REPORT OF THE LYNN PIERSON THERAPEUTIC RESEARCH PROGRAM
NEW MEXICO STATE DEPARTMENT OF HEALTH
Oral vs. Inhaled Cannabinoids for Nausea/Vomiting from Cancer Chemotherapy. 1. Methodology and Efficacy of Initial Dose*
Daniel A. Dansak, M.D.
Department of Psychiatry
College of Medicine
University of South Alabama
1504 Springhill Avenue
Mobile, Alabama 36604
Katy Brazis, MA, RN
Department of Psychiatry
School of Medicine
University of New Mexico
2400 Tucker NE
Albuquerque, New Mexico 87131
Edward B. Deaux, Ph.D.
Director, Information Management Services
Health Planning Division
State of New Mexico
Santa Fe, New Mexico 87501**
Harold D. Delaney, Ph.D.
Department of Psychology
University of New Mexico
Albuquerque, New Mexico 87131
Paul R. Duncan, M.D.
Clinical Associate Professor
Department of Medicine and
Director of Medical Oncology
St. Joseph's Hospital
Albuquerque, New Mexico 87102
*This study was conducted under Contract Number 72-665.63.13-001 from the State of New Mexico, Health and Environment Department. Correspondence regarding manuscript should be directed to Daniel A. Dansak, M.D.
**Dr. Deaux is presently a health care consultant at P.O. Box 92379 Anchorage, AK 99509-2379.
One-hundred-sixty-nine cancer patients received oral delta-9-tetrahydrocannabinol, or smoked marijuana, to reduce nausea and vomiting from chemotherapy. Both forms were effective with the inhaled form superior for vomiting only. Chemotherapy severity was a significant predictor of improvement. Patients on mild or moderate nausea/emetic provoking chemotherapy improved more than those on severe. Prior use of marijuana did not predict improvement. Euphoria ("high") was not associated with efficacy. Anticipatory nausea and vomiting was highest in patients receiving oral THC and mild chemotherapy. Ninety percent of patients chose to continue the drug after the first dose. Prior use and mild or moderate chemotherapy were marginally associated with continuation. Side effects were minimal for most patients; only three required medical intervention. Oral cannabinoid was associated with more drop outs due to side effects or ineffectiveness. Mean cannabinoid use on the program was 735 mg (forty-nine 15 mg doses or six two-day treatments).
Based on the study of Sallan et al1 and anecdotal reports, the State of New Mexico Legislature, in February, 1978, passed the Controlled Substance Therapeutic Research Act. This document permitted cancer chemotherapy patients to use cannabinoids as anti-emetics subject to existing Federal regulations, and only when conventional anti-emetics failed or were contraindicated. A research protocol, approved by the Food and Drug Administration (FDA), National Institute of Drug Abuse (NIDA), National Cancer Institute (NCI), and the Drug Enforcement Administration (DEA), was implemented in February, 1979, and completed in June, 1986. This report will present the initial results of the study.
Since inception of this project, results appeared of numerous other studies on delta-9-tetrahydrocannabinol (THC). Several reviews concluded that THC seems efficacious in alleviating nausea/vomiting provoked by anti-cancer chemotherapy.2-6 The reviewers' conclusions were somewhat tentative because of many methodologic, pharmacologic, and patient response problems. Carey et al7 and Lover et al8 discussed these problems in detail. When this study was designed and implemented, the authors were aware of many of these difficulties, so the detailed data necessary to account for some were gathered for later statistical analysis.
The purpose of the study was four-fold: 1) assess the efficacy of cannabinoids as anti-emetics; 2) compare the efficacy of synthetic oral delta-9-tetrahydrocannabinol (oral THC) with natural inhaled marijuana cigarettes (inhaled THC); 3) assess the side effects and long-term efficacy of the cannabinoids in cancer patients; 4) ascertain psychosocial or pharmacologic predictors of response and side effects. This report discusses the first three only.
It was hypothesized that a) both oral and inhaled cannabinoids would produce significant reduction in nausea and vomiting; b) inhaled cannabinoids would be significantly better than oral; c) repeated intermittent dosing of either cannabinoid would not result in tolerance to the antiemetic action nor produce significant side effects.
