Background-justification

Cannabis is the most commonly abused psychoactive substance, under international legal control.^[1]In 2018, an estimated 192 million people aged 15-64 years used cannabis for nonmedical purposes globally.^[1]The Global Burden of Disease study (2010) estimated that, across the globe, there were more than 13 million people with cannabis dependence.^[2] Moreover, the same study calculated that cannabis dependence could be accounted for 2 million Disability Adjusted Life Years (DALY), globally. This was an apparent increase of 22% since 1990. Another recent review, covering 195 countries and territories estimated nearly 1 million DALY could be attributed to cannabis dependence (or use disorders).^[3] Another important point to note that cannabis dependence mostly affects young adults (20-24 years) and thus could have significant negative impact on the growth and productivity of not only these individuals but also to the societies and nations.^[2]

From the global, let us zoom in to the national scenario. Cannabis is the most commonly misused illicit drugs in India as well. As per the National Household Survey (NHS), the estimated number of cannabis users in the country, was around 8.75 million.  Among them, 25.7% were dependent on cannabis. Therefore the number of dependent cannabis users would be around 2 million.^[4]

In addition to the dependence syndrome, cannabis use is associated with increased risk of psychosis, cognitive dysfunction, academic problems, and road side accidents.^[5]

Despite this huge burden attributed by cannabis dependence, there is no approved medication to treat this disorder. Psycho-social management which are found to be useful are resource intensive.^[6] Research on Repetitive Transcranial Magnetic Stimulation (rTMS) for the treatment of substance dependence showed encouraging results so far, especially with regard to the reduction of craving for drug use. The effect size is modest and the efficacy does not seem to differ significantly across various substances.^[7]There is limited evidence on the persistence of rTMS addiction treatment effects, as few studies include follow-up visits after the end of treatment. Randomized trials on patients with alcohol and cocaine dependence had shown persistent reduction of craving even after 1-2 months of ten sessions of high frequency rTMS.^[7,8] However, another trial on nicotine dependence failed to show any persistent effect.^[9]So far, most of the studies have stimulated (through high frequency rTMS) the left dorsolateral pre-frontal cortex (DLPFC) because of its role in substance craving.^[7] Stimulation of DLPFC has been found to increase the level of dopamine level in the subcortical regions, especially the nucleus accumbens and might influence the prefrontal glutamate transmission. Both these mechanisms might explain its role in cue induced craving.^[10] As craving perpetuates drug use and might trigger a relapse, reduction of craving by rTMS is likely to reduce both the drug use and the propensity of relapse.^[11]

The only study of rTMS on cannabis dependence, published of late, had investigated the safety and feasibility aspects and found that rTMS was well tolerated but single session of rTMS might not reduce craving in individuals with cannabis dependence.^[12]  In this background, we would like to conduct a randomized-controlled trial to investigate the effect of ten sessions of high frequency r-TMS in the left DLPFC on the reduction of craving for cannabis use in patients with cannabis dependence. To see the persistence of the effect, we will assess craving for cannabis after four weeks of completing the intervention. We would also like to see, whether the reduction of craving is associated with reduced cannabis use. We will examine the safety profile of rTMS as well.

Novelty of the research

This would be the first randomized controlled trial to determine the efficacy of the repetitive transcranial magnetic stimulation in the patients with cannabis dependence.  

Hypothesis

Superiority hypothesis- Repetitive Transcranial Magnetic Stimulation(r-TMS) in the left dorsolateral prefrontal cortex (left DLPFC), added on the standard of care will be superior to sham stimulation (on standard of care) with regard to the reduction of craving in participants with cannabis dependence.

Research Question

Does ten sessions of the high frequency r-TMS in the left DLPFC reduce craving (with a effect size of 0.5, i.e. modest) as compared to the sham stimulation, when added on the standard of care in participants with cannabis dependence seeking treatment in a tertiary care centre?

Patient= adults (18-60 years) with cannabis dependence (as defined in the International Classification of Diseases-10), seeking treatment in the Drug Deaddiction& Treatment Centre and Department of Psychiatry, PGI, Chandigarh 

Intervention= Ten sessions of repetitive high-frequency TranscranialMagnetic Stimulation(r-TMS) in the left dorsolateral prefrontal cortex (left DLPFC), added on the standard of care

Control= Sham r-TMS, added on the standard of care

Outcome= Primary outcome is reduction of craving; secondary outcomes are reduction of cannabis use, and side effects of the intervention

Time= outcomes will be assessed 4 weeks after the last session of the intervention

Study type= single blind randomized placebo controlled trial

Aim

To study the efficacy of repetitive transcranial magnetic stimulation among adult participants with cannabis dependence

