Differences In Subjective Effects Research Articles

Examining differences in the effects and contexts of naturalistic psilocybin use for White participants vs. Participants of Color: A longitudinal online survey study

BackgroundPsilocybin (a psychoactive compound found in “magic mushrooms” or “shrooms”) has been gaining increased attention in research and popular culture as a number of clinical and observational studies have demonstrated that it may have potential for improving mental wellbeing. Relatedly, there has been a substantial uptick in naturalistic (e.g., real-world, non-clinical) psilocybin use in the United States. While a number of longitudinal studies have demonstrated that naturalistic psilocybin use is linked to positive mental health outcomes on average, few studies have examined how the effects of psilocybin and contexts for psilocybin use may differ for White populations compared to Populations of Color. ObjectiveTo examine differences in health outcomes, subjective effects, and contexts of naturalistic psilocybin use in White participants compared to Participants of Color. MethodsThis study used data from a large, online longitudinal study of individuals who planned to engage in naturalistic psilocybin use (N = 2833). We used mixed-effects models to assess whether race/ethnicity (White vs. Participant of Color) moderated associations between time (Time 2 [initial assessment point for longitudinal measures], Time 5 [2–4 weeks post-psilocybin experience, and Time 6 [2–3 months post-experience]) and outcomes related to mental health (depression, anxiety, spiritual wellbeing, cognitive flexibility, emotion regulation [expressive suppression + cognitive reappraisal]). We also used exploratory chi-squared tests to examine differences in contexts for psilocybin use as well as differences in subjective effects related to the psilocybin experience. ResultsRace/ethnicity moderated the associations between time for predicting spiritual wellbeing (beta = −1.8; 95 % CI [−3.4, −0.17]; p < 0.05), cognitive flexibility (beta = −1.5 [−2.7, −0.26]; p < 0.05), and emotion regulation – expressive suppression (beta = 0.25 [0.06, 0.44]; p < 0.05) at Time 6 (but not Time 5). Additionally, Participants of Color reported minor differences in subjective effects and context for use compared to White participants (e.g., more likely to have set an intention prior to use, report time speeding up during the experience, etc.). We found reductions in anxiety and depression for both Participants of Color and White participants, and our moderation tests for these outcomes were not significant. ConclusionRace/ethnicity impacts the associations between psilocybin use and various markers of mental wellbeing. Future longitudinal studies and experimental studies with larger samples of color can further elucidate the preliminary findings from this study.

Pharmacokinetics and Pharmacodynamics of Inhaled Nicotine Salt and Free-Base Using an E-cigarette: A Randomized Crossover Study.

Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. This study investigated the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes. In this randomized, double-blind, within-subject crossover study, 20 non-nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20 mg/mL, nicotine salt 20 mg/mL, nicotine salt 40 mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed. Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0 ng/mL (1.6-27.3), 5.4 ng/mL (1.9-18.7), and 3.0 ng/mL (1.3-8.8) for nicotine salt 40 mg/mL, nicotine salt 20 mg/mL and free-base 20 mg/mL, respectively). All groups reached Cmax 2.0-2.5 minutes (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed. Free-base 20 mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20 mg/mL, while 40 mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation. Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine-free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40 mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and nonsmokers.

Evidence for sex differences in the impact of cytochrome P450 genotypes on early subjective effects of cannabis

Early positive subjective effects of cannabis predict the development of cannabis use disorder (CUD). Genetic factors, such as the presence of cytochrome P450 genetic variants that are associated with reduced Δ9-tetrahydrocannabinol (THC) metabolism, may contribute to individual differences in subjective effects of cannabis. Young adults (N = 54) with CUD or a non-CUD substance use disorder (control) provided a blood sample for DNA analysis and self-reported their early (i.e., effects upon initial uses) and past-year positive and negative subjective cannabis effects. Participants were classified as slow metabolizers if they had at least one CYP2C9 or CYP3A4 allele associated with reduced activity. Though the CUD group and control group did not differ in terms of metabolizer status, slow metabolizer status was more prevalent among females in the CUD group than females in the control group. Slow metabolizers reported greater past year negative THC effects compared to normal metabolizers; however, slow metabolizer status did not predict early subjective cannabis effects (positive or negative) or past year positive effects. Post-hoc analyses suggested males who were slow metabolizers reported more negative early subjective effects of cannabis than female slow metabolizers. Other sex-by-genotype interactions were not significant. These initial findings suggest that genetic variation in CYP2C9 and CYP3A4 may have sex-specific associations with cannabis-related outcomes. Slow metabolizer genes may serve as a risk factor for CUD for females independent of subjective effects. Male slow metabolizers may instead be particularly susceptible to the negative subjective effects of cannabis.

