Journal of Psychopharmacology

Journal of Psychopharmacology http://jop.sagepub.com

Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study AR Winstock, T. Lea and J. Copeland J Psychopharmacol 2009; 23; 84 originally published online May 30, 2008; DOI: 10.1177/0269881108089584

The online version of this article can be found at: http://jop.sagepub.com/cgi/content/abstract/23/1/84

Published by:

http://www.sagepublications.com

On behalf of:

British Association for Psychopharmacology

Additional services and information for Journal of Psychopharmacology can be found at:

Email Alerts: http://jop.sagepub.com/cgi/alerts

Subscriptions: http://jop.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.co.uk/journalsPermissions.nav

Citations http://jop.sagepub.com/cgi/content/refs/23/1/84

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 Original papers

Lithium carbonate in the management Journal of Psychopharmacology 23(1) (2009) 84–93 of cannabis withdrawal in humans: © 2009 British Association for Psychopharmacology ISSN 0269-8811 an open-label study SAGE Publications Ltd, Los Angeles, London, New Delhi and Singapore 10.1177/0269881108089584

AR Winstock National Drug and Alcohol Research Centre, University of New South Wales; and Drug Health Services, Sydney South West Area Health Service, Camperdown, New South Wales, Australia. T Lea National Drug and Alcohol Research Centre, University of New South Wales; and Drug Health Services, Sydney South West Area Health Service, Camperdown, New South Wales, Australia. J Copeland National Cannabis Prevention and Information Centre, University of New South Wales, Randwick, New South Wales, Australia.

Abstract

Cannabis is the most widely used illicit substance in the world. Estimates mean of 107 days following treatment. The mean percentage of days suggest that approximately 10–20% of cannabis users meet criteria for abstinent in the period between treatment cessation and follow-up was cannabis dependence and a significant proportion experience withdrawal 87.57%. Twenty-nine percent of participants (n = 5) reported continuous discomfort on cessation of use. To date, there has been an absence of any abstinence that was biochemically verified at follow-up. Agreement clinically validated treatments to manage withdrawal. The current study is between self-reported cannabis use and urinalysis at follow-up was an open-label trial exploring the utility of lithium carbonate for the moderate (κ = 0.47). Significant reductions in symptoms of depression and management of cannabis withdrawal symptoms in treatment seeking adult anxiety and cannabis-related problems were also reported. This study humans. In total, 20 participants were recruited to the study (19 men). All provides evidence for the potential clinical utility and safety of lithium in met DSM-IV cannabis-dependence criteria and had been smoking cannabis the management of cannabis withdrawal. A randomised, placebo- daily or almost daily for a mean 9 years. Participants were admitted to an controlled trial is recommended. inpatient detoxification facility and prescribed lithium 500 mg b.d. for 7 days. Cannabis withdrawal was assessed daily with the Marijuana Withdrawal Checklist (MWC). Two participants were withdrawn from the trial because of possible adverse effects. Sixty percent of participants Key words completed the 7-day treatment program. Follow-up was conducted at a depression; cannabis; dependence; lithium; withdrawal

Introduction ment for cannabis as the main drug of concern increased from 4% in 1990 to 22% in 2004 (AIHW, 2005). Estimates suggest that approximately 10–20% of cannabis Cannabis is the most widely used illicit substance in Australia users meet criteria for cannabis dependence (Swift, et al., with approximately one-third of the population having ever 2001). In addition, there is a growing consensus concerning used it (AIHW, 2005). Worldwide its use is increasingly recog- the existence and clinical relevance of a distinct entity of can- nised as a source of morbidity, with recent concerns focusing nabis withdrawal (Smith, 2002; Budney, 2006; Budney and on its contribution to psychosis in young people (Degenhardt, Hughes, 2006). Recent clinical studies indicate that more than et al., 2003; Semple, et al., 2005; Fergusson, et al., 2006). In half of dependent cannabis users do experience several with- Australia more disability-adjusted healthy years of life were drawal symptoms on cessation of regular use (Copeland, estimated to have been lost in 1996 because of cannabis use et al., 2001a; Budney, et al., 2004; Vandrey, et al., 2005; Bud- and dependence (4416 years) than to HIV, Hepatitis B and ney and Hughes, 2006; Copersino, et al., 2006). Symptoms Hepatitis C combined (2189 years) (Mathers, et al., 1999). In commonly experienced include sleep difficulty, increased addition, there is a growing demand for cannabis treatment anger and aggression, decreased appetite and weight loss, irri- locally and internationally. In Australia, people seeking treat- tability, nervousness and anxiety, and restlessness (Budney,

Corresponding author: Dr Adam R Winstock, Drug Health Services, Page Building, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, 2050, Australia. Email: [email protected]

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 Lithium and cannabis withdrawal 85

