Psychedelic Drug Microdosing Practices: A Qualitative Online Exploration.

"Microdosing," defined as the consumption of small, sub-hallucinogenic quantities of psychedelic drugs, has gained recent popularity. Microdosing is a relatively new concept, therefore no scientific recommendations exist on how to prepare and consume microdoses. Many consumers obtain microdosing information online. Few studies have investigated the content of this information; thus, the present study aimed to do so by collecting a large set of online microdosing information. A qualitative approach was taken to compile and characterize online microdosing information. Medical databases, video websites, online forums, drug-specific websites and forums, search engines, and social media websites were searched. A total of 174 unique resources were found, detailing the types of substances, preparation methods, doses, schedules, and safety strategies used by people who microdose. Future research is recommended to further explore how people prepare microdoses through in-person interviews and sample collection.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1).

BACKGROUND: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2). METHODS: Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5-15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen. DISCUSSION: The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial. TRIAL REGISTRATION: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023.

The New Zealand drug harms ranking study: A multi-criteria decision analysis.

AIMS: The harms arising from psychoactive drug use are complex, and harm reduction strategies should be informed by a detailed understanding of the extent and nature of that harm. Drug harm is also context specific, and so any comprehensive assessment of drug harm should be relevant to the characteristics of the population in question. This study aimed to evaluate and rank drug harms within Aotearoa New Zealand using a multi-criteria decision analysis (MCDA) framework, and to separately consider harm within the total population, and among youth. METHODS: Two facilitated workshops involved the separate ranking of harm for the total population, and then for youth aged 12-17, by two expert panels. In the total population workshop, 23 drugs were scored against 17 harm criteria, and those criteria were then evaluated using a swing weighting process. Scoring and weighting were subsequently updated during the youth-specific workshop. All results were recorded and analysed using specialised MCDA software. RESULTS: When considering overall harm, the MCDA modelling results indicated that alcohol, methamphetamine and synthetic cannabinoids were the most harmful to both the overall population and the youth, followed by tobacco in the total population. Alcohol remained the most harmful drug for the total population when separately considering harm to those who use it, and harm to others. CONCLUSIONS: The results provide detailed and context-specific insight into the harm associated with psychoactive drugs use within Aotearoa New Zealand. The findings also demonstrate the value of separately considering harm for different countries, and for different population subgroups.

Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.

BACKGROUND: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity. METHODS: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 µg LSD or an inactive placebo every 3 days for 6 weeks. First doses were given in a supervised laboratory setting, with other doses self-administered in a naturalistic setting. Results of safety data, blinding, daily questionnaires, expectancy, and pre-/postintervention psychometrics and cognitive tasks are presented here. RESULTS: The most notable reported adverse event was treatment-related anxiety, which prompted the withdrawal of 4 participants from the LSD group. Daily questionnaires showed credible evidence (>99% posterior probability) of improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, and these effects remained when controlling for preintervention expectancy. No questionnaire or cognitive task showed a credible change between baseline and 6-week assessment time points. CONCLUSIONS: Microdosing LSD appears to be relatively safe in healthy adult men, notwithstanding a risk of anxiety. While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition in healthy adults. Future microdosing trials in clinical populations will require the use of active placebos to control for placebo effects and dose titration to adjust for interindividual variability in drug response.

Why do pharmacists leave the profession? A mixed-method exploratory study.

