Psilocybin: Good Trip or Bad Trip.

Much of the history of pharmacology and therapeutics involves finding new uses for old drugs. The latest rediscovery is that of psychedelic drugs. Since they can cause profound distortions of perception and were once used as part of religious ceremonies, such research may seem unusual at this time.

Deconstructing Designer Drugs.

The concepts behind current "designer drugs" are not new. For several centuries, chemical synthesis has made drugs more specific and more selective. However, headline designer drugs now are different and a serious public health problem because they are illicit unregulated chemical knockoffs of approved psychoactive stimulant, sedative, or perception-altering controlled substances.

Abuse Potential and Pharmacodynamic Characteristics of Oral and Intranasal Eluxadoline, a Mixed µ- and κ-Opioid Receptor Agonist and δ-Opioid Receptor Antagonist.

Drugs with µ-opioid receptor (OR) activity can be associated with abuse and misuse. The peripherally acting mixed µ-OR and κ-OR agonist and δ-OR antagonist eluxadoline is approved in the United States for the treatment of irritable bowel syndrome with diarrhea. In two separate crossover studies, we evaluated the oral and intranasal abuse potential of eluxadoline versus placebo and the active control oxycodone. Healthy recreational opioid users received eluxadoline 100, 300, and 1000 mg, oxycodone 30 and 60 mg, and placebo (oral study), or eluxadoline 100 and 200 mg, oxycodone 15 and 30 mg, and placebos matched to eluxadoline and oxycodone (intranasal study). In the oral study, Drug Liking Visual Analog Scale (VAS) peak (maximum) effect (Emax) score (primary endpoint) was significantly greater with eluxadoline 300 and 1000 mg versus placebo, but scores were significantly lower versus oxycodone. Following intranasal insufflation of eluxadoline, Drug Liking VAS Emax scores were not statistically different versus placebo, and were significantly lower versus oxycodone. Across other subjective measures, eluxadoline was generally similar to or disliked versus placebo. Pupillometry indicated no or minimal central effects with oral and intranasal eluxadoline, respectively. Adverse events of euphoric mood were reported with oral and intranasal eluxadoline but at a far lower frequency versus oxycodone. These data demonstrate that eluxadoline has less abuse potential than oxycodone in recreational opioid users.

The effect of an abuse-deterrent opioid formulation (OxyContin) on opioid abuse-related outcomes in the postmarketing setting.

An extended-release opioid analgesic (OxyContin, OC) was reformulated with abuse-deterrent properties to deter abuse. This report examines changes in abuse through oral and nonoral routes, doctor-shopping, and fatalities in 10 studies 3.5 years after reformulation. Changes in OC abuse from 1 year before to 3 years after OC reformulation were calculated, adjusted for prescription changes. Abuse of OC decreased 48% in national poison center surveillance systems, decreased 32% in a national drug treatment system, and decreased 27% among individuals prescribed OC in claims databases. Doctor-shopping for OC decreased 50%. Overdose fatalities reported to the manufacturer decreased 65%. Abuse of other opioids without abuse-deterrent properties decreased 2 years later than OC and with less magnitude, suggesting OC decreases were not due to broader opioid interventions. Consistent with the formulation, decreases were larger for nonoral than oral abuse. Abuse-deterrent opioids may mitigate abuse and overdose risks among chronic pain patients.

Update on tamper-resistant drug formulations.

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes.

Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users.