et al., 2004). As with other drug withdrawal syndromes, aver- function and poor literacy. Another seven were eligible and sive symptoms may be a barrier to attaining abstinence and either declined to participate or could not be contacted. One may motivate continued use through negative reinforcement participant was eligible and commenced on treatment but was for some users. Accepting the significant adverse psychological withdrawn on day 2 as he was administered an anti-emetic and physical consequences of chronic use, investigators have medication by a new medical officer, unaware that its adminis- begun to explore potential pharmacological interventions to tration would result in the patient being excluded from the address these symptoms and to support increased rates of absti- study. Therefore, data for this participant is not included. No nence. A number of medications have been initially examined participant reported that they had ever been prescribed lithium in recent years as adjuncts to managing cannabis withdrawal, before entering the study. including buspirone, bupropion, nefazodone, divalproex sodium and oral THC (Haney, et al., 2001; Haney, et al., 2003; Haney, et al., 2004; Levin, et al., 2004; McRae, et al., Assessment 2006; Budney, et al., 2007). With the exception of oral THC, Clients seeking treatment for cannabis use from counselling none of these medications have been found to be effective in services at Drug Health Services, SSWAHS are assessed by a reducing a broad selection of experienced symptoms. counsellor using a standard clinical assessment tool covering A preclinical study investigating the effects and mechanism drug use history, previous drug treatment, personal history, of lithium on cannabinoid withdrawal in rats reported that lith- treatment planning and evidence of intoxication, dependence ium inhibited the development of withdrawal symptoms in rats and withdrawal. During the study period, in addition to the pre-treated with a synthetic cannabinoid agonist (Cui, et al., standard assessment, counsellors completed a brief eligibility 2001). The authors proposed that it was increased oxytocin checklist with all cannabis clients presenting for treatment. Cli- levels, consequent with pre-dosing with lithium, which negated ents were eligible to participate if they were between the ages of the symptoms of the withdrawal syndrome. A subsequent small 18 and 55, met DSM-IV criteria for cannabis dependence in the (n = 9), community-based, open-label study of the effects of preceding 12 months, and identified experiencing withdrawal lithium on non-treatment seeking individuals, meeting DSM- symptoms as a barrier in achieving abstinence. Clients were IV criteria for cannabis dependence, reported a variable not eligible to participate if they: 1) were alcohol dependent; response (Bowen, et al., 2005). Lithium has been used exten- 2) used drugs other than cannabis more than twice weekly or sively within psychiatry for over 30 years and is effective in a injected drugs more than once a week; 3) had a history of range of affective disorders, most commonly in the manage- schizophrenia or psychosis; 4) were at significant risk of sui- ment of acute mania and as maintenance therapy for bipolar cide; 5) had abnormal liver, renal or thyroid function; 6) were affective disorder (Tondo, et al., 1998; Geddes, et al., 2004; currently prescribed antidepressant, antipsychotic or mood sta- Ferrier, et al., 2006). The findings of preclinical and human bilising medications; 7) were currently prescribed opioid phar- trials have not supported the role of other mood stabilising macotherapies or 8) had very poor literacy. Female clients, medications as potential therapeutic agents for the alleviation who were breastfeeding, pregnant or planning on becoming of cannabis withdrawal (Cui, et al., 2001; Haney, et al., 2004). pregnant in the following month, were not eligible to The current study is an open-label inpatient trial that aimed participate. to investigate the safety, acceptability and potential utility of Clients meeting eligibility criteria were informed about the lithium carbonate in the management of cannabis withdrawal in treatment-seeking adults. This study was approved by the trial and referred to a medical officer to confirm eligibility and human research ethics committees of Sydney South West to conduct a medical assessment. Medical assessment included Area Health Service (SSWAHS) and the University of New a full clinical history, physical examination, a review of the ’ South Wales. patient s mental state and drug use history. A blood sample was taken to assess liver, renal and thyroid function. Blood results were reviewed within 48 h. Clients who were ineligible Methods and materials or who were unwilling to participate were referred back to their counsellor to devise an alternative treatment plan. A commencement date was arranged with eligible and will- Sample ing clients and a research interview was conducted to collect Participants were 20 adults seeking treatment for cannabis baseline information. Clients were provided with an opportu- dependence at Drug Health Services, SSWAHS, recruited nity to discuss the trial and written informed consent was between September 2005 and May 2006. Participants were obtained. recruited via existing referral pathways and community announcements placed in local newspapers. Thirty-four partici- Treatment pants were assessed for entry into the trial. Of these, six were excluded because they did not meet eligibility criteria – two Participants were admitted to an inpatient drug detoxification because of other substance dependence, two because of psychi- facility in SSWAHS and administered supervised lithium car- atric comorbidity and one each because of abnormal thyroid bonate 500 mg b.d. for 7 days. Dosing times were 8 a.m. and

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 86 Lithium and cannabis withdrawal

4 p.m. On the day of admission, lithium was administered at study, if the symptoms were considered to be related to lithium 10 a.m. and 6 p.m. The dose of lithium used in this study was or were of significant enough severity to warrant further inves- within the range typically used in psychiatric practice and tigation and/or the provision of other medication. In all such selected on the basis of achieving plasma levels within the ther- cases, the Chief Investigator was notified. apeutic range (0.5–1.5 mmol/L) (Caswell, 2005) while minimis- Blood samples were taken from all participants on day 4 ing the risk of precipitating lithium toxicity. The dose and and 7 of inpatient treatment to determine whether trough duration chosen was also informed by discussion with the serum lithium levels were within the therapeutic range research group who conducted an earlier human trial (Zhang, (0.5–1.5 mmol/L). Urine samples were taken on day 1 and 7 2005 [personal communication]). Although adverse effects can to confirm abstinence from cannabis. Day 1 urinalysis included occur in patients with serum levels below 1.5 mmol/L, the inci- immunoassay for amphetamines, benzodiazepines, cocaine and dence of acute severe reactions with short-term treatment is opiates, and immunoassay for cannabis with confirmation and rare (Coppen, et al., 1983; Price and Heninger, 1994; Caswell, quantitation by Gas Chromatography/Mass Spectrometry 2005). The period of dosing of 7 days was chosen based on the including carboxy-THC: creatinine ratio if positive. Day 7 uri- typical duration of the major symptoms of cannabis with- nalysis included cannabis immunoassay, quantitation and drawal (Budney, et al., 2003). carboxy-THC: creatinine ratio only. A specimen ratio of ≥0.5 Other symptomatic medications (e.g., benzodiazepines) between the day 1 and 7 carboxy-THC: creatinine ratios was were not permitted so as to avoid adverse interactions with considered indicative of cannabis use during inpatient treat- lithium and the possible confounding of withdrawal measures. ment (Huestis and Cone, 1998). Paracetamol (1 gm q.d) was permitted if requested by participants. Tobacco smoking was permitted during treatment, and nicotine replacement therapy (patches) was available upon Follow-up request. Three participants were provided with a mean 1.67 Participants were requested to attend three follow-up interviews, nicotine patches during inpatient treatment. scheduled for day 14 (follow-up 1), day 28 (follow-up 2) and On the day of admission, participants were requested to day 90 (follow-up 3) post-entry into the trial. Because of partici- attend the inpatient facility at 9 a.m., and were asked to pant availability, follow-up interviews were conducted at mean abstain from using cannabis from midnight the previous even- of 10 days (SD = 4.27; range = 5–19), 24 days (SD = 3.94; ing. Routine admission procedures were conducted including a range = 18–33) and 107 days (SD = 21.88; range = 83–146) fol- medical examination and ward orientation. lowing cessation of treatment. Urine samples were requested at During inpatient treatment, participants were reviewed each follow-up to corroborate self-reported cannabis use via daily by a medical officer, except on weekends where medical cannabis immunoassay, quantitation and carboxy-THC: officers were available for consultation, if required. Pulse, creatinine ratio. A positive cannabis urinalysis at follow-up was blood pressure, respiratory rate, weight and fluid balance indicated by the presence of cannabis metabolites in the concen- were recorded daily by nursing staff. Participants monitored tration 50 ng/mL or above (Huestis, et al., 1995). Twenty-five their withdrawal symptoms at 6 p.m. daily, using the Mari- dollars (Australian) remuneration was offered for attending each juana Withdrawal Checklist (MWC) (Budney, et al., 1999). follow-up and an additional $25 offered for attending all three As part of routine care, participants were requested to attend follow-up interviews. group activities including one relapse prevention session, one Narcotics Anonymous information session, one healthy eating session and one yoga session. Although some of these sessions Measures may have been useful to study participants, the group program was primarily developed for those with alcohol or opiate Cannabis dependence at baseline and day 107 follow-up was dependence. Participants completing the 7-day treatment pro- assessed with the Severity of Dependence Scale (SDS) (Gossop, gram were discharged on the morning of day 8. All participants et al., 1995), where a score of 3 or more is indicative of depen- were offered outpatient 1–1 or group counselling, following dence (Swift, et al., 1998a) and GAIN-I DSM-IV cannabis discharge. Six participants accepted this offer. Four partici- dependence in the preceding 12 months (Dennis, et al., 2002). pants were referred to outpatient group programs and two The Timeline Followback Method (Sobell and Sobell, 1992; were referred for 1–1 outpatient counselling. Participants dis- Sobell, et al., 1996) was used to assess daily cannabis use in charging themselves from the inpatient facility before comple- the 3 months before entering the study and cannabis use at tion of treatment (n = 6) were assessed by a medical officer each follow-up interview. A standardised baseline cannabis before leaving the inpatient facility. and other drug use history questionnaire explored demo- Lithium adverse effects and signs of toxicity were assessed graphics, cannabis initiation, patterns of cannabis use, previous daily by nursing staff and medical officers using a checklist of cannabis withdrawal symptoms, treatment history and other more commonly reported adverse effects (Caswell, 2005). Par- drug use. This was developed specifically for use in this study. ticipants reporting significant adverse effects were assessed by a The 22-item self-report Cannabis Problems Questionnaire medical officer and blood samples immediately taken to assess (CPQ) measured cannabis-related problems experienced in the serum lithium levels. Participants were withdrawn from the 3 months preceding study entry and at day 107 follow-up, and