BACKGROUND: Recent New Zealand policy documents aim for pharmacists to be retained, and promote the provision of extended clinical pharmacy services. However, younger pharmacists have expressed dissatisfaction with the profession on informal social for a. OBJECTIVES: To explore the characteristics, and perspectives of pharmacy as a career, of recent Bachelor of Pharmacy (BPharm, four-year degree) graduates who have left, or are seriously considering leaving the New Zealand pharmacy profession in the near future and where they have gone, or plan to go. METHODS: We conducted a cross-sectional study with a mixed-method explanatory sequential design. An anonymous online survey among those who completed their pharmacy undergraduate degree (BPharm or equivalent) in 2003 or later and who had left or who were seriously considering leaving the New Zealand pharmacy profession in the next five years, was open from 1st December 2018 to 1st February 2019. Recruitment occurred via University alumni databases, pharmacy professional organisations, pharmaceutical print media, social media and word-of-mouth. Ten semi-structured interviews were then conducted with a purposive sample of survey respondents. Descriptive statistics were generated from the quantitative data and qualitative data were analysed using manifest content analysis. RESULTS: We received 327 analysable surveys of which 40.4% (n=132) were from those who had already left the New Zealand pharmacy sector at the time of the data collection and the rest (59.6% n=195) were those working within the sector, but seriously considering leaving the profession. Reasons most commonly reported for studying pharmacy were having an interest in health and wanting to work with people. The most common reasons for leaving, or wanting to leave, were dissatisfaction with the professional environment, including inadequate remuneration, and a perceived lack of career pathways or promotion opportunities. A wide range of career destinations were declared, with medicine being most frequently reported. CONCLUSIONS: Most of the reasons for leaving/considering leaving the profession reported relate to the values and features of the pharmacy profession such as the professional environment, remuneration and career pathways. These findings are consistent with other studies and may represent a barrier to achieving the aims of recent health policy documents.

Why do pharmacists leave the profession? A mixed-method exploratory study

Background: Recent New Zealand policy documents aim for pharmacists to be retained, and promote the provision of extended clinical pharmacy services. However, younger pharmacists have expressed dissatisfaction with the profession on informal social for a. Objectives: To explore the characteristics, and perspectives of pharmacy as a career, of recent Bachelor of Pharmacy (BPharm, four-year degree) graduates who have left, or are seriously considering leaving the New Zealand pharmacy profession in the near future and where they have gone, or plan to go. Methods: We conducted a cross-sectional study with a mixed-method explanatory sequential design. An anonymous online survey among those who completed their pharmacy undergraduate degree (BPharm or equivalent) in 2003 or later and who had left or who were seriously considering leaving the New Zealand pharmacy profession in the next five years, was open from 1st December 2018 to 1st February 2019. Recruitment occurred via University alumni databases, pharmacy professional organisations, pharmaceutical print media, social media and word-of-mouth. Ten semi-structured interviews were then conducted with a purposive sample of survey respondents. Descriptive statistics were generated from the quantitative data and qualitative data were analysed using manifest content analysis. Results: We received 327 analysable surveys of which 40.4% (n=132) were from those who had already left the New Zealand pharmacy sector at the time of the data collection and the rest (59.6% n=195) were those working within the sector, but seriously considering leaving the profession. Reasons most commonly reported for studying pharmacy were having an interest in health and wanting to work with people (AU)

MDLSD: study protocol for a randomised, double-masked, placebo-controlled trial of repeated microdoses of LSD in healthy volunteers.

BACKGROUND: Regular ingestion of sub-hallucinogenic doses of psychedelics, referred to as "microdosing", has gained increasing popularity and attention in the press and in online forums, with reported benefits across multiple cognitive and emotional domains. Rigorously controlled studies to date, however, have been limited in scope and have failed to produce results comparable to those reported in the grey literature. METHODS: Eighty healthy male participants will receive 14 doses of placebo or 10 µg lysergic acid diethylamide orally every 3rd day over a 6-week treatment protocol. A battery of personality, creativity, mood, cognition, and EEG plasticity measures, as well as resting-state fMRI imaging, will be administered at baseline and at the end of the protocol. Creativity, mood, and plasticity measures will additionally be assessed in the acute phase of the first dose. Daily functioning will be monitored with questionnaires and a wearable sleep and activity tracker. DISCUSSION: This study will rigorously examine the claims presented in the microdosing grey literature by pairing a comparable dosing protocol with objective measures. Potential therapeutic implications include future clinical trials to investigate microdosed psychedelics as a standalone treatment or as an augmentation of psychotherapy in the treatment of depression, addiction, eating disorders, obsessive-compulsive disorders, and palliative care. TRIAL REGISTRATION: ACTRN12621000436875 . Registered on 19 February 2021.

A qualitative and quantitative account of patient's experiences of ketamine and its antidepressant properties.

