Protocol for an open label pilot study of intranasal oxytocin for methamphetamine withdrawal in women (mOXY trial)

doi:10.21203/rs.3.rs-4428433/v1

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Research Article

Protocol for an open label pilot study of intranasal oxytocin for methamphetamine withdrawal in women (mOXY trial)

https://doi.org/10.21203/rs.3.rs-4428433/v1

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Background

Methamphetamine Use Disorder (MAUD) is associated with major public heath burden worldwide, yet medication treatment options are lacking. For many patients, the first step in a treatment episode is admission to a residential detoxification or rehabilitation unit for withdrawal, however unplanned early discharge is common, and evidence suggests treatment benefits may be short-lived. Pharmacotherapy candidates for methamphetamine withdrawal have thus far failed to show sufficient benefit; there are currently no FDA/TGA approved medications for treatment of MAUD.

Oxytocin is a candidate medication with potential to increase treatment retention and reduce withdrawal symptom severity and relapse rate. It has shown promise in the context of cocaine, cannabis and alcohol use disorders. Central neuro-modulatory effects of oxytocin may aide in alleviating withdrawal symptoms and craving, evident in preclinical and clinical studies. Further research is necessary, as is addressing the critical importance of sex differences in addiction treatment. Therefore, we aim to investigate the feasibility of intranasal oxytocin as a treatment for methamphetamine withdrawal, whilst targeting the significant gap in research by focusing on women.

Methods

This open label pilot trial will investigate the feasibility of intranasal oxytocin as a treatment for methamphetamine withdrawal in women. Oxytocin is administered twice daily to 10 women during a 7-day residential inpatient withdrawal admission. The primary objective is to assess feasibility as measured through the proportion of screen failures to those who received the study drug. Secondary objectives are assessment of length of stay up to 7 days in the inpatient unit. withdrawal symptom severity, relapse rates and treatment engagement at 1-month post discharge, and safety and tolerability of intranasal oxytocin. Changes in social functioning and social cognition from baseline to 1-month post-discharge will also be assessed as exploratory endpoints.

Discussion

Outcomes from this proof-of-concept study will inform the feasibility and endpoints of a full-scale randomised clinical trial, as well as provide preliminary data on the possible mechanisms underlying the therapeutic effects of oxytocin. Furthermore, the study will build critically needed research capacity in female-specific MAUD medication treatment.

Trial Registration ClinicalTrials.gov Identifier: NCT05709353, registered February 14^th 2023 (Protocol version 2.0, 6^th January 2023; https://www.clinicaltrials.gov/study/NCT05760807).

Methamphetamine use disorder (MAUD)

stimulant use disorder

oxytocin

addiction

treatment

Methamphetamine use disorder (MAUD) is a significant public health concern with burden to individuals, families and health systems estimated to cost over $5 billion annually in Australia [1–3]. In 2021/22 there were 39,912 Australian treatment episodes for MAUD [4]. Short-term (e.g. 7 days) inpatient withdrawal is often the first step in a treatment episode, but individuals with MAUD have high rates of unplanned discharge, with previous studies suggesting a median length of stay of only 5 days (Methamphetamine Evaluation Treatment Study [MATES] sample of 112 participants [5]), with shorter stays increasing vulnerability to relapse and treatment disengagement. Early relapse is common, with an estimated 80% of methamphetamine-dependent individuals reporting relapse within the first three months post-withdrawal [5].

Compounding these difficulties, MAUD is also associated with specific impairments in social behaviour that can disrupt early recovery and social functioning [6, 7]. Recovery is underpinned by the development of new social networks [8] and forging a strong therapeutic alliance with treatment providers, one of the strongest predictors of positive long-term prognosis for substance use disorder [9]. Yet, chronic methamphetamine use is associated with relational difficulties that impact on treatment engagement and social function in early recovery, including deficits in social cognition [7], common experiences of suspiciousness, paranoia and psychosis [10], and high rates of trauma [11].