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 Lithium and cannabis withdrawal 87

has good psychometric properties (Copeland, et al., 2005). (n = 2) employed part-time, 10% (n = 2) on workers compensa- Tobacco use and severity of nicotine dependence was assessed tion and one participant (5%) was a full-time student. All par- with the 6-item self-report Fagerstrom Test for Nicotine ticipants met DSM-IV criteria for cannabis dependence in the Dependence (FTND) (Heatherton, et al., 1991), at baseline preceding 12 months, and all were cannabis dependent accord- and at day 107 follow-up. High nicotine dependence is indi- ing to the SDS (mean = 11.10, SD = 2.65). The mean number cated by scores ≥6 (Fagerström, et al., 1996). of cannabis-related problems reported in the 3 months before Cannabis withdrawal was measured during inpatient treat- study entry on the CPQ was 12.58 (SD = 5.36). Sixteen pro- ment and at each follow-up interview with a 20-item adapta- blems were endorsed by 50% or more of participants. Two pro- tion of the self-report MWC (Budney, et al., 1999). Symptoms blems were endorsed by more than 75% of the sample: ‘Have assessed included shakiness, depressed mood, decreased appetite, you been concerned about a lack of motivation?’, and ‘Do you nausea, irritability, sleep difficulty, sweating, craving to smoke usually have a smoke in the morning to get yourself going?’. marijuana, restlessness, nervousness/anxiety, increased aggres- All participants were daily or almost daily cannabis users, sion, headaches, stomach pains, strange/wild dreams, increased and had smoked a mean 21.63 cones/day (SD = 10.71, anger, chills and muscle spasms/aches. Three items were range = 5–39) in the 90 days before entering the trial. Almost included that were not in the original MWC. These were inabil- all participants smoked waterpipes (bongs) primarily (95%, ity to calm oneself, mind racing and inability to focus thoughts. n = 19), and one participant smoked joints exclusively. The These items were included based on the relevant clinical expe- amount of cannabis smoked by this participant was converted rience of members of the research team. Each item was scored from joints to cones in the ratio: 1 joint = 3 cones, consistent on a 4-point scale assessing symptom severity in the preceding with previous research (Didcott, et al., 1997; Copeland, et al., 24 h (0 = none, 1 = mild, 2 = moderate, 3 = severe). A compos- 2001b). All participants smoked cannabis mixed with tobacco, ite Withdrawal Discomfort Score (WDS) was also calculated and 65% (n = 13) regularly smoked tobacco cigarettes indepen- for each participant for each day. This score was devised by dent of cannabis use. The mean nicotine dependence score Budney, et al. (1999) including 10 MWC items reported by at using the FTND among smokers was 5.08 (SD = 2.35), with least 40% of participants in their sample. These items are 46% (n = 6) of smokers meeting criteria for co-morbid high depressed mood, decreased appetite, irritability, sleep difficulty, nicotine dependence. The mean age of initiation of cannabis craving to smoke marijuana, restlessness, nervousness/anxiety, use was 14.45 years (SD = 2.26) with a mean 3.10 years headaches, strange/wild dreams and increased anger. The WDS (SD = 3.35) to daily or almost daily use from the time of initi- has been shown to have good reliability (α = 0.89) (Budney, ation. Participants had been smoking cannabis daily or almost et al., 1999). The MWC has not been psychometrically daily for a mean 9.0 years (SD = 5.78), and 40% (n = 8) had validated. previously sought treatment for their cannabis use. Other self- Psychological symptoms were assessed at baseline with the reported drug use in the month preceding study entry is dis- Symptom Checklist-90-R (SCL-90-R) (Derogatis, 1994) and played in Table 1. only the Global Severity Index (GSI), a summary measure of psychological distress, is presented here. The Beck Depression Treatment compliance Inventory II (BDI-II) (Beck, et al., 1996), State-Trait Anxiety Inventory (STAI) (Spielberger, et al., 1983) and the State-Trait Sixty percent of participants (n = 12) completed the 7-day inpa- Anger Expression Inventory-2 (STAXI-2) (Spielberger, 1999) tient treatment program and were compliant with all adminis- were administered at baseline and at day 107 follow-up to tered lithium doses. Three participants (15%) were discharged assess changes in depression, state and trait anxiety, and state on day 2 of treatment, one participant (5%) on day 3 and four and trait anger, respectively. participants (20%) on day 5. Of those, two participants (10%) Urinalyses for cannabis and other drugs were conducted by were withdrawn from the trial because of possible adverse Pacific Laboratory Medicine Services (PaLMS), Macquarie effects related to lithium. The first withdrew from the study Hospital, Sydney. Blood tests were conducted by South on day 2 because of jaw tremor and the second withdrew on Western Area Pathology Service, Liverpool Hospital, Sydney. day 3 because of headache/migraine. The remaining six participants who did not complete treatment were discharged against medical advice. The main reason for early discharge Results cited by these participants was difficulties with inpatient facility staff or clients (10%, n = 2), boredom (10%, n = 2) and other Sample personal reasons (10%, n = 2). There was no evidence of new cannabis use in any partici- Ninety-five percent of participants (n = 19) were men and the pant between the time of the first urine sample taken at study mean age was 30.05 years (SD = 7.13). Ninety percent (n = 18) entry (mean carboxy-THC: creatinine ratio = 1248.08) and the identified as Australian and 10% (n = 2) as Aboriginal or sample collected on day 7 (mean carboxy-THC: creatinine Torres Strait Islander. All participants reported English as ratio = 143.44). their first language. At baseline, 45% (n = 9) of participants Lithium adverse effects were monitored daily by medical or were unemployed, 30% (n = 6) were employed full-time, 10% nursing staff with a self-completion checklist. Four adverse

