“The effects of cannabidiol and analgesic expectancies on experimental pain reactivity in healthy adults: A balanced placebo design trial”
Martin De Vita, Syracuse University, Department of Psychology
Despite its frequent use for pain relief, no experimental pain research has tested the analgesic effects of cannabidiol (CBD) in humans.This study aimed to experimentally test the effects of CBD (50mg) and expectancies for receiving CBD on human pain reactivity. Drug administration and verbal instruction sets were experimentally manipulated using a crossover, 2×2 factorial balanced placebo design. Fifteen healthy adults each completed 4 separate experimental sessions.Participants were randomly assigned to different counterbalanced manipulated conditions at each session: control (told inactive – given inactive); expectancy (told active CBD – given inactive); drug (told inactive – given active CBD); and expectancy+drug (told active CBD – given active CBD). Primary outcomes were pain threshold, tolerance, intensity, unpleasantness, conditioned pain modulation (CPM), and offset analgesia (OA). The results showed a significant main effect of instructions on OA, such that the OA response was significantly larger when participants were told that they received CBD, regardless of drug content. Pain unpleasantness was significantly reduced in the drug, expectancy, and expectancy+drug conditions, relative to the control condition. The drug and expectancy conditions separately improved CPM, whereas the expectancy+drug and control conditions produced the lowest CPM change scores. We did not detect significant effects for pain threshold, tolerance, or intensity.
Cannabidiol (CBD) has attracted widespread interest as a nonintoxicating alternative to traditional cannabinoid-based analgesics.1 CBD has shown a good safety profile and low abuse potential in humans.2-5 Cross-sectional research has implicated pain as the most common medical condition for which CBD is used.2 Among those using CBD to treat pain, the majority reported believing that CBD works “very well” to “moderately well” for relieving their pain.2 Despite its frequent use for pain relief, no experimental pain trials have tested the analgesic effects of pure CBD in humans.
A recent meta-analytic review concluded that cannabinoid drugs may not reduce the intensity of experimental pain, but instead make pain feel less unpleasant, suggesting a notable influence on affective processes.6 What remains unclear is whether cannabinoid analgesia is attributable to intoxication (e.g., feeling “high”), analgesic expectancies, and/or pharmacological action. Experimental pain studies have exclusively administered cannabinoids (e.g., Δ9-THC) with intoxicating properties.6 Blinding procedures in placebo-controlled cannabinoid trials often fail due to these effects,7 which may interact with widely held expectancies (e.g., cannabis reduces pain) to produce placebo effects. Expectations for receiving pain-relieving substances can induce robust placebo analgesia.8,9 Despite receiving little empirical attention, expectancies likely play an important role in cannabinoid analgesia.
One promising approach to address these questions involves testing the effects of CBD and analgesic expectancies on human pain reactivity using a balanced placebo design. This experimental design crosses instructions about the substance to be administered with the substance that actually is administered.10-12 Experimental pain methods systematically apply quantifiable sensory stimuli to evaluate perceptual pain reactivity.13-16 Experimental pain assessment methods can yield insights into multiple aspects of cannabinoid analgesia.6 Laboratory pain assessments avoid confounds present in clinical data by studying how controlled cannabinoid doses affect quantifiable responses to painful stimuli in healthy humans.17 To date, no experimental pain study has examined cannabinoid analgesia using a balanced placebo design. Given its purported analgesic effects, as well as widely held beliefs that CBD is an effective pain reliever, CBD is an ideal candidate for balanced placebo design trials.
Using a crossover, balanced placebo 2 x 2 factorial design, we tested the effects of CBD and expectancies for receiving CBD on experimental pain reactivity (i.e., pain threshold, tolerance, intensity, unpleasantness, conditioned pain modulation, offset analgesia) by manipulating both drug administration (given inactive substance or given CBD) and instructions (told inactive substance or told CBD) in healthy humans. We hypothesized that telling participants they received CBD (versus inactive substance) would produce significant analgesic effects, independent of whether participants received CBD. We also hypothesized that we would not detect drug (CBD) or CBD x instructions interaction effects. This study was preregistered on the Open Science Framework (doi: 10.17605/OSF.IO/5UN2D).
