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PubMed1998

Flunitrazepam and triazolam: a comparison of behavioral effects and abuse liability.

The performance, observer-rated, and participant-rated effects of orally administered placebo, and two benzodiazepines, flunitrazepam (2, 4 and 8 mg/70 kg) and triazolam (0.25, 0.5 and 1 mg/70 kg), were compared in 14 sedative drug abusers using a double-blind crossover design. Both flunitrazepam and triazolam produced dose-related decrements in memory and psychomotor/cognitive performance, and increases in many participant- and observer-rated measures. Effects of flunitrazepam had an earlier onset and a longer duration than those of triazolam. Although there was evidence that the flunitrazepam doses selected for study were somewhat higher overall relative to the selected triazolam doses, analysis of the participant-rated measures collected 24 h after drug administration (next-day) suggests that flunitrazepam may have a greater abuse liability than triazolam when abuse liability is assessed 24 h after drug administration. The highest flunitrazepam dose produced effects that were significantly greater than those of the highest triazolam dose on next-day ratings of good effects, take again, and worth; all tested flunitrazepam doses produced effects greater than any triazolam dose on next-day ratings of liking and take again. The highest flunitrazepam dose, but no triazolam dose, significantly increased the maximum dollar value at which participants chose drug over money in a Drug versus Money Choice Procedure.

Adult↗
PubMed2003

The role of cytochrome P450 2C19 activity in flunitrazepam metabolism in vivo.

Flunitrazepam, a hypnotic benzodiazepine, is widely prescribed around the world for the treatment of insomnia and as a preanesthetic. In vitro studies have shown that the metabolism of flunitrazepam to desmethylflunitrazepam and 3-hydroxyflunitrazepam is mediated in part by the polymorphic enzyme CYP2C19. The objective was to examine the role of CYP2C19 activity in determining flunitrazepam kinetics in vivo. Sixteen healthy volunteers (14 genotypic extensive metabolizers and 2 poor metabolizers) were recruited who had a wide range of CYP2C19 activity (0.50-28.8), as determined by the omeprazole/ 5-hydroxyomeprazole ratio (OMR) at 3 hours following administration of omeprazole, 20 mg orally. Each subject received flunitrazepam, 1 mg orally. Blood samples were collected immediately before and up to 48 hours after drug administration and were assayed by HPLC for flunitrazepam and its metabolites, 7-aminoflunitrazepam, desmethylflunitrazepam, and 3-hydroxyflunitrazepam. Spearman correlations were determined for OMR and pharmacokinetic parameters. With increasing OMR (decreasing CYP2C19 activity), the ratio of flunitrazepam to both desmethylflunitrazepam and 3-hydroxyflunitrazepam AUCs increased ( r = 0.55, p = 0.03 and r = 0.65, p = 0.01, respectively). However, variation in CYP2C19 activity did not significantly affect the AUCs of flunitrazepam or its metabolites. The authors conclude that CYP2C19 contributes to the metabolism of flunitrazepam to desmethylflunitrazepam and 3-hydroxyflunitrazepam in vivo, but these data suggest that its role is minor and that differences in CYP2C19 activity do not likely substantially influence its clinical effects.

Adolescent↗
PubMed1997

Flunitrazepam and its involvement in date or acquaintance rape.

An estimated 1 in 4 women in the United States will be raped in their lifetimes. Approximately 75% of all rapes are date or acquaintance rapes. Recently the illegal use of flunitrazepam (Rohypnol), a benzodiazepine, as a prelude to the assault has been reported. Flunitrazepam readily dissolves, and once in solution, is colorless, odorless, and tasteless. The predominant clinical manifestations are drowsiness, impaired motor skills, and anterograde amnesia. Due to the amnestic effects of flunitrazepam, historical clues of the rape event are difficult to obtain. Patients with a complaint of sexual assault who appear intoxicated or have anterograde amnesia should be suspected of unknowingly ingesting flunitrazepam. In addition to adhering to standard rape protocols, a urine specimen should be analyzed for flunitrazepam metabolites using gas chromatography/mass spectrometry. If the hospital, local, or forensic laboratory is unable to analyze for flunitrazepam, Hoffmann-La Roche Inc., the manufacturer of Rohypnol, should be contacted. Hoffmann-La Roche has a mechanism for definitive testing for flunitrazepam, at no cost, for health care providers, rape treatment centers, and law enforcement agencies. A network of organizations is attempting to reduce the abuse of flunitrazepam in association with date rape.