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 88 Lithium and cannabis withdrawal

Table 1 Other drug use preceding and following lithium treatment

Drug type Baseline (n = 20) Follow-up 1 (n = 14) Follow-up 2 (n = 17) Follow-up 3 (n = 17) %used Mean no. %used Mean no. % used Mean no. %used Mean no. previous month days used previous week days used previous 2 weeks days used previous month days used

Alcohol 75 6 69 3 88 3 77 8 Tobacco 65 30 92 7 77 14 71 30 Caffeine 95 25 69 7 77 13 88 24 Opiates5120064615 Amphetamines 20 1 0 0 6 2 24 1 Cocaine0 00 0 0 00 0 Benzodiazepines00006268 Hallucinogens0 00 0 0 00 0 Ecstasy 5 1 0 0 0 0 0 0 effects of at least mild severity (rating ≥ 1) were reported during Peak severity score for MWC items are presented in Table 3 lithium treatment by 25% or more of participants. These for participants completing ≥5 days of lithium treatment adverse effects were: increased frequency of daytime urination (n = 16). Of those, seven participants (44%) reported six or (n = 7), fatigue (n = 7), increased thirst (n = 6) and feeling more symptoms of at least moderate severity on at least one slowed up (n = 5). day during treatment (rating ≥2). Only three participants Blood samples were taken from participants remaining in (19%) reported four or more symptoms as severe on at least the inpatient unit at day 4 and 7 to assess trough serum lithium 1 day during treatment (rating = 3). levels. Sixty-one percent (n = 11) of participants had trough serum lithium levels within the therapeutic range at day 4 Tobacco use (mean = 0.59; SD = 0.20; range = 0.38–1.05), and 50.0% (n = 6) were within the therapeutic range at day 7 Regarding tobacco use during lithium treatment, 55% of parti- (mean = 0.53; SD = 0.20; range = 0.15–0.91). No participants, cipants (n = 11) were regular tobacco smokers who continued including those withdrawn from the study, had serum lithium to smoke at their previous levels, 10% (n = 2) were regular smo- levels above the therapeutic range at either time. kers who increased their tobacco use, 20% (n = 4) were non- The mean total amount of paracetamol taken by partici- smokers who did not use tobacco during treatment and 15% pants during inpatient treatment was 1.25 g (SD = 1.65; (n = 3) were non-smokers who used tobacco during treatment. range = 0–5). Fifty percent (n = 10) required no paracetamol during treatment. Abstinence at follow-up Cannabis withdrawal The percentage of participants attending follow-up was 70% (n = 14) at day 10, 85% (n = 17) at day 24 and 85% (n = 17) The mean severity of cannabis withdrawal symptoms experi- at day 107. Fifty-five percent (n = 11) attended all follow-up enced during the course of lithium treatment, as assessed by interviews. The proportion of participants abstinent and per- the MWC, are presented for each participant in Table 2. Parti- centage of days abstinent at each follow-up is displayed in cipants endorsed a mean 4.75 symptoms (SD = 5.13) that Table 4. Forty-one percent of participants were abstinent at achieved a mean rating of at least mild severity (rating ≥1) cal- day-107 follow-up. The mean amount of cannabis smoked culated over the course of lithium treatment. Five participants daily in the period between treatment cessation and day-107 endorsed one or more symptoms that achieved a mean rating follow-up was 1.75 cones (SD = 4.25; range = 0–15). of at least moderate severity (rating ≥2) (mean = 3.20; Abstinence from cannabis was corroborated with urinalysis SD = 1.48). at day-107 follow-up with cannabis metabolite concentration Participants who were within the therapeutic lithium range of 50 ng/mL or greater being indicative of cannabis use. Two for management of bipolar affective disorder on day 4 did not participants did not provide urine samples. One of these parti- have significantly different mean WDS scores during inpatient cipants reported cannabis use in the period between treatment treatment compared with those below the therapeutic range on cessation and follow-up, whereas the other reported no canna- day 4 (t = −0.22, df = 16; P = 0.83). Participants who were reg- bis use in this period. There was generally a high level of con- ular tobacco smokers did not differ from non-smokers in mean cordance between self-reported cannabis use and urinalysis. Of WDS scores during inpatient treatment (t = −0.55, df = 17; the remaining 15 participants, there was disagreement between P = 0.59). However, the clinical use of these two findings is self-report and cannabis metabolite concentrations for four limited by the small sample size and lack of statistical power. participants (κ = 0.47). Of these four, one participant reported

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 Lithium and cannabis withdrawal 89

Table 2 Mean MWC ratings of individual participants during lithium treatment (0 = none; 3 = severe)