Objectives

Primary: To compare the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) in the left dorsolateral pre-frontal cortex (DLPFC) [active rTMS] and the sham rTMS on intensity of craving, in patients with cannabis dependence

Secondary:

1.    To study and compare the effect of active and sham rTMS with regard to reduction of cannabis use

2.    Comparison of adverse effects in both the groups

Methodology

Study population

We will select subjects from both the out-patient and the inpatient of the Drug De-addiction and Treatment Centre (DDTC) and Department of Psychiatry. The eligibility criteria for the subjects will be as follows-

Inclusion criteria

1.    Diagnosis of cannabis dependence (as per ICD 10)

2.    Age between 18 to 60 years

3.    Right handed

 Exclusion criteria

1.    Current Co-morbid depressive disorder (Hamilton Depression Rating scale > or = 7)

2.    Current psychosis: Any one of three Positive and Negative Syndrome Scale subscales (positive, negative, general psychopathology) with a mean score of ≤2 (minimal) at a single time point evaluation

3.    History of neurological illness, especially epilepsy

4.    Contraindications to rTMS  (cardiac pacemakers, aneurysm clip, cochlear implants, history of metal fragment in eyes, claustrophobia, orthodontic braces)

Study design

It will be a randomized control trial, where the participants will be randomly allocated to either receive the active intervention (rTMS) or the sham intervention, added on the standard of care. 

Operational definition

We will use the International Classification of diseases 10^th version (ICD-10) criteria for the diagnosis of cannabis dependence. Primary outcome craving will be measured with a standardized scale discussed below.

Sampling procedure

Group allocation

We will allocate the eligible participants to either active r-TMS group or the sham r-TMS group with a 1:1 ratio between the groups. We will use permuted block randomization with random block size, to ensure equal number of allocation in both the groups and allocation concealment.

Allocation concealment

Random block size (ensure unawareness of the next participant’s group assignment while allocation) and ssequentially numbered opaque sealed envelopes (SNOSE) methods will be used for the allocation concealment.

Blinding: Single blind

Participants will be blind to the intervention to minimize the errors in classification of exposure.  Investigator and the assessor of the final outcome will also be blinded to minimize the errors in classification of outcome. However, research assistant administering the rTMS will not be blind.

Sample size:

Till now there is no published clinical trial on the efficacy of rTMS in cannabis dependence.  The only trail, published in 2018 was on feasibility and safety of rTMS.^[12] We expect rTMS to have a modest effect (effect size = 0.5) on the reduction of craving. To have a power of 80%, an expected level of significance (alpha value) 5%, and equal number of participants in both the groups, each group should consist of 64 subjects.  We also assume a 20% drop out. Therefore the total number of subjects to be recruited would be 160, i.e. eighty in each group.

[Formula used for sample size calculation: n = (1+r) X

For taking into account drop out: N = n/ (1-D)

N= Final sample size; n= sample size without considering drop-out;  r= ratio of two groups; d= effect size; a= alpha=0.05; b=beta=0.8; D= proportion of drop out]

Data collection:

We will administer three groups of instruments. The first group, to assess eligibility for the study, second is to assess the outcome parameters, and the third is to assess potential confounders. The first four instruments, mentioned below will be administered to assess for eligibility. 

Edinburgh Handedness Inventory (EHI)

Those subjects with a diagnosis of cannabis dependence would be subjected to this scale. It is a brief and easy to use method for quantitative assessment of handedness. It is a self- rated questionnaire with dichotomous responses to an inventory of 10 items of everyday habit which allow for distinction in laterality.^[13] We will recruit only right handed subject. This is required as we will administer rTMS on the left (dominant)-dorso-lateral prefrontal cortex.

The Mini International Neuropsychiatric interview (MINI)

This instrument will be applied in all potential participants.

The Mini-International Neuropsychiatric Interview (M.I.N.I) was developed to meet the need for a short and accurate structured psychiatric interview for multicentre clinical trials and other studies. It comprises of 17 modules to, each targeting common Axis 1 disorders. It is compatible with the Diagnostic and Statistical manual-IV (DSM-IV) as well and the International Classification of Disease (ICD-10) for psychiatric disorders. The test is available in several languages and would be well suited to our interview as it is available in Hindi as well. The questions are phrased to prompt “yes” and “no”answers and It is comprehensive, covering major diagnostic categories with high sensitivity. Being fully structured it can be administered by a non-specialised interviewer and is a pen and paper test and takes on average 15- 21 minutes to administer.^[14] This instrument will be applied for the diagnosis of cannabis dependence and other psychiatric co-morbidity.

