Psychosis is a severe mental disorder resulting from a complex interplay between genetic and environmental determinants leading to a disruption of central nervous system function [1
]. In order to better understand its pathophysiological mechanisms, different models of psychosis have been proposed [2
]. Over the last two decades, there has been growing interest in the drug-induced model of psychosis, due to the potential of several pharmacological agents to elicit psychotomimetic symptoms that resemble those observed in psychosis patients [3
]. In particular, in-human models of psychosis have become available involving the acute administration of dopaminergic [4
], serotoninergic [5
], glutamatergic [6
], and cannabinoid compounds [7
]. Compared to animal models, which have been implicated as not adequately modeling the complexity of the disorder [9
], the transient symptoms induced by acute challenge with psychotomimetic drugs in healthy individuals are of interest, as they may share pathophysiological mechanisms with the full-blown disorder.
The administration of cannabis’ key psychoactive ingredient delta-9-tetrahydrocannabinol (∆9-THC) has been shown to induce transient psychosis-like symptoms in otherwise healthy individuals [10
]. The association between cannabinoids and psychosis is further supported by several lines of research: (i) the evidence for a higher risk of psychosis in cannabis users [14
], especially against a specific genetic background [17
]; (ii) the evidence that cannabis use can exacerbate psychotic symptoms and cause relapse in patients with schizophrenia [19
]; and (iii) the evidence that the endocannabinoid system might be disrupted in patients with schizophrenia both in the context of cannabis use and in its absence [24
], as well as involved in modulating cognitive function in healthy individuals [26
Although clinical research is needed to further understand psychosis in cannabis users, limited evidence from anecdotal studies has been published on the nature of the transient clinical manifestations of acute cannabis intoxication in healthy individuals [29
]. In many respects, experimental studies examining the nature of the psychotomimetic effects of ∆9-THC may arguably be a priority because they can inform further studies of cannabis-associated psychosis, including aetiology, course, prognosis, and treatment. Previous studies that have assessed the acute psychotomimetic effects of ∆9-THC have reported them as summary measure using the PANSS (Positive and Negative Syndrome Scale) [11
], BPRS (Brief Psychiatric Rating Scale) [37
], SSPS (State Social Paranoia Scale) [35
], or self-report questionnaires [12
]. A limited range of other effects has also been investigated using self-report questionnaires and visual analogue measures, including dissociation [12
], affect and mood [11
], sedation and intoxication [11
], and anxiety and panic [11
Also, evidence indicates that frequent cannabis users have a more blunted response to the acute psychotomimetic effects of ∆9-THC compared to a group of healthy controls, suggesting the potential development of tolerance [38
]. Thus, studies conducted among frequent users may have limited usefulness in informing on the nature of the symptoms acutely induced by cannabis in healthy individuals.
Employing a placebo-controlled acute pharmacological challenge design, the aim of this study was to investigate the symptomatic effects of acute ∆9-THC administration under controlled experimental conditions in a group of healthy individuals with modest previous cannabis use.
2. Materials and Methods
This study employed a double-blind, randomized, placebo-controlled, repeated-measures, within-subject design, with a counterbalanced order of drug administration, using an established protocol [13
]. Sixteen healthy participants (seven males) were assessed on two different occasions separated by at least a two-week interval, with each session preceded by intravenous administration of Δ9-THC (1.19 mg/ 2 mL) or placebo. All the subjects underwent structural Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) scanning in both sessions. The present report focuses on the psychopathological assessment.