MWC Item Individual participant mean withdrawal scores

1234567891011121314151617181920

Shakiness 0.29 0.00 1.00 0.00 1.40 0.00 0.00 0.14 0.86 0.00 0.00 0.43 0.00 0.00 0.00 0.00 0.14 0.00 0.00 1.25 Depressed mood 1.29 0.29 2.00 0.00 0.20 0.14 0.00 0.43 0.14 0.00 0.20 0.14 0.00 0.14 1.00 0.71 1.00 0.00 0.29 1.25 Decreased 0.29 0.00 1.00 1.00 1.20 0.14 0.50 0.00 0.00 0.00 0.40 0.29 0.14 0.43 1.50 1.14 2.14 0.29 1.00 0.75 appetite Nausea 0.29 0.00 0.50 0.00 1.20 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.14 1.00 0.00 0.43 0.00 0.14 1.75 Irritability 1.43 1.00 1.50 0.00 1.40 0.14 0.00 0.71 1.00 0.33 0.00 0.00 0.00 0.57 2.00 0.43 0.71 0.29 0.00 0.75 Sleep difficulty 1.14 1.43 1.50 0.00 1.20 0.71 1.00 0.43 1.29 0.50 0.40 0.17 1.43 1.33 2.00 2.67 2.00 0.67 0.29 0.33 Sweating 1.71 0.29 1.00 0.00 1.80 0.57 0.50 0.14 0.86 0.25 0.00 0.57 0.00 0.14 2.00 0.71 0.43 0.00 .71 1.75 Marijuana craving 0.43 0.86 2.50 0.00 1.20 0.86 1.00 1.29 0.14 0.75 0.00 0.00 0.00 0.29 0.50 0.14 1.43 0.14 1.14 1.50 Restlessness 1.14 1.29 2.00 1.00 1.40 0.57 0.50 1.17 1.00 0.75 0.20 0.00 0.57 1.00 2.00 0.86 1.00 0.14 0.71 2.00 Nervousness/ 0.71 0.14 1.50 0.00 1.80 0.29 0.00 0.43 0.86 0.50 0.00 0.00 0.43 0.43 1.50 0.86 1.00 0.33 0.00 2.00 anxiety Increased 1.57 0.43 0.00 0.00 0.00 0.00 0.00 .29 0.00 0.25 0.00 0.00 0.00 0.43 0.50 0.29 1.14 0.00 0.00 0.25 aggression Headaches 0.43 0.71 0.00 0.00 1.00 0.00 0.00 0.00 0.14 0.00 0.40 0.00 0.00 0.29 2.00 0.57 0.00 0.00 0.00 2.00 Stomach pains 0.14 0.29 0.00 0.00 1.40 0.14 0.00 0.00 0.14 0.25 0.00 0.00 0.00 0.00 0.50 0.29 2.29 0.00 0.14 1.25 Strange/wild 0.71 0.29 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.57 0.57 1.17 0.00 0.14 0.00 0.00 0.00 1.33 dreams Increased anger 1.71 0.57 0.00 0.00 0.00 0.29 0.00 0.14 0.00 0.25 0.00 0.00 0.00 0.29 1.00 0.43 1.00 0.00 0.00 0.00 Inability to calm 0.71 0.14 0.00 0.00 1.20 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.29 0.50 0.57 0.86 0.00 0.00 0.75 oneself Chills 0.43 0.14 0.50 0.00 1.40 0.00 0.00 0.29 0.29 0.00 0.00 0.00 0.00 0.29 1.50 0.43 0.14 0.00 0.57 1.75 Mind racing 1.71 0.57 1.50 0.00 1.60 0.43 0.00 0.00 0.14 0.25 0.20 0.00 1.00 0.57 1.00 0.71 1.14 0.00 0.57 2.25 Inability to focus 1.43 1.14 1.50 0.00 0.75 0.43 0.00 0.29 0.29 0.50 0.00 0.00 0.00 0.29 0.50 1.00 1.43 0.67 0.00 1.50 thoughts Muscle 0.43 0.14 0.50 0.00 1.60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.86 0.57 0.00 0.00 1.25 spasms/aches WDS 9.29 6.57 12.00 2.00 9.40 3.14 3.00 4.43 4.57 3.25 1.60 1.14 3.14 5.57 13.50 7.57 10.29 1.71 3.43 11.50 Daysintreatment772257277557773 77775

MWC, Marijuana Withdrawal Checklist; WDS, Withdrawal Discomfort Score. no cannabis use but was THC-positive. The remaining three At day-107 follow-up, the mean SDS score was significantly reported cannabis use but were THC-negative. Five of the lower than at baseline with approximately half of participants seven participants who reported continuous abstinence (47%; n = 8) scoring 3 or more, indicative of cannabis depen- throughout the follow-up period had cannabis metabolite con- dence. The mean number of cannabis-related problems centrations consistent with self-report. Thus, 29% (n =5) reported on the CPQ in the 3 months before follow-up reported continuous abstinence that was biochemically verified. (mean = 4.00) was significantly lower than recorded at base- Although cannabis withdrawal data was collected at each line. There was no significant change in nicotine dependence follow-up interview it is not presented here because of signifi- from baseline to day-107 follow-up (see Table 5). Other drug cant limitations in their interpretation resulting from missing use reported at each follow-up interview is displayed in data and a variable return to cannabis use during the follow- Table 1. up period among some participants.

Follow-up psychological symptoms, cannabis Discussion dependence and cannabis problems

Psychological symptoms assessed at baseline and follow-up are The findings of this open-label study provide preliminary evi- presented in Table 5. Significant reductions in depressive symp- dence that lithium has potential use as a safe, acceptable and toms, state and trait anxiety and trait anger are reported clinically useful treatment modality for the alleviation of many between baseline and day 107. The mean SCL-90 GSI score commonly experienced symptoms of cannabis withdrawal. at baseline was suggestive of higher than normal levels of psy- Follow-up of study participants showed a high rate of absti- chological distress. The SCL-90 was not administered at nence from cannabis use and significant improvements in mea- follow-up. sures of psychological wellbeing.

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 90 Lithium and cannabis withdrawal

Table 3 Peak MWC severity for participants completing ≥5 days of lithium treatment

MWC Item None Mild Moderate Severe n % n % n % n %

Shakiness 9 56 4 25 3 19 —— Depressed mood 3 19 9 56 4 25 —— Decreased appetite 4 25 8 50 2 13 2 13 Nausea 10 63 3 19 2 13 1 6 Irritability 4 25 6 38 6 38 —— Sleep difficulty ——744319638 Sweating 3 19 7 44 5 31 1 6 Marijuana craving 3 19 5 31 5 31 3 19 Restlessness 1 6 6 38 8 50 1 6 Nervousness /anxiety 3 19 8 50 5 31 —— Increased aggression 8 50 5 31 2 13 1 6 Headaches 8 50 3 19 5 31 —— Stomach pains 6 38 7 44 2 13 1 6 Strange/wild dreams 8 50 5 31 2 13 1 6 Increased anger 8 50 6 38 1 6 1 6 Inability to calm oneself 8 50 5 31 3 19 —— Chills 6 3874421316 Mind racing 3 19 5 31 4 25 4 25 Inability to focus thoughts 4 25 8 50 3 19 1 6 Muscle spasms/aches 10 63 3 19 1 6 2 13

MWC, Marijuana Withdrawal Checklist.