Positive and negative syndrome scale (PANSS)

This instrument will be used only in those subjects with a diagnosis of psychotic illness in the MINI. PANSS was developed for an objective rating of the positive and negative symptoms and global psychopathology of schizophrenia. Its assessment consists of 30 psychiatric parameters, divided as Positive and Negative consisting of 7 each and the remaining 16 designated to a General Psychopathology Scale. The test takes on average about 45-50 minutes to administer and does require training. As per the guidelines laid down by the Remission in Schizophrenia Working Group in 2003, an absolute threshold of the severity of diagnostic symptoms was used as compared to percentage improvement. As per these guidelines the symptoms severity when rated on PANSS must consider the following 8 items – delusions (P1) Conceptual disorganization (P2) Hallucinatory behaviour (P3) Blunted affect (N1) Social Withdrawal (N4) Lack of Spontaneity (N6) Mannerisms/Posturing (G5) and Unusual thought content (G9). The ratings on each item must be mild or less i.e. a score of < 3 and this must be maintained for a period of 6 months duration following which a patient may be said to be in remission.^[15] We will recruit subjects who are in remission, as assessed by this instrument.

Hamilton depression rating scale (HDRS)

We will administer this instrument in subjects with depressive episode in MINI. It consists of 21 items. Total score range from 0-54. It is a Clinician rated scale. It is not standard tool to include neuro-vegetative symptoms. It takes around 10 minutes for its assessment. The reliability is good (Internal Consistency is 0.48- 0.92). ^[16] To ensure remission, subjects with score less than or equal to 7 will be recruited for the study.

Marijuana craving questionnaire (MCQ)

MCQ will be used to measure craving which is the primary outcome of our study. It is a seventeen item instrument, where the items are to be scored in a seven point Likert scale (from strongly disagree to strongly agree). Higher score in MCQ indicates higher severity of craving. It measures instantaneous craving. All the eligible subjects would be assessed by the MCQ.^[17]

Timeline follow-back (TLFB)

TLFB is a clinical and research tool, used for the quantitative assessment of the various drugs of abuse, including cannabis. TLFB will be used to assess one of the secondary outcomes, i.e. reduction of the use of cannabis. We will use the interviewer administered version and ask participants for retrospective estimation of their cannabis use, over last one month. TLFB can give reliable estimate for past seven days to last 2 years. ^[18]

Urine chromatographic immune assay for tetrahydrocannabinol (THC)

This will be supplementary information to the TLFB method. It gives test result within ten minutes. Participants with about a month of abstinence from cannabis should produce a negative immune-assay.

Assessment of adverse events

There is no structured instrument for the assessment of adverse events due to rTMS.We have incorporated a list of side effects in the Appendix section.

Severity of dependence scale (SDS) for cannabis

It measures the use of cannabis in last 3 months. It has five items. SDS is a 4-point Likert scale. Higher score indicate higher severity of cannabis dependence. This is to be administered by the interviewer and requires minimal training. This instrument will also be applied in all the participants because severity of cannabis dependence is a potential confounder.^[19]

Other clinical variables (age of onset of cannabis use, duration of dependence) which can confound the study results will also be assessed by clinical history.

Table: Assessment protocol of eligible participants

MCQ- Marijuana craving questionnaire; TLFB- Timeline follow-back; SDS- Severity of dependence scale; THC- Tetrahydrocannabinol

Details of the intervention (rTMS or sham)

We will administerrTMS with the help of Magstim rapid2 rTMS machine using a figure of 8 coil. The area of the brain to be targeted is the left dorso-lateral prefrontal cortex (DLPFC). DLPFC will be identified by the 10-20 EEG system. The motor threshold (MT) for the left abductor pollicis brevis (APB) will be determined using the visual method. The lowest intensity that is enough to produce a visible twitch in 5 out of 10 stimuli will be considered the motor threshold. Ten daily sessions of rTMS treatments will be administered over the left DLPFC (at 110% of the MT determined) with figure-of-eight coil. High-frequency (10 Hz) stimulation will be administered for 4 seconds per train, with inter-train interval of 26 seconds, and a total of 25 trains per session. Each patient will receive 1000 pulses per day.

The sham group will be administered rTMS with the same parameters, at the same site using a sham coil which is available with the investigators.

Standard of care

All participants will receive standard relapse prevention therapy sessions (six sessions) focussing on ways to deal with high-risk situations, management of craving, lifestyle changes, building up an alternative social network, and lapse management strategies. We will adhere to the module developed by the NIMHANS, Bangalore. ^[20] 

Statistical analysis

We will do data analysis by the Statistical Package for Social Sciences (SPSS version 14 for Windows). Intention to treat analysis (ITT)will be used to account for drop-outs and to minimize misclassification bias. ITT will also help in minimizing the effect of confounders (which has been initially minimized by random allocation). Independent-sample t-test to test the group differences in clinical (including the severity of dependence, age of onset and duration of cannabis use, i.e. potential confounders) and socio-demographic characteristics between the active and sham groups. Any clinical or demographic variables which are significantly different between the groups will be used as co-variates in the final multivariate analysis. Generalized estimating equation (GEE) will be used to examine the group differences and group X time effect. Appropriate confounding variables will be entered as co-variates. 