BACKGROUND: Ketamine is central to one of the most rapidly growing areas of neuroscientific research into novel treatments for depression. Limited research has indicated that the psychedelic properties of ketamine may play a role in its antidepressant effects. AIM: The aim of the current study was to explore the psychedelic experiences and sustained impact of ketamine in major depressive disorder. METHODS: In the current study, ketamine (0.44 mg/kg) was administered to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil, in a magnetic resonance imaging (MRI) environment. The 11-dimension altered states of consciousness questionnaire and individual qualitative interviews were used to capture the acute psychedelic experience. The Montgomery-Asberg Depression Rating Scale and further interviewing explored lasting effects. The second qualitative interview took place ⩾3 weeks post-ketamine. RESULTS: Greater antidepressant response (reduction in Montgomery-Asberg Depression Rating Scale at 24 h) correlated with the 11-dimension altered states of consciousness dimensions: spirituality, experience of unity, and insight. The first qualitative interview revealed that all participants experienced perceptual changes. Additional themes emerged including loss of control and emotional and mood changes. The final interview showed evidence of a psychedelic afterglow, and changes to perspective on life, people, and problems, as well as changes to how participants felt about their depression and treatments. CONCLUSIONS: The current study provides preliminary evidence for a role of the psychedelic experience and afterglow in ketamine's antidepressant properties. Reflexive thematic analysis provided a wealth of information on participants' experience of the study and demonstrated the psychedelic properties of ketamine are not fully captured by commonly used questionnaires.

Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors.

Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration.

Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder.

BACKGROUND: The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity. METHODS: The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery-Åsberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine. RESULTS: Montgomery-Åsberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10-11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation. CONCLUSIONS: This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine.

Simultaneous EEG/fMRI recorded during ketamine infusion in patients with major depressive disorder.

A single subanaesthetic dose of ketamine rapidly alleviates the symptoms of major depressive disorder (MDD). However, few studies have investigated the acute effects of ketamine on the BOLD pharmacological magnetic resonance imaging (phMRI) response and EEG spectra. In a randomised, double-blind, active placebo-controlled crossover trial, resting-state simultaneous EEG/fMRI was collected during infusion of ketamine or active placebo (remifentanil) in 30 participants with MDD. Montgomery-Asberg depression rating scale scores showed a significant antidepressant effect of ketamine compared to placebo (69% response rate). phMRI analyses showed BOLD signal increases in the anterior cingulate and medial prefrontal cortices and sensitivity of the decrease in subgenual anterior cingulate cortex (sgACC) BOLD signal to noise correction. EEG spectral analysis showed increased theta, high beta, low and high gamma power, and decreased delta, alpha, and low beta power with differing time-courses. Low beta and high gamma power time courses explained significant variance in the BOLD signal. Interestingly, the variance explained by high gamma power was significantly associated with non-response to ketamine, but significant associations were not found for other neurophysiological markers when noise correction was implemented. The results suggest that the decrease in sgACC BOLD signal is potentially noise and unrelated to ketamine's antidepressant effect, highlighting the importance of noise correction and multiple temporal regressors for phMRI analyses. The lack of effects significantly associated with antidepressant response suggests the phMRI methodology employed was unable to detect such effects, the effect sizes are relatively small, or that other processes, e.g. neural plasticity, underlie ketamine's antidepressant effect.

Influence of student debt on health career location and specialty.

INTRODUCTION In New Zealand (NZ), there are shortages of health professionals in rural areas and in primary care. AIM This study aims to examine the association of student debt levels of medical, nursing, pharmacy and optometry students with: (1) preferred geographical location of practice, specifically preference to work in urban vs. rural areas; and (2) preferred career specialties, specifically interest in primary health care. METHODS Medical, nursing, pharmacy and optometry students completed a questionnaire at graduation that included questions about levels of New Zealand Government Student Loan debt and preferences regarding location of practice and career specialty. In an additional survey, medical students were asked to self-rate the effect of financial factors on their career choices. RESULTS Debt patterns varied across programmes. Medical and pharmacy students with high debt were significantly more likely than students with low debt to prefer rural over urban practice (P = 0.003). There was no difference in level of interest in a primary care specialty by debt level for any programme. Medical students reported little influence of debt on career choice, although students with high debt levels were less concerned over career financial prospects than students with lower levels of debt. DISCUSSION Current levels of student debt do not deter students from planning a career in rural or primary care settings. Somewhat surprisingly, higher levels of debt are associated with greater rural practice intentions for medical and pharmacy students, although the underlying reasons are uncertain.