Direct comparisons with other studies on measures of with- toms as severe on at least 1 day. The number of symptoms drawal are difficult because of wide variations in duration of reported in the study article was also less than in another treatment, methodology, withdrawal measures, sample selec- research study assessing current withdrawal symptoms where tion, setting and levels of cannabis use. With these limitations 78% of participants experienced four or more significant within mind, compared with a number of previous studies, the drawal symptoms on the MWC during a period of abstinence range of cannabis withdrawal symptoms prospectively reported (Budney, et al., 2003). by participants including their mean and peak severity appear Because of the inpatient setting variable return to cannabis notably less. In a retrospective study of 54 treatment seeking use and the small sample size, despite collecting follow-up data cannabis users, participants reported a mean 9.6 withdrawal it is not possible to accurately determine whether lithium’s symptoms in relation to their most recent period of abstinence, major effect, if any, is upon the time course or severity of can- with 57% reporting six or more symptoms of at least moderate nabis withdrawal. severity and 47% rating four or more symptoms as severe (Bud- The high rates of self-reported absolute abstinence, corrob- ney, et al., 1999). Although withdrawal assessment in our study orated with urinalysis for 29% of the 85% of participants fol- was confounded by both an inpatient setting and prospective lowed up at day 107 were impressive and greater than those recall, only 44% (n = 7) reported experiencing six or more reported in the follow-ups of primarily psychologically based symptoms with a peak moderate severity on at least 1 day of interventions in cannabis smokers [e.g., 15% continuously treatment, with only 19% (n = 3) reporting four or more symp- abstinent at 242 days in condition receiving six sessions of

Table 4 Self-reported cannabis abstinence at follow-up interviews

Follow-up No. attended % abstinenta %daysabstinentb

Follow-up 1 (day 10) 14 64% (n = 9) 88.67 ± 24.67; 8.33–100 Follow-up 2 (day 24) 17 65% (n = 11) 88.41 ± 21.31; 33.33–100 Follow-up 3 (day 107) 17 41% (n = 7) 87.57 ± 20.41; 33.82–100 aCalculated as a proportion of those attending follow-up. bMean ± SD; range.

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 Lithium and cannabis withdrawal 91

Table 5 Psychological symptoms, cannabis dependence, cannabis problems and nicotine dependence assessed at baseline and day-107 follow-up

Measure Baseline (day 1)a Follow-up 3 (day 107)a Significance

SCL-90 (GSI) 1.25 ± 0.86; 0.13–3.02 —— BDI-II 21.25 ± 10.70; 0–44 8.53 ± 10.98; 0–35 t = 4.77, df = 16; P < 0.001 STAI State Anxiety 47.85 ± 8.23; 29–64 31.24 ± 10.74; 20–54 t = 5.50, df = 16; P < 0.001 Trait Anxiety 51.30 ± 8.93; 29–66 38.94 ± 14.45; 21–67 t = 3.89, df = 16; P <0.01 STAXI-2 State Anger 18.75 ± 6.62; 15–43 15.59 ± 1.23; 15–19 t = 1.79, df = 16; P =0.09 Trait Anger 22.25 ± 5.22; 13–33 17.94 ± 5.38; 11–30 t = 3.08, df = 16; P <0.01 SDS 11.10 ± 2.65; 6–15 3.94 ± 4.88; 0–14 t = 5.81, df = 16; P < 0.001 CPQ 12.58 ± 5.36; 1–21 4.00 ± 4.92; 0–13 t = 6.60, df = 15; P < 0.001 FTND 5.08 ± 2.35; 0–8 4.75±2.86;1–9 t = 1.75, df = 10; P =0.11

SCL-90, Symptom Checklist-90; GSI, Global Severity Index; BDI-II, Beck Depression Inventory II; STAI, State-Trait Anxiety Inventory; STAXI-2, State- Trait Anger Expression Inventory-2; SDS, Severity of Dependence Scale; CPQ, Cannabis Problems Questionnaire; FTND, Fagerstrom Test for Nicotine Dependence. aMean ± SD; range. cognitive behavioural therapy (Copeland, et al., 2001b); mean reflects the ongoing level of concern regarding cannabis use in 55% days abstinent at 9 months in condition receiving nine ses- the early stages of abstinence (Copeland, et al., 2001b). sions of motivational enhancement therapy (Marijuana Treat- A major limitation of the study was the use of a fixed dosing ment Project Research Group, 2004)]. Even among those who regime, which does not reflect the dose titration approach used reported some cannabis use during the follow-up period, there when medicating individuals within psychiatric practice. As a was evidence of a marked reduction in the number of days used result, 39% of participants at day 4 and 50% of participants at in the previous month and the amount used on a typical smok- day 7 did not achieve serum lithium levels within the therapeu- ing day. Although tobacco use increased following abstinence tic range. This may provide some explanation for variations in for some participants during inpatient treatment and in the clinical response. Lithium appeared to be well tolerated and period between treatment cessation and day-10 follow-up, had a mild adverse effects profile, with the incidence and sever- tobacco use appeared to return to previous levels by day-107 ity of adverse effects being comparable with that reported in follow-up. That all participants in the current study typically other studies exploring its long-term use in clinical practice. mixed cannabis with tobacco is consistent with other Austra- In a survey of 237 patients in long-term lithium treatment, lian research where 75% of long-term cannabis users mixed only 10% reported no current side effects (Vestergaard, et al., with tobacco (Swift, et al., 1998b). 1980). One participant in the current study experienced jaw Reductions in measures of psychological symptoms were tremor, an adverse effect associated with lithium treatment also reported between baseline and follow-up. The significant (Johnson, 1984) that has a reported incidence of 4–65% reduction in mean BDI scores from 22 to 8 with the proportion (Gelenberg and Jefferson, 1995). No participant achieved scoring above the cut-off for moderate depression (28) falling serum lithium levels above 1.5 mmol/L. This finding does not from 25% at baseline to 6% at day 107 is of particular interest lend support to the concern that the presence of cannabis may and supports the clinical practice of refraining from diagnosing increase the risk of lithium toxicity as raised in a single case depression in current cannabis smokers and waiting for a report (Ratey, et al., 1981). In any future trial, it is suggested period of abstinence before reassessing mood and considering that individuals have their lithium dose titrated against plasma antidepressant medication. The persistence of clinically mean- levels and clinical response. Where problematic, adverse effects ingful scores in some clients may suggest pre-existing pathol- may be addressed through dose reduction (Coppen, et al., ogy. In addition, marked reductions were noted in both state 1983; Bowden, 1998). and trait anxiety, with less-marked reductions also noted in Although our findings are generally positive we were not state and trait anger measures. able to elucidate the mechanism underlying the therapeutic Although the mean SDS score remained above the cut-off effects of lithium. That the proposed mechanism of action of of 3 for almost 50% of the participants at follow-up, this lithium is by its effect on mood is biologically plausible and occurred in the context of marked reductions in the number of consistent with the prosocial and mood enhancing effects of cannabis-related problems endorsed. Furthermore, the level of oxytocin (Insel, 1992; Uvnas-Moberg, 1998; Heinrichs, et al., reduction in cannabis dependence symptoms is similar to that 2003; Heinrichs and Gaab, 2007). Further elucidation of the reported in trials of psychological interventions and probably role of oxytocin in mediating the positive effects and