Fifteenhealthy adults (67% Female; Mage = 20.73, SD = 2.60) completed 4 weekly experimental sessions. They were randomly assigned to 1 of 4 counterbalanced manipulated conditions at each session: control (told inactive – given inactive); expectancy (told active – given inactive); drug (told inactive – given active); and expectancy + drug (told active – given active). At session 1, participants completed baseline self-report measures before undergoing a pre-manipulation experimental pain assessment administered using a Q-Sense unit (Medoc LTD.) equipped with two 30×30 mm contact-heat thermodes. Participants then received 1 of the 4 the instructional set and drug administration combinations according to their order assignment. Following a 30-minute absorption period, post-manipulation pain assessments were performed. Afterwards, participants completed manipulation check measures. All sessions followed similar procedures.
In active drug conditions, participants received 50mg of CBD isolate sublingually via oil dropper. Fractionated coconut oil (the CBD oil base) was administered in equal volume in inactive conditions. Verbal instructional sets were used to manipulate expectancies for receiving CBD (told active) or coconut oil (told inactive). The pain reactivity assessment protocol was as follows.
Static pain reactivity measures evaluated responses at a specific moment in time, and included pain threshold, tolerance, intensity, and unpleasantness. Pain threshold was the lowest stimulus intensity (°C) perceived as being painful. Tolerance was the maximum intensity that a participant could withstand, as determined by use of a method of limits.18 Pain intensity and unpleasantness ratings were measured using scales that assessed sensory and affective dimensions of pain, respectively.18 Participants provided ratings using a visual analogue scale (VAS) ranging from 0 to 100 (maximum intensity/unpleasantness possible) at 30-second intervals throughout a 2-minute continuous application of suprathreshold heat pain. Scores were averaged across measurement intervals.
Dynamic pain reactivity measures were used to activate and evaluate complex pain processing systems. Conditioned Pain Modulation (CPM) and Offset Analgesia (OA)are two dynamic measures used to evaluate central nervous system mechanisms that inhibit pain signaling. CPM represents a “pain-inhibits-pain” spatial processing mechanism, where participants first received a single experimental pain stimulus on their dominant arm, followed by an additional competing stimulus administered on the other arm.19 Participants rated their pain intensity continuously using a computerized VAS, and typically perceived the first stimulus as being less painful (or inhibited) when the competing stimulus was applied, despite the stimulus input remaining constant. OA represents a temporal pain processing mechanism, where a small decrease in the intensity of a painful stimulus produces a disproportionate analgesic effect on pain intensity.20 In the OA protocol, suprathreshold pain was administered and held for 5 seconds, followed by a 1°C increase for an additional 5 seconds, and then a subsequent 1°C decrease for 20 seconds. Following the 1°C decrease, participantstypically experienced disproportionately robust pain reductions (inhibition).
Pre-post change scores were computed for each pain outcome. Two-way repeated measures ANOVAs tested for main and interaction effects on QST outcomes and side-effects in SPSS v23. Significant interactions were followed up with paired samples t-tests to identify simple main effects between conditions.
All participants reported receiving the substance consistent with their instructional set for each condition. No participants endorsed feeling deceived about drug content. Order assignment was not significantly correlated with any QST outcome (ps > .05). No cannabis-related side-effects were detected or observed (ps > .05). Table 1 presents results for the two-way repeated measures ANOVAs for experimental pain outcomes. Figure 1 presents the mean change scores in each condition for all experimental outcomes.
Static Pain Measures. We detected no main or interaction effects for pain threshold, tolerance, or intensity. There were no main effects for pain unpleasantness, but results revealed a significant interaction (F[1, 14] = 8.45, p = .011, h2p = .376). In follow-up comparisons, paired-samples t-tests revealed significantly greater pain unpleasantness reductions in the expectancy (t = 3.26, p = .006, d = .860), drug (t = 3.17, p = .007, d = .820), and expectancy+drug conditions (t = 2.36, p = .033, d = .616) when compared to the control condition.