Intranasal oxytocin presents a novel therapeutic option that could improve treatment retention and engagement in early recovery [12–14], and may potentially play a role in ameliorating social dysfunction seen in methamphetamine relapse. Oxytocin is a naturally occurring neuropeptide that has been found to modulate a range of social behaviours across studies of healthy volunteers and individuals with mental health disorders [15]. Previous work supports its use in addiction by decreasing withdrawal severity through reversal of neuroadaptation in dopamine and glutamate systems, promoting pro-social behaviours through impacts on social processing, and protecting against vulnerability to stress-induced relapse [16–18].

Consistent with this, several pre-clinical and clinical studies support oxytocin as a treatment for addiction [13, 16, 19–21]. The medication has typically been administered twice daily, being a short-acting neuropeptide with a brief half-life, with lower doses potentially having more potent pro-social effects than higher doses [22]. It has been found to be safe and well-tolerated across studies, and pilot trials (recruiting between 11–80 alcohol-dependent participants) suggest promise in treating alcohol withdrawal [13, 23]. There is consistent evidence from pre-clinical studies that centrally administered oxytocin can reduce relapse to stimulant use. Preliminary findings in cocaine dependent humans are promising [24], but no fully powered randomised controlled trials to support oxytocin’s use for this indication have been undertaken. Oxytocin has limited abuse potential and therefore could be prescribed as a take-home medication, making it a potentially scalable and cost-effective adjunct to the management of MAUD.

To date, the only published clinical trials exploring the effects of oxytocin in stimulant use disorders recruited male-only samples [14, 25]. A study on males with MAUD found that oxytocin, when paired with motivational interviewing group therapy (MIGT) over 6 sessions, increased session attendance compared to placebo. There was a small effect on group cohesion, but no significant effect on craving or anxiety. This study administered oxytocin intranasally 6 times over a 6-week period with no adverse events reported. A more recent trial by the same group investigated oxytocin for stimulant use disorder in male veterans taking part in an opioid treatment program (n = 42) [25]. Forty International Units (IU) of oxytocin or placebo was administered intranasally twice daily for 6 weeks. Like their previous work, oxytocin was found to have no effect on craving, yet treatment attendance was significantly increased compared to placebo (OR: 1.39; CI: 1.04–1.86; p = 0.03). These studies demonstrate that oxytocin may increase treatment engagement among male stimulant users. There is a paucity of research in women with MAUD, despite reported sex differences in methamphetamine pharmacokinetics, drug-induced behavioural changes, cognitive processing, structural brain changes and effects on neurotransmitter systems [26].

We therefore propose to focus on women with MAUD for three specific reasons. First, there are demonstrated, clinically important sex differences at every stage of stimulant use disorder from initiation, to use disorder, to withdrawal. For instance, women show a telescoping phenomenon in stimulant use, whereby the progression of illness severity and complexity occurs more quickly than it does in men [27]. Second, research on oxytocin more broadly shows more consistent behavioural effects in females than males [28, 29]. Third, rates of methamphetamine treatment-seeking tripled for Australian women between 2010 and 2016 (compared to doubling for men) [30], but there is a significant gap in research on female-specific treatment approaches. Our proposed focus on women is also consistent with international initiatives recognising the critical importance of sex differences in addiction treatment, such as the US National Institute of Drug Abuse (NIDA) Women and Sex/Gender Differences Research Program [31].

No effective pharmacotherapy exists for methamphetamine withdrawal [32]. This pilot study will investigate a novel treatment option in an under-researched population and will explore potential mechanisms of effect and impacts on treatment engagement, social processing and social connection, which are crucial to MAUD recovery. Outcomes will inform the feasibility, design and endpoints of a larger scale randomised controlled trial.