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 92 Lithium and cannabis withdrawal

determination of the dose and therapeutic range required for Budney, AJ (2006) Are specific dependence criteria necessary for dif- optimal effects is also required. ferent substances: how can research on cannabis inform this issue? This study has several limitations including the absence of a Addiction 101: 125–133. placebo, small number of participants and open-label design. Budney, AJ, Hughes, JR (2006) The cannabis withdrawal syndrome. – In addition, the inpatient setting is likely to have contributed Curr Opin Psychiatry 19: 233 238. both to the successful attainment of at least initial abstinence Budney, AJ, Hughes, JR, Moore, BA, Novy, PL (2001) Marijuana abstinence effects in marijuana smokers maintained in their home and may have contributed to the comparatively low number environment. Arch Gen Psychiatry 58: 917–924. and severity of withdrawal symptoms. This would be consistent Budney, AJ, Hughes, JR, Moore, BA, Vandrey, R (2004) Review of with previous work suggesting that cannabis withdrawal is per- the validity and significance of cannabis withdrawal syndrome. ceived as less severe in inpatient settings (Budney, et al., 1999; Am J Psychiatry 161: 1967–1977. Haney, et al., 1999a,b; Budney, et al., 2001). The exclusion of Budney, AJ, Moore, BA, Vandrey, RG, Hughes, JR (2003) The time clients with significant mental health problems may also have course and significance of cannabis withdrawal. J Abnorm Psychol been a contributing factor to the low mean withdrawal severity 112: 393–402. scores reported because co-morbid psychiatric disorder has Budney, AJ, Novy, PL, Hughes, JR (1999) Marijuana withdrawal been associated with more severe withdrawal in cannabis among adults seeking treatment for marijuana dependence. Addic- users (Budney, et al., 1999). The inclusion of only one woman tion 94: 1311–1322. also limits the generalisability of the findings and the capacity Budney, AJ, Vandrey, RG, Hughes, JR, Moore, BA, Bahrenburg, B to detect possible gender differences in treatment outcome. (2007) Oral delta-9-tetrahydrocannabinol suppresses cannabis with- – This study, however, does address some of the methodological drawal symptoms. Drug Alcohol Depend 86:22 29. Caswell, A, (ed) (2005) MIMS Annual 2005. CMPMedica, Sydney. limitations of a smaller open-label human study (Bowen, et al., Copeland, J, Gilmour, S, Gates, P, Swift, W (2005) The Cannabis Pro- 2005). The sample size is more than doubled, the inpatient blems Questionnaire: factor structure, reliability, and validity. Drug design enabled enhanced monitoring of withdrawal symptoms, Alcohol Depend 80: 313–319. higher doses and longer duration of lithium treatment was used Copeland, J, Swift, W, Rees, V (2001a) Clinical profile of participants and the majority of participants were followed-up. in a brief intervention for cannabis use disorder. J Subst Abuse The identification of an effective intervention for managing Treat 20:45–52. cannabis withdrawal is of clinical importance particularly in Copeland, J, Swift, W, Roffman, R, Stephens, R (2001b) A random- those with mental health problems where ongoing use is asso- ized controlled trial of brief cognitive-behavioral interventions for ciated with poorer clinical outcomes (Hides, et al., 2006). If as cannabis use disorder. J Subst Abuse Treat 21:55–64. with tobacco, withdrawal is identified as a significant barrier in Copersino, M, Boyd, S, Tashkin, D, Huestis, M, Heishman, S, achieving abstinence the availability of a safe and effective Dermand, J, Simmons, M, Gorelick, D (2006) Cannabis with- medication would be valuable not only in supporting attain- drawal among non-treatment-seeking adult cannabis users. Am J – ment of abstinence but also as a means of attracting cannabis Addict 15:8 14. users into treatment. The findings of this study support the Coppen, A, Abou-Saleh, M, Milln, P, Bailey, J, Wood, K (1983) Decreasing lithium dosage reduces morbidity and side-effects dur- need for further research, using lithium in a randomised, ing prophylaxis. J Affect Disord 5: 353–362. placebo-controlled study among treatment-seeking cannabis- Cui, S-S, Bowen, RC, Gu, G-B, Hannesson, DK, Yu, PH, Zhang, X dependent adults. (2001) Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation. J Neurosci 21: Acknowledgements 9867–9876. We would like to extend our thanks to the study participants, staff at Degenhardt, L, Hall, W, Lynskey, M (2003) Testing hypotheses about the inpatient unit, and the counsellors and medical officers who con- the relationship between cannabis use and psychosis. Drug Alcohol ducted clinical assessments. In particular, we are grateful to Dr Peter Depend 71:37–48. McCaul, Lucinda Scopelliti and Claire Honey for their assistance in Dennis, M, Titus, J, White, M, Unsicker, J, Hodkgins, D (2002) the clinical delivery of the trial. We would also like to thank the Cana- Global Appraisal of Individual Needs (GAIN): Administration dian researchers who shared their pilot study experience. This project Guide for the GAIN and Related Measures. Bloomington, IL: was funded by a research grant from the NSW Department of Health. Chestnut Health Systems. Derogatis, LR (1994) Symptom Checklist 90-R: Administration, Scor- References ing and Procedures Manual, third ed. Minneapolis: NCS Pearson. AIHW (2005) Alcohol and Other Drug Treatment Services in Austra- Didcott, P, Reilly, D, Swift, W, Hall, W (1997) Long-term cannabis lia 2003–04: Report on the National Minimum Data Set. Can- users on the New South Wales North Coast (Monograph 30). berra: Australian Institute of Health and Welfare. Sydney: National Drug and Alcohol Research Centre, University Beck, AT, Steer, RA, Brown, GK (1996) BDI-II Manual, second ed. of New South Wales. San Antonio, TX: Psychological Corporation. Fagerström, KO, Kunze, M, Schoberberger, R, Breslau, N, Hughes, Bowden, CL (1998) Key treatment studies of lithium in manic- JR, Hurt, R D, Puska, P, Ramstrom, L, Zatonski, W (1996) Nico- depressive illness: efficacy and side effects. J Clin Psychiatry 59: tine dependence versus smoking prevalence: comparison among 35–36. countries and categories of smokers. Tob Control 5:52–56. Bowen, R, McIlwrick, J, Baetz, M, Zhang, X (2005) Lithium and mar- Fergusson, DM, Poulton, R, Smith, PF, Boden, JM (2006) Cannabis ijuana withdrawal. Can J Psychiatry 50: 240–241. and psychosis. BMJ 332: 172–175.