Anti-Anxiety Agents↗
PubMed1996

Interaction between erythromycin and the benzodiazepines diazepam and flunitrazepam.

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double-blind, cross-over studies. Healthy volunteers ingested erythromycin for one week 500 mg t.i.d. On the 4th day they ingested a single 5 mg dose of diazepam (6 subject, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively. Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam. In Study 1 erythromycin increased the area under the diazepam plasma concentration-time curve [AUC (0-42 hr)] by 15% (P < 0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P < 0.05). The median peak concentration (Cmax) and the half-life (t1/2) of diazepam were increased but they did not change significantly (P = 0.17 and 0.12, respectively). Plasma N-desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P < 0.05). In Study 2 the AUC (0-42 hr) of flunitrazepam was increased by 25% (P < 0.05) during the erythromycin treatment. The t1/2 of flunitrazepam increased significantly (P < 0.05), but the Cmax remained unchanged. The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin. These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam. The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.

Adult↗
PubMed1998

Abuse liability of flunitrazepam among methadone-maintained patients.

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4mg caused euphoria-related effects as measured by increases in ARCI-MBG and "high" scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential.

Adult↗
PubMed2005

Flunitrazepam does not alter cerebral distribution of buprenorphine in the rat.

Deaths have been reported among heroin addicts related to combined buprenorphine and flunitrazepam use. The aim of this study was to determine the existence of a drug-drug interaction during the distribution phase of buprenorphine. Arterial blood gases were measured after intravenous administration of buprenorphine alone (30 mg/kg), flunitrazepam alone (40 mg/kg) or both drugs in rats. Buprenorphine kinetics was studied in plasma and in striatum using cerebral microdialysis, both alone and after rat pretreatment with flunitrazepam. In contrast to buprenorphine or flunitrazepam alone, buprenorphine in combination with flunitrazepam induced a significant, rapid and sustained respiratory depression. Arterial PCO2 was increased at 1.5 min (6.7+/-0.2 versus 5.4+/-0.3 and 5.5+/-0.3 kPa, respectively, P=0.04) (mean+/-S.E.M.), and arterial pH decreased (7.37+/-0.02 versus 7.45+/-0.02 and 7.45+/-0.01, respectively, P=0.03). Plasma buprenorphine kinetics was well described by a three-compartment linear model, with a distribution half-life of 7.4+/-2.7 min and an elimination half-life of 463.9+/-152.3 min. However, neither plasma nor striatal buprenorphine kinetics were significantly altered by pre-administration of flunitrazepam. The adverse interaction between flunitrazepam and buprenorphine cannot be explained by a pharmacokinetic drug-drug interaction during the distribution phase of buprenorphine.

Animals↗
PubMed2001

Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

Animals↗
PubMed1984

[Comparative hemodynamic effects of midazolam and flunitrazepam in head injury patients under controlled ventilation].

The haemodynamic effects of midazolam were compared with those of flunitrazepam in 10 patients with severe head injury under controlled ventilation. Right atrial pressure, pulmonary pressure, pulmonary capillary wedge pressure and cardiac output were measured using a Swan-Ganz thermodilution catheter. Arterial pressure (Pa) was recorded by radial arterial canulation. All patients in this cross-over study received midazolam (0.15 mg X kg-1) and flunitrazepam (0.02 mg X kg-1) intravenously randomly, with 24 h between the two injections. The measurements were first carried out before and then 5, 10, 20, 30 and 60 min after injection. The only significant variations after midazolam and flunitrazepam were a fall in Pa (from 93 +/- 12 to 81 +/- 11 mmHg for midazolam and from 89 +/- 14 to 78 +/- 20 mmHg for flunitrazepam) and in cardiac index (from 4.80 +/- 1.03 to 4.17 +/- 1.14 l X min-1 X m-2 for midazolam and from 5.18 +/- 1.32 to 4.54 +/- 1.03 l X min-1 X m-2 for flunitrazepam). The small decrease in heart rate was not significant. The cardiovascular changes after midazolam and flunitrazepam were small and similar for both drugs. It seemed that midazolam and flunitrazepam were safe for sedating head injured patients under controlled ventilation.

Adult↗
PubMed2000

Flunitrazepam: more than a date rape drug.