Table 1. Study Objectives and Endpoints

	Objectives	Corresponding Endpoint
Primary	To assess length of stay in the inpatient withdrawal unit.	Medical chart review to determine number of days stayed in the inpatient withdrawal unit.
Secondary	To assess methamphetamine withdrawal symptom severity from Admission Day1 to Day7.	Amphetamine withdrawal questionnaire (AWQ)*.
	To assess methamphetamine craving from Admission Day1 to Day7.	Visual analogue scale for craving (VAS-C)*.
	To assess sleep dysfunction from Admission Day1 to Day7.	Insomnia severity index (ISI)*.
	To assess mood disturbance from Admission Day1 to Day7.	Abbreviated profile of mood states – revised version (POMS)*.
	To assess methamphetamine relapse rates at 1-month post- discharge.	Timeline Follow Back (TLFB28) to assess any relapse in 28 days following detox and number of days of use over past 28 days, based at the 1-month follow-up visit.
	To assess treatment engagement at 1-month post-discharge	Yes/No attendance at any form of treatment.
	To assess therapeutic alliance at 1-month post-discharge.	Working Alliance Inventory-Short Form Revised (WAI-SR).
	To assess safety and tolerability of intranasal oxytocin.	Number of participants with adverse events (AE) related to study drug.
	To assess perceived burden of intranasal oxytocin from Admission Day1 to Day7.	Visual Analogue Scales for Medication Utilisation Burden (VAS-M)*.
Exploratory	To assess social cognition at 1- month post-discharge compared to baseline.	Change in performance on the Facial Emotion Recognition Task (FEEST).
	To assess mentalisation at 1- month post-discharge compared to baseline.	Change in performance on the Reading the Eyes in the Mind Task (RMET).
	To assess social functioning at 1-month post-discharge compared to baseline.	Change in score on the Social Functioning Questionnaire (SFQ).
	To assess change in sleep-wake cycles before, during and after methamphetamine detoxification.	Actigraphy monitoring for 7-days prior, during, and 7-days post- admission.
	To assess change in sleep quality before, during and after methamphetamine detoxification.	Actigraphy monitoring for 7-days prior, during, and 7-days post- admission.
	To assess change in sleep duration before, during and after methamphetamine detoxification.	Actigraphy monitoring for 7-days prior, during, and 7-days post- admission.
	To assess subjective sleep quality at 1- month post-discharge compared to baseline.	Pittsburgh Sleep Quality Index (PSQI).
	To assess rhythmicity of sleep-wake cycles at 1-month post-discharge compared to baseline.	Reduced 5-item Morningness-Eveningness Scale (rMEQ)

*Average score across the participants’ length of stay in the inpatient withdrawal unit.

Participants

Participants (n=10) will be adult females, with moderate-severe MAUD recruited from the community, via online and social media advertising (self-referral), general practitioner (GP) and alcohol and other drug (AOD) clinician referrals, as well as via opportunistic study promotion (using advertising material in hospital/community newsletters, dissemination of study brochures/posters, clinician talks or seminars) to attract a diverse sample of women seeking treatment for MAUD.

Participants are included in the trial only if they meet all the following criteria:

Inclusion

Adult females (aged ≥18 to ≤65 years) (biological sex assigned at birth), admitted to the residential withdrawal unit at Turning Point, a large metropolitan addiction treatment service in Melbourne, Australia.
Meeting DSM-5 criteria for MAUD, moderate or severe (assessed by treating physician on pre-admission to residential withdrawal).
Able to comply with study protocols.
Able to provide informed consent to participate.

Exclusion

Non-English-speaking women.
Women lactating, pregnant or of childbearing potential who are not willing to use an effective means of contraception for the duration of the trial.
Meeting DSM-5 criteria for moderate-severe substance use disorder other than methamphetamine, nicotine and cannabis, as assessed by treating physician on pre- admission to residential withdrawal.
Clinically significant or unmanaged medical or psychiatric illness (e.g., renal insufficiency, cirrhosis, unstable hypertension, unstable diabetes mellitus, seizure disorder, history of DSM-5 psychotic or bipolar disorder, current severe major depression, current suicidal ideation), assessed by treating physician on pre-admission to residential withdrawal.
Current participation in another trial.

