent look ahead. Enriquez was the founding director of the Harvard Business School Life Sciences Project, and has published widely on topics from the technical (global nucleotide data flow) to the sociological (gene research and national competitiveness), and was a member of Celera Genomics founder Craig Venter's marine-based team to collect genetic data from the world's oceans. Transcript Available? NoAudio file available? Yes6.4 MB http://www.ted.com/index.php/talks/download/audio/224/talk/463Podcast Download? Yes60.1 MB http://www.ted.com/index.php/talks/download/video/6076/talk/463Podcast viewing notes
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1 A proposal to evaluate the legitimacy of Sanitary and Technical measures in Brazil Sílvia Helena Galvão de Miranda Geraldo Sant'Ana de Camargo Barros San Diego – CA 4-6 th December 2005
2 Summary 1.Introduction: –Concepts 2.Objectives 3.Important Previous Work 4.Relevance Index –Economic Relevance –Legitimacy Legality Consistency 5.Final comments
3 1 - Introduction LDCs need to develop tools to: –antecipate and/or react to sanitary and technical barriers; –rationalize decisions on public policies Public and private interests Complexity to define/identify sanitary and technical barriers => establish some criteria to build a ranking of priorities Need to evaluate benefits and costs of sanitary and technical barriers
4 Concepts Developed Countries => Sanitary and technical requirements Developing Countries –Problems on accessing information and scarcity of trained personnel and financial resources –Difficulties to implement necessary changes: Capital investments ($) to meet requirements Technology gap: –Availability –Technological change in production Technical and financial assistance from Developed Countries –Developing Countries: welfare gains from restrictions
5 2 - Objectives Propose a relevance index to react to technical and sanitary measures. –Which elements should be part of the criteria? –Suggest a weighing system of such elements –Suggest a checklist to be used by policymakers and trade negotiators
6 3 - Important Previous Work Roberts et al. (1999) – two-step classification system for technical barriers WTO Trade Policy Staff Committee (TPSC, 1998): a questionnaire to evaluate the Consistency of Trade Measures with the SPS Provisions Popper et al (2004): USA National Institute of Standards & Technology (NIST) checklist as identification criteria for TBT
7 4 – Relevance Index Nature of the measure: a regulation on –technical, sanitary regulation,on conformity assessment,or a standard (mandatory or voluntary) Economic Relevance –Does the measure have significant impact on trade and other economic variables (employment)? Legitimacy –Legality Is the measure nationally and internationally legal? –Consistency Is the measure technically and scientifically justifiable?
8 Economic Relevance Sector's relevance for the affected Country Trade Balance? Current and potential domestic relevance? Employment and wages national and regional income Relevance for the other country (that proposed the regulation)? within the production structure and interest groups trade relevance of the good
9 Economic Relevance Checklist 1.Range of the measure and impact on trade balance: specific for a good, set of goods or sector(s) ? 2.Is it a new requirement? Existing but not currently enforced one. 3.Intensity of impact on current and future exports 4.Impact on current and future market prices? 5.Does it affect a traditional trade partner or a new one? 6.Additional costs associated with compliance to new requirements ? 7.Delays in the customs procedures? 8.Immediate or progressive adjustment required? 9.Impact on trade of the country imposing the measure 10.Are there alternative, politically preferred, suppliers to that country?
10 Legality Adequacy of the measures to the SPS, TBT and WTO provisions? Legality elements: –Transparency –Non-discrimination among foreign suppliers – Non-discrimination between domestic and imported goods –Scientific basis
11 Legality Checklist 1.To what extent the proponent complied with all the legal requirements to implement the measure: - proper deadlines to consult on the notifications; - fair deadlines to implement the measure and - level of compliance with the comments and criticisms from the other WTO members 2.Does the measure discriminate between foreign and domestic suppliers? 3.Does it discriminate among different foreign suppliers? 4.Is there a scientific support for its proposition? Is it from international organisms ? 5.Does it refer to the Agreements' legitimate objectives?
12 Consistency Technical and scientific background: –IPPC, the IOE and the Codex Alimentarius? –Other scientific institutions? –Type of risks Sanity: human, animal or plant health Environment Quality attributes –Seriousness of the problem intended to be mitigated Lethality Reversibility Mitigating costs
13 Consistency checklist 1.What is risk level of not complying with the proposed measure? 2.Is there scientific proof of this risk level and of the necessity of applying the measure? 3.What is the degree of scientific convergence about the issue? 4.Is the scientific basis recognized internationally, or only in a domestically context? 5.Are there lower cost alternatives? Have they already been tried by the affected countries? Do they assure the same required level of security/safety? 6.Is the required technology available to implement the measure? What are costs (labs, personnel) related to its compliance?