STUDY OBJECTIVE: To evaluate the independent relationship between depressive symptoms. self-esteem. and drug resistance self-efficacy, and future intentions to use flunitrazepam. DESIGN: Cross-sectional survey. SETTING: Community-based family planning clinics. PARTICIPANTS: 865 sexually active women who self-identified as Caucasian. African-American. or Mexican American. denied using flunitrazepam in the last 12 months and reported intentions to use or not use this substance in the next 12 months. INTERVENTIONS: None. MAIN OUTCOME MEASURE: An anonymous self-report measure assessed the patient's intentions to use flunitrazepam in the next 12 months: other lifetime drug use: and standardized measures of depression. self-esteem, and drug resistance self-efficacy. We hypothesized that future potential users of flunitrazepam would exhibit an increased number of depressive symptoms, lowered self-esteem, and limited drug resistance self-efficacy. RESULTS: Of the 865 subjects. 16 (1.8%) reported using flunitrazepam in their lifetime but not in the last 12 months. and 46 (5.3%) were identified as potential users. Logistic regression analyses controlling for confounding factors found that potential to use flunitrazepam was significantly associated with limited drug resistance self-efficacy (adjusted odds ratio [AOR] = 9.3) and the presence of both severe depressive symptoms and lowered self-esteem (AOR = 3.2). CONCLUSIONS: These data suggest that young women with severe depressive symptoms and diminished self-esteem are at high risk for future flunitrazepam use and may use this drug to self-medicate psychological distress.

Adolescent↗
PubMed1999

Pharmacokinetics and tolerance of flunitrazepam in neonates and in infants.

OBJECTIVE: To study the pharmacokinetics of flunitrazepam (used for sedation in neonates and infants), to determine the influence of both gestational and postnatal age on the pharmacokinetic parameters, and to analyze the relationship between the hemodynamic parameters and flunitrazepam plasma concentration. METHODS: Flunitrazepam was infused for 20 minutes as a single dose (0.2 mg x kg(-1)) and as multiple doses (0.1 mg x kg(-1)). Six to eight 1-mL blood samples were collected per patient. Flunitrazepam plasma concentration was measured by gas chromatography-mass spectrometry. RESULTS: Thirty-one patients (25 neonates and six infants) were included in the study. Only three of them received multiple doses. After the single dose (n = 28), half-life was 22.6 +/- 7.3 hours, clearance was 0.15 +/- 0.14 L x kg x h(-1), and volume of distribution was 4.6 +/- 4.1 L x kg(-1) (mean +/- SD). Plasma clearance and volume of distribution significantly increased with postnatal age (P < .05), but no pharmacokinetic parameter varied significantly with gestational age. Diastolic blood pressure significantly decreased with increasing flunitrazepam plasma concentrations (P < .05). CONCLUSION: Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants. Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration.

Age Factors↗
PubMed1980

Comparison of the subjective effects and plasma concentrations following oral and i.m. administration of flunitrazepam in patients.

The use of flunitrazepam 1 and 1.5 mg was compared as a premedicant with diazepam 10 mg and lorazepam 2.5 mg. Plasma flunitrazepam concentration were measured after oral and i.m. administration. Flunitrazepam and diazepam had a similar onset time and duration of action, both being more rapid in onset and shorter in duration than lorazepam I.m. flunitrazepam had a slightly greater sedative effect than oral flunitrazepam and plasma concentrations correlated well with the onset of the sedative effect by either route of administration. The i.m. injection of flunitrazepam was not as painful as that of diazepam, but slightly more painful than lorzepam. A second peak occurred at about 5 h and flunitrazepam was still detectable at 48 h. The plasma half-life was 3-4 h.

Administration, Oral↗
PubMed1976

Amnesic action of and skills related to driving after intravenous flunitrazepam.

Amnesic action, skills related to driving and the ability to discriminate the fusion of flickering light were measured double-blind in 29 healthy volunteers before and after three doses of intravenous flunitrazepam. Every subject experienced amnesia for the pinching of the abdomen after being injected with flunitrazepam. Even the smallest dose of flunitrazepam (0.01 mg/kg) caused the amnesia without affecting the level of consciousness. The late effects of flunitrazepam were the most harmful to coordination. With 0.01 mg/kg eye-hand coordination was slightly impaired for as long as 6 h after the injection, and after 0.02 and 0.03 mg/kg the impairment was still significant (P less than 0.05) at the last observation period 10 h after the injection. It was concluded that, because the amnesic action of flunitrazepam is more effective than that of clinically comparable doses of diazepam, further clinical experiments with flunitrazepam are warranted. Its longer and more harmful effects on psychomotor performance than those of equipotent doses of diazepam suggest that doses of 0.02 mg/kg or more of flunitrazepam should be avoided in outpatient anaesthesia or sedation.