Study Procedure

Recruitment and consent process

Participant recruitment commenced on 08 March 2023 and the first participant was enrolled on 23 March 2023. Completion of recruitment is expected within 18 months of commencement. Individuals from all recruitment pathways are subject to a pre-screening telephone interview with research study staff, and if determined to be potentially eligible, they are provided with a copy of the Human Research Ethics Committee- approved Participant Information and Consent Form (PICF) to read. An appointment for the written informed consent process and the full medical screening and baseline assessment is subsequently arranged.

During the Screening visit, potentially eligible individuals are asked to provide written informed consent prior to undergoing a full eligibility assessment at an appointment with a trial physician and study researcher at the study site. Participants are enrolled into the study after the informed consent process has been completed and the participant has been assessed to meet all the inclusion criteria and none of the exclusion criteria.

The screening visit was designed to incorporate information routinely collected at Victorian residential withdrawal pre-admission appointments. Table 2 below (Schedule of Assessments) presents all tasks. Wherever possible, the screening and baseline assessments are performed on the same day.

Standard state-wide Victorian alcohol and other (AOD) drug intake processes apply for inpatient withdrawal admission to the residential withdrawal unit. Upon consenting to participate and to be referred to residential withdrawal, the research team liaise with the individual’s allocated local AOD service to support referral to the withdrawal unit for a 7-day residential withdrawal admission.

Baseline Assessment

Baseline assessment tasks are completed by the study researcher after eligibility is confirmed. At this appointment, participants complete the baseline battery of surveys, including the Social Functioning Questionnaire (SFQ), 28-day Timeline Follow Back (TLFB28), Caffeine Intake Questionnaire (CIQ), Pittsburgh Sleep Quality Index (PSQI), and reduced Morningness and Eveningness Questionnaire (rMEQ). Social cognition is measured via two computer tasks, the Reading the Eyes in the Mind Task (RMET) and the Facial Emotion Recognition Task (FEEST). After the appointment with the participant has concluded, the trial physician completes the Clinical Global Impression - Severity Scale (CGI-S; this measure is not completed with the participant).

Admission and Intervention

Residential Admission

Day 1

At admission to the residential withdrawal unit, the participant has consent verbally re-confirmed by the admitting trial physician. A pregnancy test is completed to re-confirm eligibility, and the participant completes a urine drug screen test. The trial physician then charts oxytocin on the participant’s inpatient medical chart, instructs the participant how to self-administer the oxytocin, and reviews concomitant medications and adverse events (AEs). Vital signs are also taken prior to the first oxytocin administration. During Day 1 of their admission, the participant also completes a brief set of questionnaires/scales, including the Amphetamine Withdrawal Questionnaire (AWQ), Insomnia Severity Index (ISI), Profile of Mood States (POMS), Visual Analogue Scales for Craving (VAS-C), and - Medication Utilisation Burden (VAS-M).

Day 2-7

On Days 2-7 of the participant’s admission, the participant completes a brief set of questionnaires/scales, including the AWQ, ISI, POMS, VAS-C, and VAS-M daily. On Days 3 and 7 only, the participant will also complete the Treatment Satisfaction Questionnaire (TSQ).

Ward medical staff meet with the participant daily and review safety and AEs. In addition, the participants’ concomitant medications and vital signs are recorded. Vital signs are taken once daily in the morning prior to the first oxytocin administration of the day.

The trial team also make telephone contact with each participant on Day 2, 4 and 6 of their admission to monitor compliance with the protocol.

Participants are discharged the morning of Day 8 (there are no trial assessments on this day).

Early Discharge

If a participant chooses to leave the residential unit earlier than planned, they are asked to complete an early discharge form exploring reasons for discharge. The participant’s consent to be contacted for follow-up at 1-month is also confirmed.