Project implementation (including quality assurance)

We will employ a clinical psychologist and a project technician. The clinical psychologist will do all the assessments and the project technician will administer the rTMS after a training period of one month. Training will be done by the investigators (AbhishekGhosh and Shubh Mohan Singh). Even after a period of one month, for another month the project technician will administer rTMS under supervision of a senior resident (a qualified psychiatrist, posted in the rTMS clinic of our department). The clinical psychologist will apply the entire research instruments. The outcome measures will be assessed by the clinical psychologist who will remain blind about the intervention. The PI will reassess at least 5% of the subjects who were excluded from the study and another 5% of whom had met the selection criteria, to ensure the fidelity of selection in the study. PI (or other investigator) will meet both the research workers on a weekly basis to check the completeness and correctness of the data and to address doubts. Incomplete data will be entered during the next assessment of the participant. The PI (or other investigators) will also reassess the outcome parameters in at least 5% of the participants. The data entry will be done by the clinical psychologist and partial data cleaning will done in an ongoing basis.

We expect that we will be able to recruit 160 participants over a period of 2.5 years. Data entry in the SPSS will be ongoing. We will need around 6 months to analyze, interpret the data, and to write a project report. 

Bias and limitations

To take care of confounders, the study sample will be randomized to receive (or not receive) the intervention. It will preferably distribute the confounders randomly in both the groups. However, at the end of the study, we will compare the groups with regard to potential confounders (clinical and demographic). Should we find significant differences in some parameters, these variables will be entered as co-variates in the generalized estimating equation (GEE). The intention to treat analysis is also likely to maintain the random distribution of confounders. We will try to minimize the drop-out to 20%. As it is a short-term follow up study, we are likely to achieve this goal. To prevent misclassification bias, the project technician (who will administer rTMS/sham stimulation) will undergo rigorous training (as explained in the previous paragraph) to have stringent adherence with the protocol. However, to technical reason we will not be able to blind the technician. However, we will blind the outcome assessor (the clinical psychologist). This should reduce the misclassification bias to a large extent. We acknowledge that the instruments to be used for outcome assessment will mostly be subjective, which could increase the chance of bias. However, supplementary assessment by the urine chromatography should provide an objective evidence for individuals who will be abstinent for the last one month. 

Ethical statement (Human participants’ protection)

In our study we will adhere to the National Ethical Guideline for Biomedical and Health Research Involving Human Participants (2017) by the Indian Council for Medical Research (ICMR), and Helsinki declaration (modified 2000), the following will be adhered in all patients enrolled in the study:

1. We will obtain a written informed consent from all the study participants.

2. Subjects will be informed of the aims, methods, the anticipated benefits and potential risks of the study and the discomfort it may entail to her if any and the remedies for the same.

3. Participants will have the right to withdraw consent at any stage.

4. No invasive procedures will be carried out as part of this study.

5. Risk to the participants: Caution and care shall be exercised at all stages of the study to ensure that the risk to the subjects is minimal and that they suffer from no irreversible adverse effects and generally, benefit from and by the study.rTMS has only minor side effect like mild and transient headache, and tingling sensation in the scalp. Seizure is a rare but serious side effect and seen only in vulnerable individuals. We will exclude participants with diagnosed epilepsy or other neurological illness- further minimizing the risk of seizure.

6. Benefits to the participants: We expect the intensity of craving to reduce among those undergoing the active intervention. This might also reduce cannabis use. Both the groups will receive the standard of care, consisting of psycho-social treatment.

7. Collection of biological specimen: urine sample will be collected for the immune-assay. The residual sample will be discarded immediately after the test.

8. Participants will be informed that unwillingness to participate in the study would not result in any change in treatment.

9. No additional benefits other than stated above will be provided to the participants as part of the study.

10. Strict confidentiality will be maintained.

11. Approval will be sought from the Ethics Committees of the Institute in which this study will be conducted.

Expected benefits

Till date there is no approved medication for cannabis dependence and approved psycho-social interventions are labour intensive. Therefore if rTMS is found to be found efficacious in this adequately powered and optimally designed randomized controlled trial, it could be used for cannabis dependence. With a few more replication, Repetitive Transcranial Magnetic Stimulation might also find its place as an approved treatment for cannabis dependence.