Adult↗
PubMed1990

Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers.

The pharmacokinetic behaviour of flunitrazepam and its main active metabolite, N-desmethyl flunitrazepam, was investigated in 12 patients with liver disease (cirrhosis or hepatitis) compared to 6 healthy volunteers. A gas-liquid chromatographic method allowing for simultaneous determination of flunitrazepam and N-desmethyl flunitrazepam in plasma samples was developed. The accuracy and the precision near the quantification limit of ca. 1 ng/ml were better than 5%. Plasma levels of flunitrazepam were not significantly altered by hepatic failure, whereas plasma levels of N-desmethyl flunitrazepam were lower in patients than in healthy subjects. Pharmacokinetic parameters did not differ significantly between healthy subjects and liver disease patients: the oral clearance was 3.5 +/- 0.8, 3.5 +/- 1.9 and 4.0 +/- 1.2 ml/min/kg, respectively in healthy subjects, patients with hepatitis and patients with cirrhosis. The apparent elimination half-life was 22 +/- 5 h in healthy subjects, 25 +/- 10 h in patients with hepatitis and 20 +/- 6 h in patients with cirrhosis. However, the expected increase of the drug free fraction during liver disease could decrease the therapeutic and toxic ranges of flunitrazepam in these patients.

Administration, Oral↗
PubMed1998

Photoaffinity labeling of the benzodiazepine binding site of alpha1beta3gamma2 gamma-aminobutyric acidA receptors with flunitrazepam identifies a subset of ligands that interact directly with His102 of the alpha subunit and predicts orientation of these within the benzodiazepine pharmacophore.

Photoincorporation of ligands into the benzodiazepine site of native gamma-aminobutyric acidA (GABAA) receptors provides useful information about the nature of the benzodiazepine (BZ) binding site. Photoincorporation of flunitrazepam into a single population of GABAA receptors, recombinant human alpha1beta3gamma2, was investigated to probe further the mechanism and orientation of flunitrazepam and other ligands in the BZ binding site. It was concluded that the receptor is primarily derivatized with the entire, unfragmented, flunitrazepam molecule, which undergoes a conformational change during photolysis and largely vacates the benzodiazepine binding site. Investigation of the BZ site after photoincorporation of [3H]flunitrazepam confirmed that binding of other radioligands was unaffected by incorporation of flunitrazepam. This did not correlate with their efficacy but depended on the presence of particular structural features in the molecule. It was observed that affected compounds have a pendant phenyl moiety, analogous to the 5-phenyl group of flunitrazepam, which are proposed to overlap and interact with the same residue or residues in the BZ binding site. Because the major site of flunitrazepam photoincorporation has been shown to be His102, we propose that this group of compounds interacts directly with His 102, whereas compounds of other structural types have no direct interaction with this amino acid. The orientation of ligands within the BZ binding site and their specific interaction with identified amino acids are not well understood. The data in the current study indicate that His102 interacts directly with the pendant phenyl group of diazepam, and further implications for the pharmacophore of the BZ binding site are discussed.

Azides↗
PubMed2002

Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat.

Opiates and substitution products are frequently abused, alone and in association with benzodiazepines. While this combination may result in severe respiratory depression and death, the quantitative relationship remains uncertain. We performed randomized, blinded intravenous median lethal dose (MLD) studies in Sprague-Dawley rats of morphine, buprenorphine, and methadone, alone and in combination with intraperitoneal flunitrazepam pretreatment. We employed the up-and-down method, performed in quadruplicate, comparing time to death following opioid injection. Results are expressed as median of four series (extremes). The MLDs of morphine, buprenorphine, and methadone alone were 64.0 (33.6:79.5), 234.6 (168.6:284.4), and 22.5 (19.3:24.1) mg/kg, respectively, and 60.6 (35.2:88.2), 38.4 (30.6:54.0), and 13.0 (9.7:13.8) mg/kg, respectively, after pretreatment with 40 mg/kg flunitrazepam. Times to death for morphine, buprenorphine, and methadone alone were 2.5 (0.8:24), 0.02 (0.0:24), and 2.0 (0.0:24) hours, respectively, and 13.5 (0.0:144), 24.0 (0.0:120), and 0.0 (0.0:24) hours, respectively, after pretreatment with flunitrazepam 40 mg/kg, ip. Flunitrazepam significantly altered methadone (P=0.02) and buprenorphine (P=0.02) but not morphine lethality (P=0.77). Flunitrazepam significantly prolonged time to death only for buprenorphine (P<0.01). Flunitrazepam-opioid drug-drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam-opioid lethal interactions are needed.