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009 Lithium and cannabis withdrawal 93

Ferrier, IN, Ferrie, LJ, Macritchie, KA (2006) Old drug, new data: a double-blind, placebo-controlled pilot study of Divalproex revisiting... lithium therapy. Advances in Psychiatric Treatment Sodium. Am J Addict 13: doi: 10.1080/10550490490265280. 12: 256–264. Marijuana Treatment Project Research Group (2004) Brief treatments Geddes, JR, Burgess, S, Hawton, K, Jamison, K, Goodwin, GM for cannabis dependence: findings from a randomized multisite (2004) Long-term lithium therapy for bipolar disorder: systematic trial. J Consult Clin Psychol 72: 455–466. review and meta-analysis of randomized controlled trials. Am J Mathers, C, Vos, T, Stevenson, C (1999) The Burden of Disease and Psychiatry 161: 217–222. Injury in Australia. Canberra: Australian Institute of Health and Gelenberg, AJ, Jefferson, JW (1995) Lithium tremor. J Clin Psychiatry Welfare. – 56: 283 287. McRae, AL, Brady, KT, Carter, RE (2006) Buspirone for treatment of Gossop, M, Darke, S, Griffiths, P, Hando, J, Powis, B, Hall, W, marijuana dependence: a pilot study. Am J Addict 15: 404. Strang, J (1995) The Severity of Dependence Scale (SDS): psycho- Price, LH, Heninger, GR (1994) Lithium in the treatment of mood dis- metric properties of the SDS in English and Australian samples of orders. N Engl J Med 331: 591–598. heroin, cocaine and amphetamine users. Addiction 90: 607–614. Ratey, JJ, Ciraulo, DA, Shader, RI (1981) Lithium and marijuana. Haney, M, Hart, CL, Vosburg, SK, Nasser, J, Bennett, A, Zubaran, J Clin Psychopharmacol 1:32–33. C, Foltin, R W (2004) Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology 29: 158– Semple, DM, McIntosh, AM, Lawrie, SM (2005) Cannabis as a risk 170. factor for psychosis: systematic review. J Psychopharmacol 19: – Haney, M, Hart, CL, Ward, AS, Foltin, RW (2003) Nefazodone 187 194. decreases anxiety during marijuana withdrawal in humans. Psycho- Smith, NT (2002) A review of the published literature into cannabis – pharmacology 165: 157–165. withdrawal symptoms in human users. Addiction 97: 621 632. Haney, M, Ward, AS, Comer, SD, Foltin, RW, Fischman, MW Sobell, LC, Sobell, MB (1992). Timeline follow-back: a technique for (1999a) Abstinence symptoms following oral THC administration assessing self-reported alcohol consumption. In: Litten, RZ, Allen, to humans. Psychopharmacology 141: 385–394. J, Towota, NJ, (eds), Measuring Alcohol Consumption: Psychoso- Haney, M, Ward, AS, Comer, SD, Foltin, RW, Fischman, MW cial and Biological Methods. Totowa, NJ: Humana Press, pp. 41– (1999b) Abstinence symptoms following smoked marijuana in 72. humans. Psychopharmacology 141: 395–404. Sobell, LC, Sobell, MB, Buchan, G, Cleland, PA, Fedoroff, I, Leo, GI Haney, M, Ward, AS, Comer, SD, Hart, CL, Foltin, RW, Fischman, (1996) The reliability of the Timeline Followback method applied MW (2001) Bupropion SR worsens mood during marijuana with- to drug, cigarette, and cannabis use. Presented at the 30th Annual drawal in humans. Psychopharmacology 155: 171–179. Meeting of the Association for Advancement of Behaviour Ther- Heatherton, T, Kozlowski, L, Frecker, R, Fagerström, KO (1991) The apy, New York. Fagerström test for nicotine dependence: A revision of the Fager- Spielberger, CD (1999) State-Trait Anger Expression Inventory-2: Pro- ström Tolerance Questionnaire. Br J Addict 86: 1119–1127. fessional Manual. Lutz, FL: Psychological Assessment Resources. Heinrichs, M, Baumgartner, T, Kirschbaum, C, Ehlert, U (2003) Spielberger, CD, Gorsuch, RL, Lushene, R, Vagg, PR, Jacobs, GA Social support and oxytocin interact to suppress cortisol and sub- (1983) Manual for the State-Trait Anxiety Inventory (Form Y jective responses to psychosocial stress. Biol Psychiatry 54: 1389– Self-evaluation Questionnaire). Redwood City, CA: Mind Garden. 1398. Swift, W, Copeland, J, Hall, W (1998a) Choosing a diagnostic cut-off Heinrichs, M, Gaab, J (2007) Neuroendocrine mechanisms of stress for cannabis dependence. Addiction 93: 1681–1692. and social interaction: implications for mental disorders. Curr Swift, W, Hall, W, Copeland, J (1998b) Characteristics of long-term Opin Psychiatr 20: 158–162. cannabis users in Sydney, Australia. Eur Addict Res 4: 190–197. Hides, L, Dawe, S, Kavanagh, DJ, Young, RM (2006) Psychotic Swift, W, Hall, W, Teesson, M (2001) Cannabis use and dependence symptom and cannabis relapse in recent-onset psychosis. Prospec- among Australian adults: results from the National Survey of Men- tive study. Br J Psychiatry 189: 137–143. tal Health and Wellbeing. Addiction 96: 737–748. Huestis, MA, Cone, EJ (1998) Differentiating new marijuana use from residual drug excretion in occasional marijuana users. J Anal Tox- Tondo, L, Baldessarini, RJ, Hennen, J, Floris, G (1998) Lithium main- icol 22: 445–454. tenance treatment of depression and mania in bipolar I and bipolar – Huestis, MA, Mitchell, JM, Cone, EJ (1995) Detection times of mari- II disorders. Am J Psychiatry 155: 638 645. juana metabolites in urine by immunoassay and GC-MS. J Anal Uvnas-Moberg, K (1998) Oxytocin may mediate the benefits of posi- Toxicol 19: 443–449. tive social interaction and emotions. Psychoneuroendocrinology 23: Insel, TR (1992) Oxytocin – a neuropeptide for affiliation: evidence 819–835. from behavioral, receptor autoradiographic, and comparative stud- Vandrey, R, Budney, AJ, Kamon, JL, Stanger, C (2005) Cannabis ies. Psychoneuroendocrinology 17:3–35. withdrawal in adolescent treatment seekers. Drug Alcohol Depend Johnson, FN (1984) The History of Lithium Therapy. London: Mac- 78: 205–210. Millan Press. Vestergaard, P, Amdisen, A, Schou, M (1980) Clinically significant Levin, FR, McDowell, D, Evans, SM, Nunes, E, Akerele, E, Donovan, side effects of lithium treatment. A survey of 237 patients in long- S, Vosburg, SK (2004) Pharmacotherapy for marijuana dependence: term treatment. Acta Psychiatr Scand 62: 193–200.

Downloaded from http://jop.sagepub.com at University of Sydney on May 27, 2009