Basic criteria for inclusion in the study were: a) severe nausea/vomiting from cancer chemotherapy unresponsive to one or more conventional FDA-approved anti-emetics given in adequate doses; or b) conventional anti-emetics contraindicated by medical condition or history of serious or life-threatening adverse effects from them. Relevant exclusion criteria were: a) pregnant; b) living alone or no adults available for assistance while taking the medication; c) must operate a motor vehicle or complicated machinery during medication use; d) mentally disabled by significant psychiatric or neurologic disease, or diagnosed with a condition that may be aggravated by use of cannabinoids, e.g., chronic schizophrenia, paranoid states and paranoid personality; e) patient currently enrolled in a drug or alcohol treatment program; f) liver disease manifested by total serum bilirubin exceeding 2 mg% van den Bergh or equivalent; g) renal disease with abnormal electrolytes and serum creatinine exceeding 3 mg%; h) cardiovascular disease that may be aggravated by the effects of cannabinoids, e.g., angina pectoris, conduction defects, or arrhythmias; and i) lung or gastrointestinal disease that may impair medication absorption, e.g., severe emphysema, gastric or intestinal obstruction.
The patient and attending physician requested participation in the study and completed several forms. A Medical History Form assessed the medical inclusion/exclusion criteria. Psychiatric status was screened with the Symptom Check List-90-Revised (SCL-90-R).9 Score Profile B (Normals) was used to plot its twelve subscales. Patients whose T-scores exceeded 80 on Paranoid Ideation or Psychoticism were to be excluded from the study. The severity of baseline nausea and vomiting experienced by patients during their most recent chemotherapy treatment was rated retrospectively with the Target Problem Self-Rating Scale (TPSS).10-14 Nausea and vomiting were scored on a five point scale: 1 = not a problem, 2 = slight, 3 = mild, 4 = moderate, 5 = severe. This baseline symptom data was used later to establish difference scores for assessment of drug efficacy during subsequent chemotherapy. Thus, patients served as their own controls.
A ten question Drug Use and Attitude Questionnaire (DUAQ) elicited information about the subject's past use of alcohol, marijuana or hashish, and other non-medical drugs; expectations about the use of marijuana for nausea/vomiting; and overall attitude toward the use of drugs. For this report, the primary concern was that prior use of cannabinoids might influence efficacy and side effects.
The patients and their attending physician read and signed a consent form approved by the University of New Mexico Human Research Review Committee. The attending physician's participation provided implicit confirmation of the severity of the patient's nausea and vomiting from chemotherapy. Also, since the oncologist author (PRD) reviewed each Medical History, there was additional oversight and confirmation of symptom severity. Parents of cancer patients under 18 years old and the attending physician signed a slightly modified consent form approved by the same committee.
Accepted patients were randomized initially to oral or inhaled forms, with those refusing the offered form automatically receiving the other. (Of the first 80 patients, sixteen refused the randomized form; thirteen refusing cigarettes). Later, this partial randomization procedure was terminated because it essentially permitted patient choice of their preferred drug form. Patients were then allowed to openly self-select oral or inhaled drug forms. However, sufficient subjects accrued (N = 59) so it was possible to statistically assess pre- and post- randomization groups on the null hypothesis of no difference in efficacy.
On the day of chemotherapy, patients were prepared as usual by their attending physician for treatment, be it in the office, clinic or hospital. The nurse administering the chemotherapy was instructed earlier by the research nurse about the protocol and completion of the study data sheets. When feasible, the research nurse acquired the data or directly assisted data gathering by the attending nurse. Direct involvement of the research nurse occurred for 87% of the patients. Chemotherapy agents, dose, route, and time of administration were also recorded.
Patients completed the TPSS again immediately before (Pre-THC) and four hours after (Post-THC) cannabinoid intake. Supine, sitting, and standing blood pressures and pulse rates were taken pre-drug and hourly thereafter for four hours. The presence or absence of eight side effects (Euphoria, Sleepy, Agitation, Depression, Fearful, Anxious, Visual Hallucinations, Other) were also recorded during this four hour observation period.
After recording baseline measures, patients ingested 15 mg oral synthetic THC (in soft gelatin capsules with sesame oil vehicle) with fresh tap water 30 minutes before chemotherapy. Or, they smoked a marijuana cigarette (900 mg with 2% THC) as tolerated in the 10 minutes preceeding chemotherapy.* Typically, at least three fourths of the cigarette was smoked. These time intervals were chosen to assure some near-peak blood level of THC at the expected onset of nausea and vomiting. Above doses were selected after reviewing previous reported studies and consulting with investigators at NIDA.*
*The authors and patients gratefully acknowledge the invaluable assistance and technical support of the FDA (especially John Scillagno, Ph.D.) and NIDA (especially Robert Hawkes, Ph.D.)