Animals↗
PubMed2000

Elimination of 7-aminoflunitrazepam and flunitrazepam in urine after a single dose of Rohypnol.

The hypnotic benzodiazepine flunitrazepam (Rohypnol) has been identified as the drug of choice for the purposes of "drugging" unsuspecting victims and raping them while they are under the influence of this substance. The objective of this paper was to study elimination of flunitrazepam and 7-aminoflunitrazepam in urine collected from ten healthy volunteers who received a single 2 mg oral dose of Rohypnol, to determine how long after drug administration 7-aminoflunitrazepam can be detected. A highly sensitive NCI-GC-MS method for the simultaneous quantitation of flunitrazepam (LOQ 100 pg/mL) and 7-aminoflunitrazepam (LOQ 10 pg/mL) in urine was developed. All samples were screened for benzodiazepines using optimized micro-plate enzyme immunoassay. The highest concentrations of 7-aminoflunitrazepam (70-518 ng/mL) and flunitrazepam (0.7-2.8 ng/mL) in urine were observed 6 h after drug administration in nine subjects and after 24 h in one subject. In six subjects 7-aminoflunitrazepam was detected up to 14 days after flunitrazepam administration, in one subject up to 21 days and in three subjects up to 28 days. In urine samples collected from six volunteers, flunitrazepam was detected three days after Rohypnol intake, in three subjects 24 h, and in one subject 5 days later. Benzodiazepine micro-plate enzyme immunoassay kit allowed the detection of flunitrazepam and metabolities 5 to 21 days after drug administration.

Adult↗
PubMed1988

[Comparative hemodynamic effects of midazolam and flunitrazepam as induction agents].

The cardiovascular effects of midazolam as induction agent in A.S.A. class 2 surgical patients (N = 6) were compared with a similar group of patients (N = 6) receiving flunitrazepam. An induction-sized dose of midazolam was 0.17 +/- 0.03 mg/kg and the dose of flunitrazepam was 0.036 +/- 0.0039 mg/kg. The induction-sized dose of midazolam produced a moderate cardiovascular depression, similar to flunitrazepam. Cardiac index, left ventricular stroke work index and mean pulmonary pressure were decreased significantly after injection of midazolam and mean arterial pressure, cardiac index and left ventricular stroke work index were decreased significantly after administration of flunitrazepam. Following the administration of midazolam, there were decreasing tendency of mean pulmonary pressure and pulmonary artery occluded pressure, and no change of central venous pressure, while increasing tendency of central venous pressure with flunitrazepam. Unlike flunitrazepam, midazolam may act capacitance vessels. However in this study, statistical significant differences between the hemodynamic effects of midazolam and those of flunitrazepam were not obtained.

Adjuvants, Anesthesia↗
PubMed1993

Amnesic effects and subjective ratings during repeated dosing of flunitrazepam to healthy volunteers.

Flunitrazepam (1 mg) or placebo was administered once daily over a treatment period of 8 days to healthy, male volunteers to study the time course of the effects on memory functions and on subjective ratings of alertness and tension. The plasma level of flunitrazepam increased by approximately 40% (P < 0.05) during the treatment period. The mean pre-dose level of flunitrazepam on day 4 and day 8 was approximately 0.005 microM, and no residual effects on memory functions were observed. Intake of flunitrazepam decreased the number of freely recalled words by about 85% (P < 0.05) and significantly affected the subjects' rating of attention when tested during the first few hours after drug intake on day 1 of treatment. However, no significant effect on the subjects' rating of relaxation was observed. When tested similarly after 8 days treatment, flunitrazepam significantly affected the subjects' rating of relaxation (P < 0.01). Furthermore, no tolerance developed for the effect of flunitrazepam on free recall (P > 0.3) and the subjects' rating of attention (P > 0.7), and these effects had nearly equal time courses during the treatment period. This may indicate that the amnesic effect of benzodiazepines is at least partially mediated through the effects on attention or general arousal. Two of the subjects in the active drug group reported adverse reactions or incidents of discomfort during the 1st week following the treatment period, whereas none in the placebo group reported such reactions.

Adult↗