14 Example Economic Relevance High impact Medium impact Low impact Legality Highly contestable Partially contestable Uncontestable Consistency Highly consistent Partially consistent Inconsistent LEGITIMACYLEGITIMACY WTO Dispute Disputing Negotiation Requirements accepted Relevance Index => Government reaction Collaborative Negotiation
15 Weighing system for Economic Relevance Checklist * The higher the number of points, the higher would be the priority in questioning to WTO.
16 Weighing system for Legality Checklist * The higher the number of points, the higher would be the priority in a questioning to WTO. Level of not-compliance Weigh* Completely legal 0 Close to legality 1 Close to illegality 2 Highly illegal 3 Special case (completely illegal) 4
17 Weighing system for Consistency Checklist * The higher the number of points, the higher would be the priority in a questioning to WTO. Level of consistency Weigh* Highly consistent 0 Medium consistency 1 Low consistency 2 Highlyinconsistent 3 Special Case (Inconsistent) 4
18 EXAMPLE –FMD – Brazil – Indonesia ban on exports of beef Economic Relevance Checklist: a)beef share in the Brazilian agribusiness exports: –i) more than 10% (weigh 3) –ii) from 5% to 10% (weigh 2) –iii) from 1% to 5% (weigh 1) –iv) less than 1% (weigh 0)
19 b) Brazilian market-share in Indonesian beef imports i.more than 50% (weigh 3) ii.from 50% to 30% (weigh 2) iii.from 30% to 10% (weigh 1) iv.less than 10% (weigh 0)
20 Legality Checklist: i. There is no international reference to support the proposed measure (weigh 3) ii.There are some international references to support the measure (weigh 2) iii.There is almost a consensus about the few international references available to support the technical or sanitary measure (weigh 1) iv.The measure is totally based on the international references (weigh 0)
21 Consistency Checklist: a) risk for human health if the regulation is not adopted : i.zero probability (weigh 3) ii.low probability (weigh 2) iii.high probability (weigh 1) iv.almost sure (weigh 0)
22 Consistency Checklist: b) risk for animal health if the regulation is not adopted : i.zero probability (weigh 3) ii.low probability (weigh 2) iii.high probability (weigh 1) iv.almost sure (weigh 0)
23 Example: Economic Relevance - Ilegitimacy Low Priority Disputing Negotiation High Priority Disputing Negotiation High Priority Collaborative Negotiation Low Priority Disputing Negotiation High Priority Disputing Negotiation
26 5 - FINAL COMENTS Proposals for addressing these questions 1 - Keep track of the notifications on SPS and TBT 2 - Develop an automatic consulting system of based on a network of agents from scientific institutions, firms and government organisms 3 - Develop criteria to classify – with priority ranks - the private and public demands of actions to solve sanitary and technical complains 4 –Develop detailed studies and strategies for the cases considered relevants.
27 Sílvia Helena Galvão de Miranda firstname.lastname@example.com Geraldo Sant'Ana de Camargo Barros firstname.lastname@example.com Phone: 55 – 19 – 3429 8801 http://www.cepea.esalq.usp.br
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When meeting up take sensible precautions. Meet in a public place and let others know where you are going. You can also meet mums on your local site here.
Durham / Teeside / Tyne & Wear Meet up and random chat thread.
(895 Posts)Next meet up, Tuesday 4th September.
During the day, either Botanic Gardens in Durham or the Slug and Fiddle near the Gala Theatre in Durham City centre.
Now for some random chat.
DS sang a song about bolognaise today. And DD walked some more. But still prefers crawling and using my nipples as handholds on Mount Starbuck.
Excellent timing And sleep is always helpful!
Do you have a name?
Wooooooooo leggy
<cracks open the champers>
Yay! Well done you. HUGE congrats!
Congratulations Leggy.
Grand mercis tous les mondes!
Currently far less tired than I have any right to feel. Living the day-dream that second baby would be mellow. I'm sure it'll last all of 48 hours...
Yeah, I hate to tell you this but that was how Cara started out...
Ds2 slept really, really well until 4 month. He is still really mellow though.
Spiggy did I see that you got the free entry to Jumbo Jungle thing too on FB? Does anyone fancy a half term meet there? Jumbo Jungle in Consett.
All mine had a honeymoon period of about 2 weeks before they showed their true colours
Indith I got the free entry but not sure if I'll be able to make it . Think I'm only going to be free on the tues. I'm acting up for one of the next grade up in Feb so can't really take leave.
Rubbish. Do you think they will count the weekends?
DS2 is in the throws of another developmental thing. Waking every bloody half hour.