Dynamic Pain Measures. There were no significant main effects for CPM, but results revealed a significant interaction (F[1, 14] = 7.07, p = .019, h2p = .336). Follow-up comparisons revealed significantly greater CPM responses (i.e., more pain inhibition) in the expectancy (t = -2.75, p = .016, d = -.76) and drug (t = -3.20, p = .006, d = -0.84) conditions when compared to expectancy+drug condition. There was a significant instruction effect (F[1, 14] = 7.58, p = .016, h2p = .351) on OA, but no administration effect or interaction.
We tested the effects of CBD and analgesic expectancies on human pain reactivity by manipulating both drug administration and instructions and hypothesized finding analgesic effects of the instructional set (expectancy) manipulation, but null effects for drug administration and interactions. As predicted, there was a main effect of instructions on OA, such that the OA response was larger (i.e., greater pain inhibition) when participants were told that they received CBD, regardless of drug content. Our hypotheses were only partially supported for the pain unpleasantness and CPM results. Pain unpleasantness was significantly reduced in the drug, expectancy, and expectancy + drug conditions, relative to the control condition. Whereas the drug and expectancy conditions separately improved CPM, the expectancy + drug condition produced the lowest CPM change scores, closely resembling the control condition. We did not detect significant effects for pain threshold, tolerance, or intensity. Overall, our results indicated that separate pain outcomes can be differentially affected by CBD and/or expectancies for receiving CBD. These findings suggest that the analgesic profile for CBD is complex and multifaceted.
The effects of CBD and analgesic expectancies on pain unpleasantness were robust. Our results were consistent with previous meta-analytic findings that cannabinoid administration primarily decreases the unpleasantness, but not intensity of experimental pain.6 Until now, cannabinoid analgesia trials have been unable to determine whether decreases in unpleasantness are attributable to intoxication, expectancies, and/or pharmacological action. Our study was designed to address these questions. Specifically, we found that cannabinoid-induced reductions in pain unpleasantness were caused by both psychological expectancies for receiving a CBD analgesic and pharmacological administration of CBD. Notably, these effects occurred without intoxicating side-effects. Given its low abuse liability and good safety profile,21 CBD may have potential as a therapeutic alternative to traditional cannabinoid-based analgesics.
The finding that expectancies play a large role in CBD analgesia has several clinical implications. Indeed, there is an emerging clinical consensus that expectancy-induced analgesia can be leveraged to enhance pain interventions.22-29 Brief psychological interventions may promote analgesic expectancies and optimize pain treatments. Verbal instructions emphasizing analgesic treatment outcomes are particularly effective in reducing clinical pain.30 Verbally emphasizing the positive and realistic effects of CBD on pain, without overemphasizing negative side-effects, may optimize analgesic responses. Nonetheless, specifying the mechanisms underlying individual and combined effects of CBD and expectancies on pain is needed.
The current study has notable strengths. It is the first balanced placebo design experiment to examine both drug and expectancy effects in cannabinoid analgesia. This study is also the first experimental pain study to test the analgesic effects of pure CBD. Our novel approach enhanced the feasibility of experimental manipulations while overcoming blinding failures that confound placebo-controlled cannabinoid trials.
Several limitations should be considered. Our study employed experimental pain measures, which approximate clinical pain features.31 Research conducted in clinical samples is needed to test the generalizability of our findings. This study was limited to testing acute analgesic effects of a single sublingual 50mg CBD isolate dose. Future work should examine CBD analgesia using varying doses/preparations.
Despite its frequent use for pain relief, no experimental pain research has tested the analgesic effects of cannabidiol (CBD) in humans. We experimentally tested the effects of CBD and expectancies for receiving CBD on human pain reactivity. This study found that CBD analgesia was driven by both psychological expectancies and pharmacological action. Future investigations of the psychological and pharmacological mechanisms underlying CBD analgesia are warranted.