There were 125 different combinations of anticancer drugs, dosages, and routes of administration that eventually appeared. To simplify, chemotherapy severity was classified as mild, moderate or severe based on data from Cadman15 and Drapkin.16 Verification of the classification was done by surveying four oncology nurses and six oncology physicians. Correlation coefficients ranged from .44 to .78, with the three highest coefficients (.70, .71, and .78) occurring with medical oncologists. (Dansak DA, Brazis K: unpublished data).
After the four hour observation period, the patient, if agreeable, received additional marijuana cigarettes or THC capsules to use at home or in hospital at 4-6 hour intervals. Patients released home were cautioned not to drive or use complicated machinery for 24 hours after the last dose of drug. (To assure safety, all patients were driven home by a friend or family member.) Within the next four days, patients or family were contacted to assess their desire to continue on the program or drop out and their reason for stopping. Patients electing to stop for any reason were asked to return the unused portion of medication directly to the University of New Mexico Hospital Pharmacy. Patients electing to continue were permitted additional doses in conjunction with each scheduled chemotherapy session and in accord with the duration and intensity of nausea/vomiting experienced thereafter. Any patient could terminate participation at any time and for any reason.
A sample size of N = 180 was determined retrospectively from Cohen's matched pair t-test tables17-18 for a small difference between population means at alpha = 0.05 and beta = 0.80.
Difference scores, post-THC minus baseline, for nausea and vomiting self-ratings were used as measures of cannabinoid anti-emetic efficacy (Baseline = chemotherapy plus conventional antiemetics; Post-THC = chemotherapy plus cannabinoids). Acceptance of the null hypothesis that difference scores were greater than or equal to zero would indicate no efficacy of cannabinoids against nausea and vomiting. The alternative is that the differences are less than zero. A difference score of minus 2 or less was arbitrarily deemed "clinically significant", since this would mean, on the rating scale, a change from severe to mild, moderate to slight, or mild to not a problem.
All data was analyzed using the General Linear Models procedure in the Statistical Analysis System (SAS) release 82.4 on the IBM 3081 at the University of New Mexico.
To July 1, 1984, one hundred ninety-six cancer patients received oral or inhaled cannabinoid. Only 169 will be reported because the remainder returned incomplete data (N=13), received concurrent conventional anti-emetics (N=ll), or didn't receive chemotherapy (N=3). These 27 patients did not differ from the experimental group on age, group assignment, sex, cancer stage, prior marijuana use, or baseline and pre-cannabinoid nausea and vomiting ratings.
Tables 1-3 list frequencies and means of pertinent variables.
Matched pair t-tests showed significant reduction in nausea (-2.50, SD = 1.32, p < .0001) and vomiting (-2.52, SD = 1.46, p < .0001)
Between baseline rating and ingestion of cannabinoid, 90 % of the patients did not change category of chemotherapy severity, 2 % changed to more severe, and 8 % to less severe. The median interval between baseline ratings and THC ingestion was 12 days (Range 0 - 150 days).
Because of the non-uniform symptom baseline measures, an initial multi-variate analysis of variance (MANOVA) used post-THC nausea and vomiting scores as dependent variables with baseline nausea and vomiting scores as covariates, and group (oral, inhaled), chemotherapy severity (mild, moderate, severe), and their interaction as independent variables. Chemotherapy severity was the only predictor of nausea (p < .0018) and vomiting (p < .0004) self-ratings four hours post THC ingestion. Mean nausea scores were curvilinear from mild to severe chemotherapy (1.80, 1.68, 2.44), while mean vomiting scores were more linear (1.24, 1.37, 2.22). Pairwise comparisons (experiment-wise) showed mean nausea scores for severe chemotherapy to be significantly higher than the mild or moderate classes (p < .05). For vomiting, the pairwise comparisons (experiment-wise) indicated that mild and moderate subclasses both were significantly different from the severe subgroup (p < .05). A differential efficacy of cannabinoid versus chemotherapy severity is thus suggested.