2.1. Experimental Procedure
Prior to each study visit, participants were advised to get at least six to eight hours sleep overnight and to refrain from smoking for four hours, taking caffeine for 12 h, and consuming alcohol for 24 h. Also, subjects had been abstinent from cannabis for at least six months before the first study visit, and were advised to abstain from using any substance throughout the duration of the study. On arrival at the study center in the morning, participants had a light standardized breakfast after an overnight fast. All the subjects had a negative urinary drug screen for amphetamines, benzodiazepines, cocaine, opiates, and Δ9-THC, and were tested on each study day using immunometric assay kits. All the female participants had a negative pregnancy test; also, all of them were consistently using a reliable contraceptive method, apart from a single subject who underwent both study visits in the first week of the menstrual cycle. After a physical examination performed by a medical doctor, an indwelling intravenous line in the non-dominant arm was placed by a trained nurse. This cannula was used for the intravenous administration of Δ9-THC (1.19 mg/ 2 mL, ≥99% pure; THC-Pharm, Frankfurt, Germany, http://biochem.thc-pharm.de
; pharmaceutical formulation at the Barts Health NHS Trust pharmacy according to previous work [41
]) or placebo as well as blood collection a different time points before and after drug challenge. A dose of 1.19 mg was used, as previous work has suggested that an intravenous dose range between 0.015–0.03 mg/kg is consistently associated with an induction of psychotomimetic symptoms [42
]. Heart rate and blood pressure were monitored via a digital recorder and an automated arm cuff for the entire duration of the study.
Sixteen healthy, English-speaking, right-handed individuals participated in this study. Demographic information such as age, ethnicity, and level of education was recorded. All the subjects gave written, informed consent, and completed all of the components of the study. Personal or family history of psychiatric illness in first-degree relatives represented an exclusion criterion. None of the subjects included in the study had used more than 21 units/week of alcohol on a regular basis. Only three subjects had a regular smoking habit (two of them smoking <10 cigarettes/day and one smoking two cigarettes/week), six had smoked occasionally/experimentally, and seven had never smoked. Apart from three subjects who had a single experimental use of 3,4-Methylenedioxymethamphetamine (MDMA), all the remaining participants had never used any other substance. Regarding previous lifetime cannabis exposure, nine subjects had used cannabis ≤5 times, three subjects ≤10 times, two subjects ≤20 times, one subject 20 times, and one subject 60 times.
2.3. Psychopathological Assessment
All the participants were interviewed by a psychiatrist with a specific expertise in Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) schizophrenia and other psychotic disorders as well as substance use disorders [43
], using the Structured Clinical Interview for DSM-5 (SCID-5) as a guide for the assessment of the psychotic spectrum [44
]. Assessments were carried out immediately before and at 20 min and 2.5 h after drug administration, and clinically discussed with a senior psychiatrist at the end of each study visit. Psychopathological ratings were recorded using the Positive and Negative Syndrome Scale [45
] (PANSS), which is a well-established scale that is used for measuring the symptom severity of individuals with psychosis. Verbatim quotations from participants were also recorded, as research evidence indicates that the inclusion of excerpts from transcripts might help clarify links between data, interpretation, and conclusion [46
]. Participants were contacted the day after each study visit for a health check as part of the study standard operating procedure (SOP). Putative symptoms lasting longer than expected or occurring after the end of the study visit were also recorded.
2.4. Ethics Approval
The study was approved by the Joint South London and Maudsley (SLaM) and Institute of Psychiatry, Psychology & Neuroscience (IoPPN) National Health Service Research Ethics Committee (PNM/13/14-38), and the investigators had a license to use Δ9-THC for research purposes.
The purpose of this clinical investigation was to systematically assess the transient psychotic reaction to the intravenous administration of pure Δ9-THC in healthy subjects in a controlled setting, which was in line with the evidence that this cannabinoid represents a valid pharmacologic model for psychosis [10
]. Results from this study indicate: (i) detectable acute Δ9-THC-induced symptomatic effects in over 90% of the cohort, with moderate to severe symptoms having a lower prevalence (<20%); (ii) protracted minimal to mild Δ9-THC-induced symptomatic effects in 50% of the cohort (~2.5 h after the exposure); (iii) acute physical reactions to Δ9-THC in about 30% of the cohort and only in female participants; (iv) long-lasting Δ9-THC-induced physical symptoms and psychosis-related symptomatic effects in less than 40% and 6% of the cohort, respectively; (v) detectable and mild symptomatic effects after placebo administration in less than 20% of the cohort; (vi) protracted minimal and questionable symptomatic effects after placebo administration in 6% of the cohort (~2.5 h after the exposure); (vii) acute physical reactions to placebo in about 12% of the cohort and only in female participants; and (viii) long-lasting symptomatic effects of placebo in only 6% of the cohort.