Lorcaserin is a selective and potent serotonin 2C receptor subtype (5-HT(2C)) agonist under development for the treatment of obesity. This study assessed the drug's abuse potential on the basis of its pharmacological profile. For this purpose, a double-blind, double-dummy, placebo-controlled, randomized seven-way crossover study with single oral doses of lorcaserin (20, 40, and 60 mg), zolpidem (15 and 30 mg), ketamine (100 mg), and placebo was conducted in recreational polydrug users (N = 35). Subjective and objective measures were assessed up to 24 h after the dose. We found that zolpidem and ketamine had significantly higher peak scores relative to placebo on the primary measures as well as on most of the secondary measures. The subjective effects of a 20-mg dose of lorcaserin were similar to those of placebo, whereas supratherapeutic doses of lorcaserin were associated with significant levels of dislike by users as compared with placebo, zolpidem, and ketamine. Perceptual effects were minimal after administration of lorcaserin and significantly lower than after administration of either ketamine or zolpidem. The findings suggest that, at supratherapeutic doses, lorcaserin is associated with distinct, primarily negative, subjective effects and has low abuse potential.

Oral ketamine as a positive control in human abuse potential studies.

The selection of a relevant and appropriate positive control is of key importance in the design of a clinical abuse potential study. Ketamine is a N-methyl-d-aspartate receptor antagonist used clinically as an anaesthetic, yet also abused for its euphoric and perceptual properties. The current study sought to identify 2 doses of oral ketamine that are safe and produce subjective effects that would make them suitable for use as positive controls in abuse potential studies. A single-center, partially double-blind, placebo-controlled, ascending dose (65, 100 and 150 mg) study was carried out in 11 healthy recreational polydrug users who first passed a pharmacologic qualification session to ensure they could distinguish and like the effects of a psychoactive drug (20mg d-amphetamine) compared to placebo. Subjective data were collected through questionnaires (e.g., Addiction Research Center Inventory [ARCI] scales) and visual analog scales (VAS). Generally, oral ketamine was well tolerated and could be used safely at 65 mg and 100mg. Peak responses to ketamine were significantly different (p<0.05) from placebo on measures of positive (e.g., drug liking VAS), perceptual (e.g., VAS of floating, detached, hallucinating) and sedative (e.g., ARCI phenobarbital-chlorpromazine-alcohol group scale) effects. Effects were generally not dose-dependent, though significant differences for some subjective effects measures were observed between 65 mg and 100mg ketamine. The current study indicates that oral ketamine doses of 65 mg and 100mg are useful positive controls for future abuse potential studies of compounds with a similar mechanism of action, or with possible perception-altering and euphoric effects.

Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users.

Tesofensine is a (triple) reuptake inhibitor of noradrenaline, dopamine, and serotonin that is in development for the treatment of obesity. The abuse potential of triple reuptake inhibitors is not yet known, and so this study was undertaken to evaluate the potential abuse-related effects of tesofensine in humans. It was designed as a single-dose, randomized, double-blind, crossover study involving tesofensine vs. placebo, D-amphetamine (positive control for dopaminergic/stimulant effects), bupropion, and atomoxetine (negative/unscheduled controls) in recreational stimulant users (N = 52). Subjective and objective measures were assessed for 48 h after drug administration. The study results show that the effects of D-amphetamine were significantly greater than those of placebo on all primary and secondary subjective measures. The effects of tesofensine were not significantly different from those of placebo and were lower than those of D-amphetamine 30 mg on all primary and most secondary measures. The effects of tesofensine were either lower than or not different from those of bupropion or atomoxetine. These results demonstrate that the abuse potential for tesofensine is no greater than that of bupropion or atomoxetine, and tesofensine is therefore unlikely to be recreationally abused.

Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers.

Varenicline is an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist developed as an aid for smoking cessation. This study evaluated varenicline's potential for abuse by smokers (n = 23) and nonsmokers (n = 22). The study used a randomized, double-blind, placebo-controlled, double-dummy crossover design with five treatment periods: 15 and 30 mg amphetamine, 1 and 3 mg varenicline, and placebo. Following each treatment, the participants were assessed on aspects relating to potential abuse of the drug (e.g., drug liking, drug high, and drug monetary value). The positive effects measured for 3 mg varenicline were similar to those for the placebo, and significantly lower than those for amphetamine in both smokers and nonsmokers. Unpleasant effects were reported for 3 mg varenicline in both participant groups. For 1 mg varenicline, the overall patterns were similar, with the exception that the nonsmokers group showed some small positive effects balanced by some negative effects when compared with the effects of placebo. These findings lead to the conclusion that varenicline is unlikely to be abused.