Post-Treatment

Follow-up Assessment

Follow-up interviews occur four (up to +2 weeks) weeks post-discharge and are completed in-person at the study site. During the follow-up visit, the participant completes the FEEST and RMET social cognition tasks and a battery of questionnaires and rating scales (refer to Table 1 for the specific questionnaires/scales administered). Their concomitant medications and AEs are also reviewed. Participants are remunerated for participation in the follow-up assessment.

Ancillary and Post-Trial Care

Participants only receive the Investigational Product (IP) during the treatment period of the study; they do not have access to the IP after the treatment phase or upon completion of the study. Participants receive treatment as usual throughout and upon completion of the study.

Schedule of Assessment

Table 2. Schedule of Assessments. An itemised list of measures is included as Appendix.

Study Visit		Pre-Screen	Screening¹	Baseline¹	Admission/Intervention			Follow-Up *(1-month post-discharge)*
			N/A	Day 0	Day 1²	Day 2-6²	Day 7²	Day 36
Visit Window (days)		/	/	-14	0	0	0	+14
PRE-SC	Pre-screen³	X
PICF	Informed Consent		X		X⁴
SCR	Screening (inclusion/exclusion)		X
DEM	Demographics		X
MED	Medical Assessment⁵		X
MINI	Mini Neuropsychiatric Interview⁶		X
AUDIT	Alcohol Use Disorders Identification		X
DUDIT	Drug Use Disorders Identification		X
K10	Kessler-10 Psychological Distress Scale		X
WHO-QOL-BREF	World Health Organization Quality of Life Brief		X
PCL-5	Posttraumatic Stress Disorder Checklist for DSM-5		X					X
SDS	Severity of Dependence		X
SFQ	Social Functioning Questionnaire			X⁷				X
TLFB28	Timeline Follow Back 28 Days			X⁷				X
CIQ	Caffeine Intake Questionnaire			X⁷				X
PSQI	Pittsburgh Sleep Quality Index			X⁷				X
rMEQ	Morningness-Eveningness Questionnaire-Reduced Scale			X⁷				X
CGI-S	Clinical Global Impression - Severity Scale⁸			X⁷				X
CGI-I	Clinical Global Impression - Improvement Scale⁸							X
FEEST	Facial Emotion Recognition			X⁷				X
RMET	Reading the Eyes in the Mind			X⁷				X
OXY	Oxytocin Administration				X	X	X
AWQ	Amphetamine Withdrawal Questionnaire				X⁹	X⁹	X⁹
ISI	Insomnia Severity Index				X⁹	X⁹	X⁹
POMS	Abbreviated Profile of Mood States – Revised Version				X⁹	X⁹	X⁹
VAS-C	Visual Analogue Scale-Craving				X⁹	X⁹	X⁹
VAS-M	Visual Analogue Scale-Medication Utilisation Burden				X⁹	X⁹	X⁹
TSQ	Treatment Satisfaction Questionnaire					X^{10, 9}	X⁹
TELE	Telephone Check-in					X¹¹
LOS	Length of Stay						X
TRE	Treatment Engagement							X
WAI-SR	Working Alliance Inventory-SR							X
UDS	Urine Drug Screen		X		X
PREG	Pregnancy Test		X		X
VS	Vital Signs		X		X¹²	X¹²	X¹²
CONMED	Concomitant Medications¹³			X⁷	X	X	X	X
AE	Adverse Events (SAFTEE)				X	X	X	X
REB	Participant Reimbursement		$50					$100