Sex differences in the acute effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC).

Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated the sex differences in the acute subjective, psychotomimetic, cognitive, and physiological effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. Healthy male and female individuals, with limited exposure to cannabis, participated in a double blind, placebo-controlled study of intravenous (IV) placebo or THC at two doses (0.015mg/kg and 0.03mg/kg). Visual analog scale (VAS) was used to measure subjective effects, Psychotomimetic States Inventory (PSI) and the Clinician-Administered Dissociative Symptoms Scale (CADSS) were used to assess the psychotomimetic effects and perceptual alterations, respectively, and Rey Auditory Verbal Learning Task (RAVLT) was used to evaluate cognitive effects. Outcome variables were represented as the peak change from baseline for each variable, except RAVLT which was used only once per the test day after the subjective effects. A total of 42 individuals participated in this study. There were no significant differences between male and female participants in background characteristics. There was a significant main effect of sex on the VAS scores for THC-induced "High" (F1,38 = 4.27, p < 0.05) and a significant dose × sex interaction (F2,77 = 3.38, p < 0.05) with female participants having greater "High" scores than male participants at the lower THC dose (0.015mg/kg). No other sex differences were observed in acute subjective, psychotomimetic, cognitive, or physiological effects of THC. There were significant sex differences in subjective effects of feeling "High" at a lower dose of THC. However, there were no other sex-related differences in the subjective, physiological, or cognitive effects of THC.

Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey

Rationale.Classic psychedelics are currently being studied as novel treatments for a range of psychiatric disorders. However, research on how psychedelics interact with other psychoactive substances remains scarce.ObjectivesThe current study aimed to explore the subjective effects of psychedelics when used alongside cannabis.MethodsParticipants (n = 321) completed a set of online surveys at 2 time points: 7 days before, and 1 day after a planned experience with a serotonergic psychedelic. The collected data included demographics, environmental factors (so-called setting) and five validated questionnaires: Mystical Experience Questionnaire (MEQ), visual subscales of Altered States of Consciousness Questionnaire (ASC-Vis), Challenging Experience Questionnaire (CEQ), Ego Dissolution Inventory (EDI) and Emotional Breakthrough Inventory (EBI). Participants were grouped according to whether they had reported using no cannabis (n = 195) or low (n = 53), medium (n = 45) or high (n = 28) dose, directly concomitant with the psychedelic. Multivariate analysis of covariance (MANCOVA) and contrasts was used to analyse differences in subjective effects between groups while controlling for potential confounding contextual ‘setting’ variables.ResultsThe simultaneous use of cannabis together with classic serotonergic psychedelics was associated with more intense psychedelic experience across a range of measures: a linear relationship was found between dose and MEQ, ASC-Vis and EDI scores, while a quadratic relationship was found for CEQ scores. No relationship was found between the dose of cannabis and the EBI.ConclusionsResults imply a possible interaction between the cannabis and psychedelic on acute subjective experiences; however, design limitations hamper our ability to draw firm inferences on directions of causality and the clinical implications of any such interactions.

Investigating sex differences in acute intoxication and verbal memory errors after ad libitum cannabis concentrate use

BackgroundAn innovative naturalistic at-home administration procedure was used to investigate sex differences in subjective drug effects and verbal memory errors after ad libitum use of high potency state legal market Δ9-tetrahydrocannabinol (THC) concentrate. MethodsRegular concentrate users were randomly assigned to ad libitum administration of one of two cannabis concentrate products (70 % or 90 % THC) that they purchased from a dispensary. 65 participants (N = 34 men, N = 31 women) were assessed in a mobile pharmacology lab before, immediately after, and 1 -h after ad libitum concentrate use. Plasma cannabinoids (THC, 11-OH-THC, CBD), subjective drug effects, and verbal memory errors were assessed at all three time points. ResultsAlthough men and women exhibited similar plasma 11-OH-THC levels across time (p = .10), sex differences were found in plasma THC and CBD after legal market concentrate use, with men displaying significantly higher levels of plasma THC and CBD immediately after cannabis concentrate use (plasma THC [ng/mL]: Mmen = 489.88, Mwomen = 135.08, p < .001; plasma CBD [ng/mL]: Mmen = 1.14, Mwomen = 0.53, p = .04). Despite this, sex differences in subjective effects and verbal memory errors did not emerge, although women reported a steeper decrease in drug liking after use (p = .04). ConclusionThese data provide the first look at sex differences after acute naturalistic cannabis concentrate use, and suggest much higher THC exposure in men versus women, but similar acute drug and impairment effects across the sexes. Further studies are needed to determine the mechanisms (e.g. tolerance, cannabinoid metabolism, smoking topography) behind these findings.

Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Yellow Oil in Healthy Participants.

Due to a lack of published pharmacokinetic (PK) and/or pharmacodynamic (PD) data, decision-making surrounding appropriate dosing of cannabis used for medical purposes is limited. This multiple-dose study evaluated the safety, tolerability, PK and PD of Spectrum Yellow oil [20 mg/mL cannabidiol (CBD)/<1 mg/mL ∆9-tetrahydrocannabinol (THC)]. Participants (n = 43) were randomized to one of five groups: 120 mg CBD and 5.4 mg THC daily, 240 mg CBD and 10.8 mg THC daily, 360 mg CBD and 16.2 mg THC daily, 480 mg CBD and 21.6 mg THC daily or placebo. Study medication was administered every 12 h for 7 consecutive days. Treatment-emergent adverse events (TEAEs); plasma and urine concentrations of THC, CBD and metabolites; and self-reported subjective effects were collected. Nearly all TEAEs (44/45) were of mild or moderate severity; none was serious. The highest incidence of TEAEs (67%) was in the two higher-dose treatment groups. The highest number of TEAEs (17/45) occurred on the first treatment day. Steady-state plasma CBD concentrations were reached by Day 7. On Day 7, CBD exposure showed dose proportionality (AUC0–t slope = 1.03 [0.70, 1.36], Cmax slope = 0.92 [0.53, 1.31]). Most plasma THC concentrations were below the limit of quantification. Across Days 1 and 7, there were no consistent differences in subjective effects between placebo and active study medication. A prudent approach to improve tolerability with Spectrum Yellow oil might involve initial doses no higher than 240 mg total CBD and 10.8 mg total THC daily in divided doses, with titration upward over time as needed based on tolerability.

Potential Moderating Effects of Sex/Gender on the Acute Relative Reinforcing and Subjective Effects of Reduced Nicotine Content Cigarettes in Vulnerable Populations.

Reports in relatively healthy smokers suggest men are more sensitive than women to the subjective effects of reduced nicotine content cigarettes (RNCCs). We know of no reports examining sex differences in the relative reinforcing effects of RNCCs, an important outcome in assessing smoking's addiction potential. The aim of the present study is to address this gap by examining sex/gender differences on reinforcing effects while examining whether sex differences in subjective effects are discernible in vulnerable populations. Secondary analysis of a within-subject, double-blinded experiment examining acute effects of cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg/g) among 169 adult smokers with psychiatric conditions or socioeconomic disadvantage. Effects of dose, sex, and their interaction were examined on reinforcing (concurrent-choice and Cigarette Purchase Task [CPT] testing), and subjective effects (Cigarette Evaluation Questionnaire [CEQ] and craving/withdrawal ratings). Reducing nicotine content decreased the relative reinforcing effects of smoking in concurrent-choice and CPT testing (p's < .05) with no significant effects of sex nor dose × sex/gender interactions. Reducing nicotine content decreased CEQ ratings with only a single significant effect of sex (higher Psychological Reward scores among women than men, p = .02) and no significant dose × sex/gender interactions. Results on craving/withdrawal paralleled those on the CEQ. Reducing nicotine content decreases the addiction potential of smoking independent of sex in populations highly vulnerable to smoking and addiction, with no indication that women are less sensitive to subjective effects of RNCCs or would benefit less from a policy reducing the nicotine content of cigarettes. A policy reducing the nicotine content of cigarettes has the potential to reduce the addiction potential of smoking across men and women who are especially vulnerable to smoking, addiction, and tobacco-related adverse health impacts.

The influence of personality on the sensitivity to subjective effects of Δ9-tetrahydrocannabinol

The effects of drugs are not only determined by their pharmacological action, but also by user characteristics. This analysis explored the influence of personality on the differences in subjective effects in response to a standardized pharmacological challenge with the cannabinoid CB1/CB2 partial agonist Δ9-tetrahydrocannabinol (THC). To express the sensitivity to THC, pharmacokinetic–pharmacodynamic (PK–PD) non-linear mixed effects modelling was applied to the subjective response of 184 healthy subjects to a pharmacological challenge with inhalation of THC. The subjective effects were measured using visual analogue scales and described by three clusters: ‘perception’, ‘relaxation’ and ‘dysphoria’. The sensitivity for THC (described as EC50) was related to scores on Cloninger׳s temperament and character inventory (TCI) using multiple linear regression. Effect compartment models were used to describe the PK–PD relations of THC. Within the multivariate model, ‘harm avoidance’ was significantly correlated with changes in ‘perception’, and ‘self-transcendence’ with changes in ‘dysphoria’. Within the psychobiological model of personality, ‘harm avoidance’ is related to serotonergic systems. Subjects with either very low (easy-going) or very high (cautious) scores were less sensitive to THC-induced changes in ‘perception’. ‘Self-transcendence’ relates to schizotypy. Subjects with more schizotypy were more sensitive to the dysphoric subjective effects of THC.

Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics

This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.

Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects

The stimulant effects of cocaine and methamphetamine are mediated by changes in synaptic concentrations of brain monoamines; however, the drugs alter monoamine levels via different mechanisms. This study examined the subjective and cardiovascular responses produced by investigational administration of cocaine or methamphetamine, in order to examine the onset and patterns of subjective and cardiovascular responses. Subjects included 14 non-treatment seeking cocaine-dependent and 11 non-treatment seeking methamphetamine-dependent volunteers. As part of ongoing research studies, cocaine and methamphetamine subjects received cocaine (40 mg, IV) or methamphetamine (30 mg, IV), respectively. Subjective and cardiovascular responses were assessed for 30 min and 60 min, respectively. The data reveal significant within groups differences for all subjective effects and cardiovascular effects ( p < 0.05). Significant between group differences in subjective effects were observed for “Any Drug Effect” ( p < .008 for group, and p < .029 for group × time), for “High” ( p < .002 for group, and p < .0001 for group × time) and for “Stimulated” ( p < .001 for group, and p < .006 for group × time). Significant between group differences in cardiovascular effects were observed for Systolic blood pressure ( p < .0001 for group, and p < .002 for group × time), Diastolic blood pressure ( p < .0001 for group, though p = NS for group × time), and for Heart Rate ( p < .0001 for group, and p < .0001 for group × time). The only difference between the groups for placebo was for heart rate, where there was a significant group × time effect ( p < .005). Taken together, the data reveal that the subjective effects of cocaine tended to peak and then decline more rapidly than those produced by methamphetamine. The subjective effects of methamphetamine tended to rise more slowly, and remain elevated longer. Cardiovascular effects of cocaine and methamphetamine had similar onset, but effects of cocaine tended to decline more rapidly. Overall, the results reveal differences in the onset, pattern, and duration of subjective and cardiovascular responses following cocaine or methamphetamine administration in stimulant addicted patients. We predict that these differences may impact drug use and relapse patterns, and may have implications in medications development for these addictive disorders.

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide in healthy volunteers

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide (N 2O) was studied across five sessions. Twelve volunteers with no history of drug dependence sampled 30% N 2O and 100% oxygen for 10 min each, then chose nine times, once every 5 min, among N 2O (e.g. ‘Agent A’), oxygen (e.g. ‘Agent B’), or ‘drug-free air.’ Choice varied across subjects but was stable within subjects. Quantitative differences in subjective effects occurred within and across subjects. Some subjective effects were correlated with choice and/or differed between subjects who were consistent choosers of N 2O versus those who were not. However, drug liking and euphoria, two face-valid measures of abuse liability, were unrelated to choice. Thus, the present study found individual differences (i.e. between-subject variability) in subjective and reinforcing effects of N 2O and, in terms of within-subject variability, suggested that subjective effects fluctuate across sessions to a relatively greater extent than do reinforcing effects. The varying degrees of correlation between N 2O choice and its subjective effects emphasize the need for obtaining multiple measures when characterizing abuse liability of this drug.

Treatment of Chronic Obstructive Pulmonary Disease With Orally Administered Theophylline

Theophylline is commonly prescribed for chronic obstructive pulmonary disease (COPD), although controlled studies do not exist to support this use. We administered theophylline and placebo orally to 40 ambulatory COPD patients in a double-blind, crossover manner. Pulmonary function tests were conducted before and after isoproterenol nebulization on the final day of each four-week study period. Theophylline therapy produced small, but significant, increases over placebo in mean values. However, only the forced expiratory volume in 1 s was "improved," according to published criteria. There were no significant differences in subjective effects between treatment periods. Six patients were identified as "responders"; responder status could be predicted on the basis of improvement in flow rates after isoproterenol nebulization. Theophylline therapy is not beneficial to most COPD patients, and potential responders should be given carefully monitored therapeutic trials rather than arbitrarily being given maintenance therapy.