Assessing abuse liability during drug development: changing standards and expectations.

As public health concerns have changed, regulatory expectations for assessing abuse liability of new central nervous system (CNS) drugs have increased. All CNS-active drugs with any properties indicating stimulant, depressant, hallucinogenic, or mood-elevating effects will require an evaluation of abuse liability. Abuse liability assessment involves the collection, analysis, and interpretation of data on chemistry and tampering, animal behavioral pharmacology, clinical trial adverse events (AEs), diversion and overdose, and potentially reinforcing (subjective) effects in recreational drug users.

Inhibition of nicotine metabolism by methoxysalen: Pharmacokinetic and pharmacological studies in mice.

Studies were undertaken to examine whether methoxsalen (9-methoxyfuro[3,2-g][1]benzopyran-7-one), a specific and relatively selective inhibitor of human CYP2A6, inhibited CYP2A5-mediated nicotine metabolism in vitro. Furthermore, studies were performed in vivo to determine whether methoxsalen would modulate acute nicotine pharmacokinetics and pharmacological effects (antinociception and hypothermia) in the ICR mouse. Our results demonstrated that methoxsalen competitively inhibits in vitro nicotine metabolism in mice. The inhibition was potent, as seen in human inhibition studies, with a Ki of 0.32 microM. In addition, we found that administration of methoxsalen significantly increased the plasma half-life of nicotine (approximately doubled) and increased its area under the curve compared with saline treatment. There was a dose-dependent enhancement in the pharmacological effects of nicotine (body temperature and analgesia) after methoxsalen treatment. Methoxsalen prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg) for periods up to 180 min postnicotine administration. Furthermore, this prolongation in nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter nicotine's pharmacological effects. In conclusion, these results confirmed that methoxsalen did indeed inhibit the conversion of nicotine to cotinine both in vitro and in vivo. They also suggest that mice may represent a suitable model for studying variation in nicotine metabolism and its impact on mechanisms of nicotine dependence, including the use of inhibitors to reduce nicotine metabolism.

Mood changes during pregnancy and the postpartum period: development of a biopsychosocial model.

OBJECTIVE: Women are vulnerable to mood changes during pregnancy and the postpartum period. We set out to empirically test the hypothesis that biological and psychosocial variables interact to result in this vulnerability. METHOD: Using structural equation modeling techniques, we developed an integrative model of perinatal mood changes from clinical, psychosocial, hormone and mood data collected from 150 women in late pregnancy and at 6-weeks postpartum. RESULTS: In the prenatal model, biological variables had no direct effect on depressive symptoms. However, they did act indirectly through their significant effects on psychosocial stressors and symptoms of anxiety. The same model did not fit the postpartum data, suggesting that different causal variables may be implicated in postpartum mood. CONCLUSION: This model demonstrates the importance of considering both biological and psychosocial variables in complex health conditions such as perinatal mood disorders.

Measurement issues in postpartum depression part 2: assessment of somatic symptoms using the Hamilton Rating Scale for Depression.

Assessment of the somatic symptoms of depression in perinatal women has been debated due to potential overlap with normal physical complaints of pregnancy and childbirth. We investigated the properties of the 17-item Hamilton Rating Scale for Depression (HAMD), which includes somatic items, between 36 weeks gestation and 16 weeks postpartum in 150 women. Scores on the HAMD were highly correlated with scores on measures that avoid somatic items. Scores on somatic items were not well correlated with the total HAMD score in pregnancy, but the correlations increased at 6 weeks postpartum. In contrast, scores on HAMD item 1 ("Depression") were less well correlated with the total score at 6 weeks postpartum than prenatally, suggesting that postpartum women may be less likely to articulate their difficulties as "depression", and more likely to describe somatic complaints such as low energy or insomnia. Implications for the assessment of depression in this population are discussed.