Wherever possible, the Screening and Baseline visits should be scheduled to occur on the same day.
If the participant chooses to leave the residential unit earlier than planned (i.e., prior to the scheduled 7-days), they will be asked to complete an early discharge form exploring the reasons for discharge; consent for follow-up at 1-month will be re-confirmed.
Individuals from all recruitment pathways will be subject to a pre-screening telephone interview with research study staff. This brief contact will determine participants’ potential eligibility based on the inclusion/exclusion criteria, using the Pre-screening assessment form.
At admission to the residential withdrawal unit, the participant will have consent verbally re-confirmed by the admitting trial physician.
Includes a review of the participant’s medical history, suicide & self-harm risk, mental health, and substance use.
Only the Psychotic Disorders and Major Depressive Episode modules from the MINI are conducted.
Must be completed within 2-weeks of admission to residential withdrawal unit (i.e., no more than 14 days before the Day 1 visit). If the admission date is delayed and the baseline assessments are no longer within this window, they must be repeated. These assessments can be done over the phone; links for the FEEST and RMET tasks can be provided for online completion.
To be completed by the trial physician after the appointment (i.e., not with the participant).
Questionnaire should ideally be completed after oxytocin administration; however this is not a requirement; the questionnaire can be completed at any time during the day. The time the questionnaire was completed should be noted.
Day 3 only.
Days 2, 4 and 6 only; brief telephone call between the trial research assistant and the participant to monitor compliance with the protocol.
Vital signs are taken prior to the first oxytocin administration of the day.
Record all concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the participant in addition to the assigned study treatment from Baseline until the final Follow-Up visit.

Intervention

Description of IP

Syntro Health, a registered compounding chemist are responsible for compounding, labelling and distributing the IP (intranasal oxytocin) for the trial. The IP is prepared as an intranasal solution at a concentration of oxytocin 24IU/50 µL. The formulation also contains glycerol, sorbitol, benzyl alcohol and water for injection. The IP is packaged as a 6mL solution in 10mL amber glass bottles. The bottle is fitted with a manual spray pump and a 50µL actuator. The product is stored at 2-8°C until dispensed.

Administration of IP

On day 1 of admission to the residential admission, the participant is taught by the trial staff the appropriate self-administration technique for the intranasal oxytocin spray. During admission (day 1 to day 7), the participant self-administers the intranasal oxytocin spray twice daily under clinical supervision by the medical team. Administration involves 1 insufflation equating to an active dose of 24 IU twice daily (minimum 8 hours between doses; 48 IU per day) for the duration of their residential admission. A recent systematic review of 17 studies investigating oxytocin for treating substance use disorders reported doses ranging from a single dose of 20 IU oxytocin administered once per day to up to twice daily doses of 40 IU of oxytocin [33]. The medical team document on the ‘Drug Administration Log’ the participants' self-administration of the IP and this is confirmed by the research team to ensure the IP is only used in accordance with the trial protocol.

Participants can self-discharge from the residential withdrawal unit at any point during the 7-day admission; the participant will only receive the IP while an inpatient.

Assessments

A list of all questionnaires, rating scales and tasks are included as Appendix.

Biological tests

Urine - pregnancy test (urine hCG).
Urine - urine toxicology (dipstick).
Vital Signs - blood pressure, pulse, temperature, respiration rate.

Clinical Reports

Concomitant medications: all concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the participant in addition to the assigned study treatment, recorded from Baseline until the final Follow-Up visit.
Assessment of Adverse Events (AEs)- elicited from daily nurse ward manager general inquiry and self-report from participant. All reported AEs will be reviewed by a Trial Physician.

Data management plan

Study participants are assigned a unique code to enable data linkage throughout follow-up. All data gathered are entered, under the participant’s code, onto a password-protected secure web-based application (REDCap). All participant data is considered confidential and is treated as such with no interference or access to REDCap without the researchers’ permission. Data collection compliance and monitoring to be completed regularly by a designated research staff member.

All data collected during the study will be retained by the sponsor for a period of 7 years as outlined in the Australian Code for the Responsible Conduct of Research. Once the retention period has been reached, the data will be shredded so that the information remains confidential. Electronic versions will be deleted from all electronic media.