Opioid prescribing in general practice: use of a two-stage review tool to identify and assess high-dose prescribing.

BACKGROUND: Long-term opioid analgesic prescribing in chronic non-cancer pain (CNCP) is a growing worldwide concern. This has implications for optimal healthcare management in general and chronic pain management specifically. This work documents the development of a review tool and its use in the South West of England in a locality that showed opioid prescribing levels higher than surrounding localities. METHODS: An electronic tool which enabled calculation of total prescribed morphine-equivalent doses was developed to allow general practitioners (GPs) to undertake reviews of CNCP patients. This tool was used to assess strong opioid prescribing over a 3-month period at every GP practice (n = 41) in the locality. Every prescription for morphine, oxycodone, pethidine and fentanyl during this period was included.Aspects assessed included drug(s) prescribed, dose prescribed, whether tramadol was prescribed concurrently, whether the drugs were potentially being overused and/or whether the patient was in palliative care. Patients prescribed over 120 mg morphine equivalent per day were reviewed in greater depth, as this is an indication for specialist input. RESULTS: In total, 1881 patients received a prescription in the assessment period. Morphine was the most commonly prescribed drug (n = 847). In all, 363 CNCP patients were prescribed a dose equal to or above 120 mg morphine a day, with a maximum morphine-equivalent dose of 890 mg being prescribed. Over 11% (n = 211) of patients were concurrently prescribed tramadol. The most frequently cited reason for prescription of high-dose opioids was found to be a musculoskeletal pain of the back, neck, joints or limbs. The care of 85 specific CNCP patients was reviewed and optimised. DISCUSSION: No published work to date has documented such an in-depth analysis of primary-care opioid analgesic prescribing utilising prescriber data. Assessing total-dose morphine-equivalent prescribing using this method provides valuable insights into the potential need for urgent medication review. The tool developed may be of value to other GP practices following validation.

Pregabalin misuse: preventing potential problems in New Zealand.

AIMS: Pregabalin has not been used widely in New Zealand to this point as it has not been funded, but from May 2018 it will be available fully subsidised. This paper intends to highlight the issue of pregabalin misuse, a concern that will be unfamiliar to most clinicians in New Zealand. METHODS: A review of the literature of papers documenting the misuse of gabapentin and pregabalin was conducted with a specific focus on pregabalin. RESULTS: There is a growing body of evidence regarding the potential of misuse of pregabalin. It produces a range of sensations, including euphoria, sedation and dissociation. It is commonly used in conjunction with other drugs, most notably sedatives and opioids, which leads to an additive effect. Although generally safe when taken alone, pregabalin is a growing feature of drug-related deaths. CONCLUSIONS: Prescribers need to be alert to the potential of pregabalin misuse. This should be achieved through prescribing with great care (not prescribing to new or unknown patients; not in response to direct patient requests for it by name; supplying in limited quantities), regular review of patients and stopping treatment, by slow withdrawal, when lack of efficacy is seen.

A new approach to formulating and appraising drug policy: A multi-criterion decision analysis applied to alcohol and cannabis regulation.

BACKGROUND: Drug policy, whether for legal or illegal substances, is a controversial field that encompasses many complex issues. Policies can have effects on a myriad of outcomes and stakeholders differ in the outcomes they consider and value, while relevant knowledge on policy effects is dispersed across multiple research disciplines making integrated judgements difficult. METHODS: Experts on drug harms, addiction, criminology and drug policy were invited to a decision conference to develop a multi-criterion decision analysis (MCDA) model for appraising alternative regulatory regimes. Participants collectively defined regulatory regimes and identified outcome criteria reflecting ethical and normative concerns. For cannabis and alcohol separately, participants evaluated each regulatory regime on each criterion and weighted the criteria to provide summary scores for comparing different regimes. RESULTS: Four generic regulatory regimes were defined: absolute prohibition, decriminalisation, state control and free market. Participants also identified 27 relevant criteria which were organised into seven thematically related clusters. State control was the preferred regime for both alcohol and cannabis. The ranking of the regimes was robust to variations in the criterion-specific weights. CONCLUSION: The MCDA process allowed the participants to deconstruct complex drug policy issues into a set of simpler judgements that led to consensus about the results.