Measurement issues in postpartum depression part 1: anxiety as a feature of postpartum depression.

We investigated the contribution of anxiety symptoms to scores on the Edinburgh Postnatal Depression Scale (EPDS) between 36 weeks gestation and 16 weeks postpartum in 150 women. The 3-item anxiety subscale of the EPDS accounted for 47% of the total score in late pregnancy, and 38% of the total score in the postpartum period. Two categories of anxiety were common in the perinatal period: subsyndromal, situational anxiety (in particular during the last weeks of pregnancy); and clinically significant comorbid anxiety, which was experienced by nearly 50% of clinically depressed pregnant and postpartum women. The close relationship between anxiety and depression raises questions about whether symptoms of anxiety might be more common in the perinatal period than in other depressions. A strong role for anxiety symptoms in postpartum depression, and implications for its etiology and treatment, are discussed.

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.

Gender differences in tobacco smoking: higher relative exposure to smoke than nicotine in women.

INTRODUCTION: Men and women are thought to regulate their smoking differently and to differ in their susceptibility to nicotine addiction. METHODS AND MATERIALS: Various measures of smoke exposure were compared between 400 current regular tobacco-dependent (DSM-IV) male and female light (1-15 cigarettes per day) and heavy (>15 cigarettes per day) smokers. Between 2 and 8 PM, blood was collected for nicotine and cotinine analysis, and breath carbon monoxide (CO) was measured. Individuals with genetic variants of the CYP2A6 gene were removed from analysis (n = 25). RESULTS: No significant difference was found in the number of cigarettes per day or CO levels between the sexes. However, females had significantly lower nicotine levels than males (16.9 +/- 0.6 vs. 21.1 +/- 0.07, p < 0.01). This is only partly explained by the fact that females smoked lower nicotine-containing cigarettes. Female heavy smokers demonstrated higher -log nicotine/CO values (a representation of cost of smoking) compared with male heavy smokers (0.1 +/- 0.02 vs. 0.02 +/- 0.01 mg/L ppm, p < 0.05). CONCLUSIONS: Thus, gender differences appear to exist in smoking behaviors, nicotine sensitivity, and nicotine requirements. These differences are expected to contribute to gender differences in health risks and cancers associated with smoking.

An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles.

We developed genotyping assays for CYP2A6*7 (Ile471Thr) and CYP2A6*8 (Arg485Leu). We found higher allelic frequencies in Japanese and Chinese versus Caucasians and identified an allele in which both substitutions occur together (CYP2A6*10). We created a homology model for predicting the impact of allelic variants on enzymatic activity and subsequently tested this in vivo in a pilot kinetic study. Consistent with our homology model predictions, we found (i) that CYP2A6*7 produces an enzyme that has decreased (not inactive) activity for metabolizing nicotine and coumarin; (ii) that CYP2A6*8 is unlikely to affect catalytic activity in vivo; and (iii) that having both substitutions together on an allele (CYP2A6*10) dramatically reduces function and may be fully inactive for some substrates. In conclusion, this study identifies, at relatively high frequency in Asians, an allele with decreased activity (may be substrate selective), a fully functional allele, and an allele containing both substitutions in which function is dramatically reduced.

Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations.