Data Analysis

This proposal is for a pilot, proof of concept study designed to assess whether intranasal oxytocin is a feasible treatment option for female adults with MAUD. As this is a pilot study, it is not powered to detect differences in treatment efficacy. This study will therefore seek to enrol 10 participants, conventional for studies of this nature [34]. A recent open label feasibility study investigating inpatient methamphetamine withdrawal also recruited 10 participants [35]. Findings will inform planning for a large-scale RCT of oxytocin for treatment of methamphetamine withdrawal.

Statistical Methods

Analyses will be undertaken using Stata Version 16 (Statacorp, College Station, TX 2019). Descriptive data on outcomes will be presented. Means and standard deviations will be reported for normally distributed outcomes. Medians and inter-quartile ranges will be presented for skewed data. Comparisons will be made using t-tests for continuously distributed outcomes, Kruskal-Wallis tests for skewed continuous outcomes, and categorical variables will be compared using a Pearson’s Chi Square test. The proportion of screen failures and participants who commenced study drug; proportion who achieve each dose; and proportion who are retained in the study or revoke consent will be analysed. The study will be deemed feasible if the screen failure rate is above 20%, as reported in a similar inpatient methamphetamine withdrawal study [35]. Secondary outcomes will be analysed using an intent-to-treat approach, and secondary per protocol analyses for all participants who received at least one dose of intranasal oxytocin.

Safety Analysis

Safety analyses will report the number and percentage of participants reporting AEs and SAEs related to the study drug, consistent with measures across NIDA/NIH clinical trials in addiction. AEs will be summarised by system organ classes and preferred term.

The present protocol described a currently recruiting proof-of-concept open-label pilot trial aiming to reduce withdrawal symptoms and craving for methamphetamine, and to increase treatment engagement in women with MAUD. This research directly addresses a serious public health problem for which innovative interventions are urgently needed. Oxytocin as a therapy could be a valuable candidate therapeutic as it has no abuse potential, potent anxiolytic effect and may facilitate treatment engagement and long-term abstinence. Pre-clinical evidence in addiction has thus far been promising, and there is consistent evidence that centrally administered oxytocin can reduce ‘relapse’ to stimulant use in animal models. Translation to human samples has been less clearcut, though results have been supportive of beneficial effects in other substance use disorders [13, 33].

The only clinical trial on oxytocin in MAUD to date recruited a male-only sample [14]. Results showing improved treatment engagement were promising, yet there were no significant changes in craving nor methamphetamine usage. The present study will expand on this to examine the oxytocin’s effects in a female-only sample. Given the known sex-differences in the endogenous oxytocin system and in addiction-related behaviours, this discernment between sexes is critical to determine whether there are sex-specific effects.

This proof-of-concept trial also aims to inform estimated effect size and planning of a larger clinical trial, including collection of pilot validation data for the secondary and exploratory measures.

Strengths and Limitations

This pilot study is designed to assess feasibility and safety, and to provide preliminary efficacy data on intranasal oxytocin for MAUD withdrawal, and will also inform potential mechanisms through which oxytocin may ameliorate withdrawal symptom severity, whether it be changes in social connectedness, mood, or sleep. While the sample size is too small to draw definitive conclusions regarding the clinical applicability of oxytocin during methamphetamine withdrawal, collection of this preliminary data will provide evidence for the design of larger scale powered randomised controlled trials in the future.

This female-specific study is critical: although drug use is more common in men than women [36], women tend to initiate use at a younger age, and to display a telescoping phenomenon in stimulant use, wherein the progression from use to dependence occurs more quickly than it does in men [37]. Women report experiencing greater craving, greater difficulty abstaining from using drugs, and greater rates of relapse and use post-relapse than men [38]. This pilot study will thus address the significant gap in research regarding clinically important sex differences in relation to MAUD.

