Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function, Celia J. A. Morgan et al., 2018

Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function

Celia J. A. Morgan, Tom P. Freeman, Chandni Hindocha, Grainne Schafer, Chelsea Gardner and
H. Valerie Curran

Translational Psychiatry, 2018, 8, 181

DOI 10.1038/s41398-018-0191-x



The main active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC), can acutely induce psychotic symptoms and impair episodic and working memory. Another major constituent, cannabidiol (CBD), may attenuate these effects. This study aimed to determine the effects of THC and CBD, both alone and in combination on psychotic symptoms and memory function. A randomised, double-blind crossover design compared the effects of (i) placebo, (ii) THC 8mg, (iii) CBD 16 mg and (iv) THC 8mg + CBD 16 mg administered by inhalation through a vaporiser. Using an experimental medicine approach to predict treatment sensitivity, we selected 48 cannabis users from the community on the basis of (1) schizotypal personality questionnaire scores (low, high) and (2) frequency of cannabis use (light, heavy). The Brief Psychiatric Rating Scale (BPRS), Psychotomimetic States Inventory (PSI), immediate and delayed prose recall (episodic memory), 1- and 2-back (working memory) were assessed on each day. Results indicated that THC increased overall scores on the PSI, negative symptoms on BPRS, and robustly impaired episodic and working memory. Coadministration of CBD did not attenuate these effects. CBD alone reduced PSI scores in light users only. At a ratio of 2:1, CBD does not attenuate the acute psychotic and memory impairing effects of vaporised THC. Frequent cannabis users may show a blunted anti- psychotic response to CBD, which is of concern due to the high rates of cannabis use disorders in patients with schizophrenia.



Cannabis (marijuana) is used by over 180 million people worldwide1. Possible consequences of use include dependency, cognitive impairment and increased risk of psychotic illness2. However, most people who try cannabis do not experience prolonged adverse effects. Several factors predict vulnerability, including the rs2494732 locus of the AKT1 genotype3–5, adolescent exposure6,7, frequency of use8–10, schizotypy or schizophrenia11–15 and the type of cannabis used2,16. Although it is typically classified as a single drug, the cannabis plant can contains over 100 unique ‘cannabinoids’, with diverse and sometimes opposing pharmacological actions17.

Cannabis containing high levels of delta-9- tetrahydrocannabinol (THC) and little if any cannabidiol (CBD) is becoming increasingly prevalent18,19 and is linked to greater cannabis dependency, memory impairment and paranoia20 and increased risk of psychotic illness21.

Delta-9-THC produces the effects that users seek from cannabis, including ‘stoned’, ‘like drug effect’ and ‘want more drug’22,23. THC elicits robust, dose-dependent impairments in immediate and delayed verbal memory2,24 and transient positive and negative symptoms reminiscent of schizophrenia25,26.

CBD is non-intoxicating and does not influence ratings of ‘stoned’ following the administration of THC or cannabis2,16. However, CBD can produce opposite effects to THC across a range tasks and functional neuroimaging assessments26–28. In terms of behavioural effects, CBD given alone was found to improve memory consolidation29 and in combination with THC is associated with higher recognition memory scores in chronic cannabis users30. CBD also appeared to block the impairing effects
of THC on verbal recall in a naturalistic study31, which was replicated in a laboratory study of oral CBD and intravenous THC32.

In terms of psychosis, CBD displayed equivalent efficacy to a standard antipsychotic drug for the treatment of positive and negative symptoms33. A preliminary study with 6 volunteers found that oral CBD pre-treatment reduced acute psychotic symptoms following intravenous THC26. In a subsequent study of 48 volunteers, CBD reduced the incidence of clinically significant positive psychotic symptoms (but not their overall severity) following intravenous THC32. However, a naturalistic study did not find evidence for protective effects of CBD on THC-induced psychotic-like symptoms31.

Chronic exposure to CBD has also been linked to fewer psychotic-like symptoms in those who have been exposed to THC34, a finding that was replicated in light but not heavy cannabis users30.

Taken together, the available data provides some evidence that CBD protects against the harmful effects of THC on memory and psychotic-like symptoms. However, only one study has examined the interactive effects of inhaled THC and CBD35,36 no study to our knowledge has examined the interactive effects of THC and CBD on these variables in an experimental design with an inhaled route of administration37, which better reflects how cannabis is typically administered than oral or intravenous routes. Furthermore, preliminary data suggest that frequency of cannabis use and schizotypy may predict how an individual responds to THC and and/or CBD. However, we are unaware of any experimental studies comparing the effects of different cannabinoid combinations (e.g. THC, THC + CBD, CBD) among volunteers selected for their vulnerability or resilience.

Here, we adopted an experimental medicine approach in order to assess the effects of cannabinoids on
psychotic-like symptoms and memory function. A randomised, double- blind, crossover design was used to mimic the effects of cannabis with varying cannabinoid concentrations, as well as CBD alone. Across four sessions, each volunteer received THC (8 mg), THC (8 mg) + CBD (16 mg), CBD (16 mg) and placebo (ethanol vehicle). We predicted, firstly, that memory impairment and psychotic-like symptoms would occur following THC, secondly, CBD would offset these effects when coadministered with THC, and thirdly, CBD alone would have pro-cognitive and anti- psychotic effects. In order to extend previous work showing that schizotypy/psychosis and cannabis use frequency are possible vulnerability/ resilience factors cannabis users were selected from a large-scale study on the basis of their cannabis use and schizotypal personality scores30. We predicted that infrequent users8–10,30 and people with high psychosis proneness11,12,14,15 would show heightened susceptibility to THC, CBD, and their interactive effects.