CYP2C9 is the major P450 2C enzyme in human liver and contributes to the metabolism of a number of clinically important substrate drugs. This polymorphically expressed enzyme has been studied in Caucasian, Asian, and to some extent in African American populations, but little is known about the genetic variation in Native American populations. We therefore determined the 2C9*2 (Arg144Cys) and 2C9*3 (Ile359Leu) allele frequencies in 153 Native Canadian Indian (CNI) and 151 Inuit subjects by PCR-RFLP techniques. We also present genotyping data for two reference populations, 325 Caucasian (white North American) and 102 Chinese subjects. Genotyping analysis did not reveal any 2C9*4 alleles in the CNI, Inuit, Caucasian, or Chinese individuals. The 2C9*2 allele appears to be absent in Chinese and Inuit populations, but was present in CNI and Caucasian subjects at frequencies of 0.03 and 0.08-0.15, respectively. The 2C9*3 allele was not detected in the Inuit group, but occured in the CNI group (f = 0.06) at a frequency comparable to that of other ethnic groups. This group of Inuit individuals are the first population in which no 2C9*2 or *3 alleles have been detected so far. Therefore, these alleles may be extremely rare or absent, and unless other novel polymorphisms exist in this Inuit group one would not anticipate any CYP2C9 poor metabolizer subjects among this population.

Induction of CYP2B1/2 and nicotine metabolism by ethanol in rat liver but not rat brain.

A higher proportion of alcoholics than non-alcoholics smoke (>80 vs 30%). In animals, chronic administration of alcohol induces tolerance to some effects of nicotine. To investigate if chronic ethanol (EtOH) induces alterations in CYP2B1/2 and nicotine C-oxidation activity, male rats (N = 4-6/group) were treated once daily with saline or EtOH (0.3, 1.0, and 3.0 g/kg, p.o./by gavage) for 7 days. A quantitative immunoblotting assay was developed to detect CYP2B1/2 in the brain, where constitutive expression is low, and in the liver. Using this method, it was determined that EtOH did not alter CYP2B1/2 protein expression significantly in six brain regions (olfactory bulbs, olfactory tubercles, frontal cortex, hippocampus, cerebellum, and brainstem). However, a dose-dependent induction of CYP2B1/2 protein expression was detected in the liver. Significant induction of 2-, 3-, and 2.7-fold were observed for the 0.3, 1.0, and 3.0 g/kg doses, respectively. Increases were also observed in CYP2B1 mRNA, which was induced by 14, 38, and 43% at the same doses. Liver microsomal nicotine C-oxidation also was increased (1.3 to 4.5-fold). CYP2B selective inactivators demonstrated that approximately 70% of nicotine C-oxidation was mediated by CYP2B1/2 in both EtOH-induced and uninduced hepatic microsomes. In summary, chronic, behaviorally relevant doses of EtOH induce CYP2B1/2 protein, mRNA, and nicotine C-oxidation activity in rat liver but not in rat brain, and these increases could contribute to cross-tolerance and co-abuse of ethanol and nicotine.

Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver.

The use of ethanol and nicotine is strongly linked; 80 to 95% of heavy alcohol users are also smokers. In humans, cigarette smoking significantly enhances CYP2E1 activity, as measured by increased metabolism of chlorzoxazone in vivo. CYP2E1 metabolizes ethanol and can generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke and other procarcinogens and several hepatotoxins. We hypothesized that, like ethanol, nicotine increases CYP2E1 activity. Rats were treated once daily with saline, ethanol (0.3, 1.0, and 3.0 g/kg p.o.), or nicotine bitartrate (0.1, 0.3, and 1.0 mg base/kg s.c.) for 7 days. After ethanol or nicotine administration, immunostaining for CYP2E1 was increased in the centrilobular regions of rat liver. Western blot analyses revealed that hepatic CYP2E1 levels were increased by ethanol (1.6-2.4-fold) and nicotine (1.3-1.7-fold). In vitro chlorzoxazone 6-hydroxylation analyses demonstrated elevated Vmax values (compared with saline-treated animals) by using hepatic microsomes from high-dose ethanol (2.27 +/- 0.12 versus 1.18 +/- 0.23 nmol/mg/min, p < 0.001) or nicotine-treated rats (2.35 +/- 0.04 versus 1.32 +/- 0.55 nmol/mg/min, p < 0.005), with no change in affinity. The magnitude of enhanced chlorzoxazone metabolism by microsomes from drug-treated animals is consistent with the observed increase in CYP2E1 protein by immunoblot. These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis, neuropsychiatric motor disorders).