Pre-THC nausea and vomiting scores (an indicator of anticipatory nausea and vomiting) showed no significant predictors from group, chemotherapy severity, or their interaction.
Post-THC minus baseline difference scores on nausea and vomiting were dependent variables in a MANOVA with independent variables of group, chemotherapy severity, prior use of marijuana (at least once versus never), group by chemotherapy severity interaction, group by prior use interaction, and chemotherapy severity by prior use interaction. For nausea, only chemotherapy severity and its interaction with group proved significant (p < .038). Patients receiving mild and moderately severe chemotherapy showed the larger improvement in nausea (-2.76 and - 2.77) respectively, compared to the severe group (-2.15), but the latter was still significant. The inhaled treatment group showed slightly more improvement than the oral (-2.54 vs -2.45), but the difference is not clinically significant. Examination of the group by chemotherapy interaction showed that the mild chemotherapy subclass receiving oral cannabinoid had the least reduction in nausea (-1.88) relative to the other five subclasses (-2.14 to -3.34).
Change in vomiting was significantly predicted by group per se and its interaction with chemotherapy severity. THC smokers reported more improvement than those using oral THC (-2.69 versus -2.40). Assessment of the group interaction with chemotherapy severity showed, again, that the oral subgroup receiving mild chemotherapy had less improvement (-1.38) than the other five subgroups (-2.11 to -2.90).
The above analyses highlighted the oral THC-mild chemotherapy subset, so additional analyses were done on the baseline nausea and vomiting scores.
MANOVA of these baseline scores versus the predictor variables of group, chemotherapy severity, and their interaction showed no significant relation to nausea scores, but all three were predictive of baseline vomiting scores (Group: p < .008; Chemotherapy severity: p < .016; Interaction: p < .004). Two-way analysis of variance (ANOVA) of the six THC group by chemotherapy severity subclasses indicated, again, no effect on baseline nausea, but a significant group effect on baseline vomiting. Pairwise comparisons (experiment-wise) demonstrated that the oral THC-mild chemotherapy subclass alone is responsible because its mean vomiting score (2.86) was significantly less than those of the other five subsets (4.21 to 4.46). However, there were only eight patients in the oral THC-mild chemotherapy class, rendering interpretation of this result somewhat problematic. For information purposes, Table 4 lists pertinent demographics.
As previously noted, prior use of marijuana (at least once versus never) was not a predictor of change in nausea or vomiting scores (post-THC minus baseline). A closer look at both target symptom scores at baseline, pre-THC, and post-THC, showed prior use a predictor of baseline nausea scores only (p < .03). Non-users reported significantly higher baseline nausea scores than prior users (4.63 versus 4.38). A similar trend appeared on the pre-THC and post-THC nausea scores and vomiting scores at all three times: prior users of marijuana had lower mean scores on nausea and vomiting at all three times measured. This suggests that prior users did not exaggerate symptoms just to receive a cannabinoid.
The question arises as to how representative the subjects in this study are relative to other cancer patients. Two non-randomized control groups existed. One group (N = 26) were cancer patients who requested THC but never received it. A second (N = 27) were cancer patients who did not request THC even though aware of its availability. Both groups, in similar fashion to the experimental group, rated nausea and vomiting experienced at their most recent chemotherapy. MANOVA of the two control groups (independent variables) versus age, months with cancer, and nausea and vomiting scores disclosed no significant differences. Chi-square analysis of the two groups on sex, prior use of marijuana, stage of cancer, and chemotherapy severity showed no significant differences as well. Thus the two groups were combined (N = 53) for comparison with the experimental subjects (N = 169) using MANOVA.
There was a significant difference in mean age between the controls (50.87 years) and the experimental subjects (43.95 years), but not in mean months with cancer (Control = 18.42 vs 18.32). Nausea and vomiting scores were higher in the experimental group (Nausea: 4.52 vs 3.86, p < .0001; Vomiting: 4.25 vs 3.67, p < .0018). However, chemotherapy severity was also significantly different (Experimental: mild = 11%, moderate = 45%, severe = 44%; Control: mild = 21%, moderate = 56%, severe = 23%; chi-square = 8.56, p < .014). Chi-square analysis of sex, stage of cancer, and prior use of marijuana showed no significant differences between the two groups. The difference between groups in nausea and vomiting appears to be primarily due to the different distribution of chemotherapy severity, probably reflecting the self-selection process of the patients as well as the study criteria.
