Descriptive Psychopathology of the Acute E ffects of Intravenous Delta-9-Tetrahydrocannabinol Administration in Humans
Marco Colizzi, NathalieWeltens, Philip McGuire, Lukas Van Oudenhove and Sagnik Bhattacharyya
Brain Sciences, 2019, 9, 93
doi : 10.3390/brainsci9040093
Abstract :
Background : Cannabis use can increase the risk of psychosis, and the acute administration of its key psychoactive ingredient, delta-9-tetrahydrocannabinol (D9-THC), can induce transient psychotomimetic symptoms.
Methods : A double-blind, randomized, placebo-controlled crossover design was used to investigate the symptomatic eff ects of acute intravenous administration of D9-THC (1.19 mg/2 mL) in 16 healthy participants (seven males) with modest previous cannabis exposure.
Results : In the 20 min following acute D9-THC administration, symptomatic e ffects of at least mild severity were present in 94% of the cohort, with moderate to severe symptoms having a much lower prevalence (19%). Nearly one-third (31%) of the volunteers were still experiencing protracted mild symptomatic e ffects 2.5 h after exposure to D9-THC. Compared to the D9-THC challenge, most of the study participants did not experience any symptomatic e ffects following placebo administration (62%). Acute physical reactions were 2.5 times more frequent after D9-THC (31%) than placebo (12%). Male and female participants di ered in terms of acute D9-THC e ffects, with some negative symptoms occurring more frequently in female (56% to 89%) than male participants (0% to 29%), and acute physical reactions occurring exclusively in the female gender (56%).
Conclusions : These results have implications for future research, also in light of cannabis being the most widely used illicit drug.
Keywords : delta-9-tetrahydrocannabinol; placebo; cannabis-associated psychosis; schizophrenia
1. Introduction
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, di fferent 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 [7,8]. 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 (D9-THC) has been shown to induce transient psychosis-like symptoms in otherwise healthy individuals [10–13]. 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 [14–16], especially against a specific genetic background [17,18];
(ii) the evidence that cannabis use can exacerbate psychotic symptoms and cause relapse in patients with schizophrenia [19–23];
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 [24,25], as well as involved in modulating cognitive function in healthy individuals [26–28].
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 [29–31]. In many respects, experimental studies examining the nature of the psychotomimetic e ffects of D9-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 e ffects of D9-THC have reported them as summary measure using the PANSS (Positive and Negative Syndrome Scale) [11,12,32–36], BPRS (Brief Psychiatric Rating Scale) [37], SSPS (State Social Paranoia Scale) [35], or self-report questionnaires [12,32,34]. A limited range of other e ffects has also been investigated using self-report questionnaires and visual analogue measures, including dissociation [12], a ect and mood [11,12,32,34–37], sedation and intoxication [11,12,36,37], and anxiety and panic [11,12,36].
Also, evidence indicates that frequent cannabis users have a more blunted response to the acute psychotomimetic eff ects of D9-THC compared to a group of healthy controls, suggesting the potential development of tolerance [38,39]. 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 e ffects of acute D9-THC administration under controlled experimental conditions in a group of healthy individuals with modest previous cannabis use.
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brainsci-09-00093