The studies were granted favourable ethical opinions via the National Research Ethics Service. Permission to administer radioligand was provided by the Administration of Radioactive Substances Advisory Committee (ARSAC). The studies were conducted in accordance with the Helsinki Declaration (World Medical Association, 2008). All subjects provided informed written consent to participate after an oral and written explanation of the studies.
2.2.1 Participant Recruitment
Inclusion criteria for all participants were: minimum age 18 years, good physical health with no history of major medical condition and capacity to give written informed consent.
Exclusion criteria for all subjects were current or past psychiatric illness (except Cannabis Use Disorders in the cannabis user group and Nicotine Use Disorder in all subjects) using the Structured Clinical Interview for DSM-IV (SCID) (First et al. 1996), current use of psychotropic medication, history of serious mental illness (including psychosis) in a first degree relative determined via the Family Interview for Genetic Studies (FIGS) (NIMH Genetics Initiative 1992), evidence of an At Risk Mental State for psychosis (Phillips et al.
2000), DSM-IV TR (American Psychiatric Association 2005) Substance Dependency or Abuse (other than cannabis in the cannabis user group and tobacco for all subjects), blood and needle
phobia, contra-indications to PET (including pregnancy, breast-feeding, severe obesity, previous clinical procedures involving exposure to significant ionizing radiation within the last year), contra-indications to MRI (including claustrophobia, the presence of ferromagnetic foreign bodies including aneurysm clips, neural stimulators, cardiac pacemakers or defibrillators, cochlear implants, ocular foreign bodies [e.g. metal shavings], other implanted medical devices [e.g. Swan-Ganz catheter], insulin pump, shrapnel or bullet injuries, patients with a history of surgery of uncertain type where the presence of metal clips or wires cannot be excluded).
Detailed drug histories were obtained from all subjects using the Cannabis Experience Questionnaire (CEQ) (Barkus et al. 2006), structured interview and timeline follow-back.
Lifetime cannabis use was estimated as the total number of ‘spliffs’ (cannabis cigarettes;
‘joints’) consumed. The time taken to smoke an ‘eighth’ of cannabis (1/8 Ounce; approximately 3.5g, representing the standard unit of sale in Britain) was chosen as the primary index of cannabis use as this provides a measure of the amount of current drug consumption (shorter time indicating greater consumption). This is likely to be more accurate than subjective recall of the number of ‘spliffs’ consumed because of variability in cannabis dose between ‘spliffs’
and inconsistencies in self-reported cannabis use (Akinci et al. 2001).
2.2.2 Cannabis User Group
Cannabis user cases were recruited from an on-going cohort study in which over 400 cannabis users were tested when intoxicated with cannabis and when not intoxicated (Morgan et al. 2012). Subjects met the following criteria: current, at least weekly use of cannabis and the induction of psychotic-like symptoms in response to smoking cannabis, which was defined
as a positive change on the psychotic items score of the Psychotomimetic States Inventory (PSI) (Mason et al. 2008) measured 5 minutes after smoking their usual amount of cannabis (i.e. when acutely intoxicated) compared to when not intoxicated with the drug. Cannabis users consumed their own cannabis and testing occurred in the presence of a researcher in the environment where users habitually consumed cannabis in their usual drug-taking context (e.g.
at home), as drug effects are typically larger in naturalistic as opposed to laboratory environments (Barkus et al. 2006). Cannabis-induced psychotic-like symptoms abated within two hours of consumption and no subject met the DSM-IV TR criteria for a diagnosis of a psychotic disorder. The psychotic items from the PSI covered ‘Delusional Thinking’,
‘Perceptual Distortions’, ‘Cognitive Disorganization’ (thought disorder) and ‘Paranoia’. Each item is rated on a 4-point scale from “not at all” (score=0) to “strongly” (score=3). Examples of items include “People can put thoughts into your mind” and “You can sense an evil presence around you, even though you cannot see it”. A sample of the cannabis that each participant smoked was taken on the day of testing and analysed for levels of THC (Forensic Science Service, UK).
2.2.3 Control Group (Cannabis studies)
Non-user control subjects were recruited from the same geographic area, i.e. London, by public advertisement in a newspaper. Control subjects were required to have no lifetime history of cannabis dependence or abuse (DSM-IV), no more than 10 total uses of cannabis in their lifetime, no report of the induction of psychotic symptoms by cannabis, and no history of cannabis use in the preceding three months. Community surveys indicate over 30% of young adults in England report trying cannabis in their lifetime (Home Office 2011). Control subjects were therefore permitted to have had a minimal exposure to cannabis to ensure the control
group was representative of the same general population from which the cannabis users were recruited.
2.2.4 High Psychosocial Stress Group (“HPSS”)
Subjects with a history of high exposure to psychosocial stress were recruited by advertisement in a London-wide newspaper. HPSS “cases” were required to meet at least two of the following criteria:
A) Inner city upbringing (before age 16) or current dwelling according to the Office for National Statistics (ONS) definition of Inner London used by Eurostat i.e. residents of the City of London & the following London Boroughs: Camden, City of Westminster, Hackney, Hammersmith & Fulham, Haringey, Islington, Kensington & Chelsea, Lambeth, Lewisham, Newham, Southwark, Tower Hamlets, and Wandsworth.
AND/OR
B) History of Migration from outside the European Union (1st or 2nd generation)
AND/OR
C) History of childhood (before age 16 years) adversity and/or psychological trauma - at least one of: Parental separation/divorce OR death of a first-degree relative OR physical or sexual abuse OR neglect OR going into foster care/adoption OR major disaster OR war OR admission to hospital with life-threatening medical problem
AND/OR
D) Current adult adversity - At least one of: living with parents OR living alone for over a year OR lack of confidant OR unemployed OR not currently in a relationship.
2.2.5 Low Psychosocial Stress Group (“LPSS”)
LPSS “control” subjects were recruited from the southern United Kingdom by public advertisement and were required to meet all of the following criteria:
A) No personal history of migration from outside the European Union.
AND
B) Current rural dwelling
AND
C) No history of inner city dwelling (as above) for longer than 6 months.
AND
D) No history of significant childhood difficulty: Both parents still together at subject’s age 16 and no history of significant childhood psychological trauma (as above)
AND
E) No history of significant life-events in the 6 months prior to the study.