The constellation of symptomatic effects induced by Δ9-THC resembled several dimensions of psychotic disorders and overlapped with evidence from previous acute challenge studies with Δ9-THC [12
]. However, in order to better understand the extent of its detrimental effects, this investigation took into account the potential nonspecific effects of the drug administration, the so-called placebo effects when they are beneficial, and nocebo effects when they are harmful [47
]. Study participants reported a number of symptoms and signs when administered placebo, indicating a nocebo effect. Both psychological (conditioning, negative expectations) and neurobiological (cholecystokinin, endogenous opioids, and dopamine) mechanisms might explain the nocebo effects observed in this study [48
]. When controlling for the prevalence, quality, and severity of the subjective and objective changes occurring under placebo, the manifestation of symptomatic effects following Δ9-THC administration remained significantly higher and of greater severity, with most of the transient psychosis-like symptoms occurring only under Δ9-THC. Also, psychotomimetic symptoms lasted significantly longer under Δ9-THC compared to the placebo condition. Similarly, some objective protracted symptoms such as poor motor coordination, posture alteration, over-inclusive thinking, and internal absorption occurred only under Δ9-THC.
Relatively longer-lasting (<24 h) self-reported effects such as tiredness, sleepiness, and increased appetite occurred only under Δ9-THC. Acute physical reactions to the intravenous administration of the drug were more prevalent and clinically more severe in participants under the influence of Δ9-THC than under placebo. Also, they appeared to be gender-specific, with only female participants showing such reactions. Physical and somatic effects were not unexpected, as Δ9-THC has been shown to acutely induce sedation and intoxication [40
Upon comparing results from this study with previous research, several factors need to be considered, including, but not limited to, the degree of current cannabis use (tolerance effect) and lifetime cannabis exposure (residual effect) of the study samples, and study design. Some research evidence indicates less prominent acute behavioral effects of Δ9-THC in current cannabis users [49
], individuals with a past history of frequent cannabis use [38
], and when administering Δ9-THC orally [50
], as also recently reviewed [39
]. Further evidence suggests that the development of tolerance may be explained by the less marked effects of acute Δ9-THC administration on brain function [51
]. Participants taking part in our intravenous Δ9-THC challenge had been abstinent from cannabis for at least six months. Apart from one subject, the study cohort had also modest previous cannabis exposure. Altogether, previous evidence and our findings suggest that healthy subjects with modest previous cannabis exposure and a proper abstinent period might be more reliable to study the psychotropic effect of Δ9-THC and its underlying mechanisms.
Only individuals with negligible use of other substances (alcohol, tobacco, and other illicit drugs) were invited to take part in the study. Therefore, we can reasonably rule out the possibility that some of the results observed could be attributed to the effects of other substance use. Moreover, this study observed an interval between the two study visits of at least 14 days. This allows us to exclude the possibility of carryover effects from the first session, in light of evidence that Δ9-THC has an elimination half-life of 18 h to 4.3 days [53
]. Furthermore, all the participants’ urine samples collected at each study visit baseline were negative for the presence of Δ9-THC.
For the purpose of the study and due to ethical reasons, individuals with cannabis dependence or previous negative response to cannabis were excluded from the study. While this allowed us to examine a more homogeneous sample, this might have limited the application of the present results to the general population. Also, caution should be used when making inferences to the general population, as this experiment was conducted in a relatively small sample. The intravenous route of administration was used to allow much more consistent Δ9-THC blood levels across participants and potentially reduce inter-individual variability in drug response [12
]. For instance, absorption is slower when cannabinoids are ingested, with Δ9-THC peak concentrations that are lower and more delayed [54
], and absorption may also considerably vary between subjects [55
]. Similarly, another line of research suggests that cannabinoid levels following cannabis smoking may vary depending on how intensively and efficiently people smoke [56
]. However, the intravenous route of administration might have affected the generalizability of the results to the effects of recreational cannabis use. Future studies are needed to assess in the same individuals the effects of acute cannabis challenge using different routes of administration.