We can ask
ds 2 has taken to demanding a feed at 5.30 but just sitting there chewing on my nipple instead of feeding. When I put him back down he screams blue murder until dh goes in to him. But he won't go back down for dh until he's tried feed. It's getting rather annoying
Sounds like he and have been discussing tactics. Ds2 wakes, stands up, shouts, feeds for a few mins, fusses, chews, shouts, goes to dh to be walked to sleep. If we try to bypass the feed and just get dh to settle him he screams. If I try to just feed him to sleep and snuggle then he screams .
Congratulations, Leggy - goes to look at Jumbo Jungle thing on fb...
Not sure if it is on any more, you had to like and share a picture but they said they'd take it down after a certain number of likes. Everyone who shared would get put on a list for free entry over half term. Happy to share the love though and split the entry costs, half price would still be pretty good!
Or if I can't go then someone can pretend to be me
Indith, there are a couple of football free weekends coming up if you want to go shopping. I went to buy some new bras the other day. Went in a 30ff and came out a 28gg. I feel like a new woman one with substantial scaffolding round her chest and quite fancy some new clothes to show off the improved figure
I shall consult with dh.
Any one do cake on Tuesday 19th Feb? I don't mind where.
Or is that half term?
Oh it is, ignore me!
I think that's half term. I should be free on the Tues though.
jumbo jungle on Tuesday then? or gibside for foodie Tuesday? or botanics but less indoor space fir this time if year. or slug as usual but there will be lots of children!
I shall try and make it, will swap CM to Monday and Thursday of that week, I have plans for the Wednesday but nothing else.
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You would think that when you are diagnosed with skin cancer, you would become vigilant about protecting your skin from further damage but just the opposite seems to be true according to a recent study.
Cutaneous malignant melanoma (CMM) is the deadliest form of skin cancer. Although it makes up only between 3 and 5 percent of diagnosed skin cancers, it is responsible for 75 percent of all deaths attributed to skin cancer. Exposure to the sun's UV rays (UVR) is considered one of the largest causes of melanoma. Skin cancer patients are routinely told about the risks of sun exposure and usually given information on how to protect their skin - such as using sunscreen, wearing protective clothing, wearing wide brimmed hats and staying out of the sun between 10:00 AM and 4:00 PM when the sun's UV rays are strongest.
A recent study completed at the University of Copenhagen in Denmark found that those previously diagnosed with skin cancer actually increase the time they spend in the sun after their diagnosis. The researchers measured exposure to UVR in 40 participants, 20 who were diagnosed with cutaneous malignant melanoma and 20 control participants. Each participant wore a UVR dosimeter (in the form of a wristwatch) which measured the amount of sun exposure. Participants were also asked to keep a diary, answering questions such as "Did you sunbathe today?" and "Have you applied sunscreen today?"
The results of the study showed:
- Those diagnosed with CMM increased exposure to UVR by 25 percent in the second summer and by 33 percent in the third summer after diagnosis
- Sun exposure also increased during vacations
- 60 percent of CMM patients indicated they had been sunburned at least once during the study period as compared to 50 percent of the control group.
- During the first summer after diagnosis, CMM patients were vigilant about using sunscreen but by the third summer they were no more likely to use sunscreen than the control group
Researchers did not ask for reasons why sunscreen was not used or why participants increased their sun exposure. However, it became apparent that those diagnosed with CMM were much more lax in their attitudes toward protecting their skin from further damage.
"Melanoma Patients Increase Sun Exposure After Diagnosis," 2013, Oct. 2, Belinda Weber, Medical News Today
Published On:
December 17, 2013
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Swinging for the Fence
This is a story about how a kid from Brooklyn started from scratch, bought Yankee Stadium, and built a sports empire. On January 29, Pace Board of Trustees Chairman Mark Besca sits down with Brandon Steiner.
InsideTrack with President Stephen J. Friedman brings renowned thought leaders and policymakers to Pace University for captivating discussions on topics and issues that affect us all. However, this January, InsideTrack throws us a curve ball.
President Friedman invites you to join him and the Pace Community as he turns the Schimmel stage over to Chairman of the Pace Board of Trustees Mark M. Besca '81 and featured guest CEO of Steiner Sports Marketing, Inc. Brandon Steiner on January 29 from 7:00 p.m. to 9:00 p.m.
Besca and Steiner will sit down for a significant discussion on the intersection of business and sports and the innovative approaches to business and commerce that entrepreneurs commonly employ across all fields, not just sports marketing. In addition to his role as CEO, Steiner has made himself a permanent fixture in the media as a regular on ESPN Radio 1050 and as co-host of Yankees-Steiner: Memories of the Game on the YES Network. In his recent autobiography, You Gotta Have Balls, Steiner puts us inside his own mind, demonstrating from the inside-out the business and life philosophies that have propelled him to the top of the sports and marketing worlds.
Pace students are invited to attend the event free of charge. For more information on this InsideTrack and to register, click here.
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