Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis
Marco Colizzi, Nathalie Weltens, Philip McGuire, David Lythgoe, Steve Williams, Lukas Van Oudenhove, Sagnik Bhattacharyya
Molecular Psychiatry, 15 February 2019
The neurobiological mechanisms underlying the association between cannabis use and acute or long lasting psychosis are not completely understood. While some evidence suggests altered striatal dopamine may underlie the association, direct evidence that cannabis use affects either acute or chronic striatal dopamine is inconclusive. In contrast, pre-clinical research suggests that cannabis may affect dopamine via modulation of glutamate signaling. A double-blind, randomized, placebo-controlled, crossover design was used to investigate whether altered striatal glutamate, as measured using proton magnetic resonance spectroscopy, underlies the acute psychotomimetic effects of intravenously administered delta 9-tetrahydrocannabinol (Δ9-THC; 1.19 mg/2ml), the key psychoactive ingredient in cannabis, in a set of 16 healthy participants (7 males) with modest previous cannabis exposure. Compared to placebo, acute administration of Δ9-THC significantly increased Glutamate (Glu)+Glutamine (Gln) metabolites (Glx) in the left caudate head (P=0.027). Furthermore, compared to individuals who were not sensitive to the psychotomimetic effects of Δ9-THC, individuals who developed transient psychotic-like symptoms (~70% of the sample) had significantly lower baseline Glx (placebo; P 7=0.023) and a 2.27-times higher increase following Δ9-THC administration. Lower baseline Glx values (r=−0.55; P=0.026) and higher previous cannabis exposure (r=0.52; P=0.040) were associated with a higher Δ9-THC-induced Glx increase. These results suggest that an increase in striatal glutamate levels may underlie acute cannabis induced psychosis while lower baseline levels may be a marker of greater sensitivity to its acute psychotomimetic effects and may have important public health implications.
Cannabis is the most widely used illicit drug in Europe and over the world, with approximately 200 million users  and an estimated 13 million individuals with cannabis dependence . It represents a public health concern as cannabis use can induce transient psychotic symptoms [3–5] and trigger the onset of psychosis in vulnerable individuals . Moreover, cannabis use can exacerbate psychotic symptoms [7–9] and increase the risk of relapse [10–12] in patients with established psychosis in a dosedependent manner . Cannabis exerts its psychotomimetic effects primarily through its psychoactive component delta-9- tetrahydrocannabinol (Δ9-THC) [14–16]. Δ9-THC is a partial agonist at the endocannabinoid receptor type 1 (CB1), which is widely expressed throughout the brain  and downregulated in response to sustained cannabis use . Δ9-THC has consistently been shown to stimulate the neuronal firing of mesolimbic dopamine neurons and elevate striatal dopamine levels in animal models . However, acute administration of Δ9-THC has been shown to induce striatal dopamine release in some [20–22] but not all human studies [23, 24] (also reviewed in ), while a deficit in striatal dopamine release has been reported in cannabis dependence . Additional evidence suggests that Δ9-THC disrupts striatal function , and genetic variation in dopamine signaling modulates this effect . The difficulty in capturing the acute effect of Δ9-THC on striatal dopamine in man may be explained by the biological distance between Δ9-THC effects and dopamine dysregulation, as evidence suggests that Δ9-THC does not affect dopamine release directly but via CB1-dependent modulation of glutamate signaling . Converging evidence from preclinical studies indicates that acute Δ9-THC administration induces a dose-dependent increase in cortical extracellular, striatal, and hippocampal intracellular glutamate levels through the activation of CB1 receptors at glutamatergic presynapses in cortical and subcortical brain regions, reflecting a reduction in synaptic glutamate levels and receptor functioning [28–30], also reviewed here . A limited number of studies consistently support the evidence for altered brain glutamate levels as measured by proton magnetic resonance spectroscopy (1H-MRS) in otherwise healthy chronic cannabis users, with all [32–35] but one  of the five studies indicating reduced levels of glutamate-derived metabolites Glutamate (Glu) or Glutamate + Glutamine (Glx) in both cortical and subcortical brain areas. The only study not showing an effect of cannabis on glutamate in man investigated a modestly sized sample of cannabis users with concurrent methamphetamine use . In contrast, another study conducted in a larger sample suggested reduced Glx metabolite concentration also in individuals with a history of other illicit drug use . However, the cross-sectional case-control design of these studies does not allow one to infer a cause–effect relationship underlying the observed association between cannabis use and glutamatergic alterations in the brain. To our knowledge, no study has as yet investigated the acute effect of Δ9-THC on brain glutamate levels in man as a potential mechanism underlying its psychotomimetic effects. Therefore, we employed a placebo-controlled acute pharmacological challenge design to investigate the acute effect of Δ9-THC administration on brain glutamate levels in man. We focused on three brain regions, the striatum, the hippocampus, and the anterior cingulate cortex (ACC), as preclinical studies suggested that acute Δ9-THC administration increased glutamate levels not only in the striatum but also in other brain regions, such as the prefrontal cortex and hippocampus [28–30]. Evidence suggests that (1) Δ9-THC administration in animal models increases glutamate levels in the striatum , (2) Δ9-THC-induced increase in glutamate levels leads to an excess striatal dopamine via neuronal circuitry involving hypofunctioning N-methyl-D-aspartate (NMDA) receptors , and (3) Δ9-THC-induced modulation of striatal activation is related to the severity of acute psychotomimetic effects induced by it in humans [15, 16, 27]. Hence, we specifically hypothesized that (1) acute Δ9-THC administration would be associated with an increase in striatal glutamate-derived metabolites; (2) Δ9-THC-induced striatal glutamate increase would be associated with the development of psychotomimetic symptoms. Based on the limited evidence of a blunted effect of acute Δ9-THC administration on neurochemical markers (brain-derived neurotrophic factor (BDNF)) in cannabis users compared to healthy subjects , the following hypothesis was also tested: (3) previous cannabis exposure would modulate the acute effect of Δ9-THC on striatal glutamate. We also carried out exploratory analyses to examine whether the acute effects of Δ9-THC on brain glutamate levels in man were specific to the striatum or also noted in the hippocampus and ACC.