Post-THC minus baseline nausea and vomiting difference scores were dependent variables in MANOVA tests of the randomized (N=59) versus nonrandomized groups (N=110). No significant differences occurred, suggesting that a subtle bias operated in the initial randomization procedure via the choice to refuse a proffered form of THC.
A step-wise discriminant analysis was performed using several variables (group, chemotherapy severity, prior use of marijuana, age, THC dose per meters-squared body surface area, and SCL-90-R scales) to predict nausea and vomiting responders, i.e., those showing a difference score of two or more on the target symptoms. The significance level chosen for cut-off was p < 0.15. Chemotherapy severity, the Phobia sub-scale of the SCL-90-R, and group were predictors of nausea response at p < 0.0027, 0.1029, and 0.1164 respectively. The classification table gave true positives at 96.5% and true negatives at 13.5%. However, there were 86.5% false negatives and 3.3% false positives. In effect, knowledge of chemotherapy severity alone can correctly predict 76% of nausea responders. Patients receiving mild and moderate severity chemotherapy benefited most from cannabinoid anti-nausea.
Chemotherapy severity and group were the only predictors of improvement in vomiting (p < .0217 and .0753 respectively). The classification table showed 99.2% true positives and 5.3% true negatives. False positives were at 94.7% and false negatives at 0.8%. Again, knowledge of chemotherapy severity alone can predict 76% of responders with patients on mild and moderate chemotherapy having the greatest likelihood of anti-emetic response.
Another approach to comparative efficacy of oral vs inhaled THC concerns the number of patients electing to continue the drug after the first dose. Regardless of dose form, 90% of patients elected to continue. Chi-square analysis of dose form vs continue-discontinue showed no association. Similar analyses, but controlling for prior use, then chemotherapy severity, were also not significant, but at least one expected cell frequency was below five in each contingency table. Trends in the data showed prior users more likely to continue, whether on oral (96%) or inhaled (95%). Non-prior users were more likely to continue if on inhaled (94%) than oral (82%). Restated, non-prior users using oral THC were three times more likely to drop out than if on inhaled (18% vs 6%). Non-prior users, irrespective of dose form, were three times more likely to drop out after the first dose (14%) than prior users (4%). Four patients (2%, all on oral) dropped out because of side effects; nine patients (5%, eight on oral) stopped because it was not effective; one quit because of smoke irritation, and two because of increased nausea and vomiting (both on inhaled); one drop out gave no reason.
A comparison of group vs prior use showed significant differences in all frequencies. Sixty-nine percent of non-prior users received oral drug compared with 28% of prior users. This is consistent with the patients ability to choose a particular drug form.
For patients on mild chemotherapy (N=20), 95% elected to continue (100% of 12 inhaled and 88% of 8 oral). Of those on moderate chemotherapy (N=73), 95% continued (100% of inhaled, N=31, and 90% of oral). In the severe group (N=73), 85% continued (90% of inhaled, 82% of oral).
Pre-cannabinoid scores on nausea and vomiting were evaluated to assess presence or absence of anticipatory nausea and vomiting. ANOVA of these variables with post-cannabinoid scores were not significant, suggesting no connection between anticipatory nausea and vomiting and therapeutic response to cannabinoids.
Because of the retrospective nature of the baseline nausea and vomiting scores, patients initially gave two ratings of these symptoms, once when requesting entry into the program and the second just before receiving cannabinoid. Data was available for 74 patients and showed no difference between the two ratings. The median time between the two scorings was 11 days (range 0-150 days).
The presence or absence of eight side effects was tallied before and hourly after cannabinoid dosing for the four hour observation period: euphoria, sleepiness, agitation, depression, fearfulness, anxiety, visual and auditory hallucinations. Table III lists frequencies. Reported effects parallel the known pharmacodynamics of the oral and inhaled forms.
Three patients experienced side effects requiring medical intervention. Two had paranoid/fear responses (panic attacks) and one had an episode of paroxysmal atrial tachycardia.
Sallan et al1 indicated that euphoria from cannabinoids seemed necessary to attain anti-emesis. Chi-square analysis for euphoria vs any improvement in nausea was not significant. For euphoria vs improvement of two or more (defined as clinically significant) there was still no significant association. Results for vomiting were the same. Prior use of marijuana predicted presence of euphoria (chi-square = 10.87, p < .001), but showed no association with either type of response measure.