This research also investigates the often-overlooked social behaviour deficits associated with early recovery in MAUD by assessing treatment engagement as well as changes in social processing and connection. The development of new social networks is a cornerstone of successful recovery [8] and forging a strong therapeutic alliance with treatment providers is one of the strongest predictors of positive long-term prognosis for substance use disorder [9]. Exploration of social functioning and emotional recognition post-withdrawal will provide an evidence base for further investigation in MAUD treatment and recovery.

Limitations of this study include the lack of comparison group and small sample size; however, as this is the first time this medication has been used for this indication in an inpatient setting, a single-arm un-blinded pilot study approach is appropriate.

The authors expect to see an increase in the length of stay (LOS) in the residential withdrawal unit (compared to the MATES study median LOS duration of 5 days) [5]. Selection of length of stay as an endpoint may present a study limitation. Research into withdrawal treatment outcomes suggests that completion of drug withdrawal treatment is multifactorial. A myriad of reasons exist as to why an individual may not complete a 7-day inpatient withdrawal program, not limited to withdrawal symptom severity and / or drug craving. Reported assessments of outcomes have mainly concerned psychological (e.g., craving, mental health) and biological markers (e.g., withdrawal symptom severity, biomarkers), with social outcomes (e.g., homelessness, quality of social or family relationships) rarely measured [39]. The study accounts for this potential constraint by assessing numerous secondary objectives to ascertain the mechanisms of action of oxytocin, which could contribute to length of stay.

Dissemination

Dissemination of findings to the research community will be via peer-reviewed publications and conference presentations. Participants can elect to receive a summary of the group results when they are available.

Outcomes from this proof-of-concept study will ascertain feasibility and inform endpoints of a full-scale randomised clinical trial, as well as provide preliminary data on the possible mechanisms underlying the putative therapeutic effects of oxytocin. Furthermore, the study will build critical research capacity in female-specific MAUD treatment, potentially reducing the clinical burden of MAUD by reducing craving and withdrawal symptoms, thereby improving key patient outcomes.

Ethics approval and consent to participate

This study will be carried out according to the Declaration of Helsinki, the NHMRC National Statement on Ethical Conduct in Research Involving Humans (1999) and the Notes for Guidance on Good Clinical Practice (GCP) as adopted by the Australian Therapeutic Goods Administration (2000) (CPMP/ICH/135/95) and the ICH GCP Guidelines. This protocol and the informed consent document, and any subsequent modifications, have been reviewed and approved by the Eastern Health on the 3/9/2021 (HREC ERM Project ID: 75603; Eastern Health Site Reference Number: E21-014-75603). Written informed consent will be obtained from all participants, per approval from the HREC. A letter of protocol approval by the HREC has been obtained prior to the commencement of the study. Regulatory approval has been given by the TGA- CTN (Clinical Trial Notification) scheme.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable. This paper does not include any data as it is a protocol paper. When data is collected, we ask that readers please request it from the lead author.

Competing interests

There are no competing interests to report. SA is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (GNT2008193)

Funding

This trial is funded by a seed funding grant to A/Prof Arunogiri and awarded by the National Centre for Clinical Research on Emerging Drugs (NCCRED), which is funded by the Commonwealth Department of Health.

Authors' contributions

SA was responsible for funding acquisition, conceptualisation, and methodology, and contributed to writing and reviewing this manuscript. SC authored the original draft of this manuscript, and SC and EB contributed to methodology, study design and data collection. RM, VM, GB & DL contributed to the conceptualisation and methodology, and reviewed this manuscript.

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19 Jul, 2024
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Protocol for an open label pilot study of intranasal oxytocin for methamphetamine withdrawal in women (mOXY trial)

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Abstract

Background

Materials and Methods

Participants

Study Procedure

Recruitment and consent process

Baseline Assessment

Admission and Intervention

Post-Treatment

Schedule of Assessment

Intervention

Description of IP

Administration of IP

Assessments

Biological tests

Clinical Reports

Data management plan

Data Analysis

Statistical Methods

Safety Analysis

Discussion

Conclusion

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors' contributions

References

Supplementary Files

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