As previously noted, 90% of patients elected to continue the drug after initial dosing. Patient's reasons for later discontinuation were tabulated. Reasons included: not effective, side effects, and other (death of patient, ending or changing chemotherapy to less emetogenic forms, unknown). At the data analysis cut-off, 15 patients were actively receiving cannabinoids (6 oral, 9 inhaled). Chi-square analysis of route vs the four groups was significant. This was due to the greater number of drop outs among oral cannabinoid users. Of the 154 patients, 44 stopped the drug because it was not effective, not as effective as expected, or no more effective than conventional anti-emetics. Thirty-four were on oral drug (77%) and ten were using inhaled. Twenty-two patients stopped due to side effects, seventeen on oral (77%) drug. Eighty-eight patients quit because of other reasons: changed or discontinued chemotherapy (N=41; oral=18), death (N=21; oral=10), and unknown (N=26; oral=9).
An approach to assessing the long term efficacy of the cannabinoids is to determine the amount of drug ingested by patients. Although such data can be difficult to accurately obtain, prescriptions, returns of unused portions to the pharmacy and patient follow-up allow estimation of the amounts likely ingested. Since the initial dosing was 15 mg four times a day for two days, we assumed that less than 120 mg total usage was evidence against pharmacologic efficacy or acceptance, whereas larger amounts implied the opposite. A chi-square analysis of total dose vs route was significant (p < .0003). Thirty-six of 168 patients used less than 120 mg total. Twenty-nine of these were on oral drug (80.6%). One hundred thirty-two patients used more than 120 mg, 64 (48% were on oral form). Ninety percent of prior users ingested over 120 mg versus 69% of non-prior users. Ninety-one percent on inhaled used the larger amount vs 67% on oral. Eighty-four percent of males used larger amounts vs 72% of females. Extrapolating from total use, the mean total use was 735 mg per patient, with oral drug at 526 mg and inhaled at 908 mg.
Results acquired under the State of New Mexico's Controlled Substances Therapeutic Research Act indicate that oral THC and inhaled marijuana are both effective anti-emetics and anti-nauseants. This conclusion is based on data gathered at the time of the initial dose. The efficacy of the inhaled form is superior to the oral form, but this difference is statistically significant for vomiting only. This may be due partially or wholly to the tendency of the capsules to be regurgitated during chemotherapy, or to the sesame oil vehicle failing to consistently dissipate in the GI tract, thus preventing optimal absorption. Efficacy is related to the severity of chemotherapy with most improvement occurring in the mild subgroup than in the moderate or severe ones. Prior use of marijuana (at least once) had no effect on initial efficacy. Prior use only predicted nausea scores at application, with non-prior users reporting significantly higher levels. The latter suggests that prior users did not exaggerate their symptoms just to get marijuana.
Immediately before drug ingestion, anticipatory nausea and vomiting were evident, with the mild chemotherapy group being highest on nausea. All three groups had comparable scores on vomiting. The oral-mild subgroup had highest pre-THC nausea and vomiting scores.
When applying for admission to the study, the mild chemotherapy subgroup reported levels of nausea and vomiting comparable to the other two groups. The oral THC-mild chemotherapy subgroup had significantly lower vomiting scores at application than the other five groups. At four hours post-THC patients on severe chemotherapy had significantly higher nausea and vomiting scores than the mild and moderate categories.
Prior users of marijuana were more likely to be on the inhaled form of THC and more likely to continue after the first dose, whether on oral or inhaled. Non-prior users were more likely to continue if on inhaled than oral. Patients receiving severe chemotherapy were more likely to drop out, especially if on oral drug.
Lack of complete random assignment of dose form requires caution in data interpretation. Still, efficacy of both forms appears comparable, although the inhaled form may be especially useful with vomiting unresponsive to other anti-emetic agents.
Euphoria ("high") was not required for reduction of nausea or vomiting. Side effects were predominantly euphoria, sleepiness, and anxiety, and appeared well-tolerated by most patients. Oral cannabinoid use resulted in more drop outs due to side effects or ineffectiveness. Mean cannabinoid use on the program was 735 mg, which is actually an upper limit of ingestion.
Bryan A. Krumm
New Mexicans for Compassionate Use
phone (505) 286-1325
Albuquerque, N.M. 87196-4241