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Explorative Placebo-Controlled Double-Blind Intervention Study Cannabis and Cannabinoid Research Volume 2.1, 2017 Cannabis and DOI: 10.1089/can.2017.0018 Cannabinoid Research ORIGINAL RESEARCH Open Access Explorative Placebo-Controlled Double-Blind Intervention Study with Low Doses of Inhaled D9-Tetrahydrocannabinol and Cannabidiol Reveals No Effect on Sweet Taste Intensity Perception and Liking in Humans Suzanne E.M. de Bruijn, Cees de Graaf, Renger F. Witkamp, and Gerry Jager* Abstract Introduction: The endocannabinoid system (ECS) plays an important role in food reward. For example, in humans, liking of palatable foods is assumed to be modulated by endocannabinoid activity. Studies in rodents suggest that the ECS also plays a role in sweet taste intensity perception, but it is unknown to what extent this can be extrapolated to humans. Therefore, this study aimed at elucidating whether D9-tetrahydrocannabinol (THC) or cannabidiol (CBD) af- fects sweet taste intensity perception and liking in humans, potentially resulting in alterations in food preferences. Materials and Methods: In a randomized placebo-controlled, double-blind crossover study, 10 healthy males par- ticipated in three test sessions that were 2 weeks apart. During the test sessions, participants received THC-rich, CBD- rich, or placebo Cannabis by inhalation divided over two doses (4 + 1mgTHC;25 + 10 mg CBD). Participants tasted seven chocolate milk-like drinks that differed in sugar concentration and they rated sweet taste intensity and liking of the drinks. They were then asked to rank the seven drinks according to how much they liked the drinks and were offered ad libitum access to their favorite drink. In addition, they completed a computerized food preference task and completed an appetite questionnaire at the start, midway, and end of the test sessions. Results: Inhalation of the Cannabis preparations did not affect sweet taste intensity perception and liking, rank- ing order, or ad libitum consumption of the favorite drink. In addition, food preferences were not influenced by the interventions. Reported fullness was lower, whereas desire to eat was higher throughout the THC compared to the CBD condition. Conclusions: These results suggest that administration of Cannabis preparations at the low doses tested does not affect sweet taste intensity perception and liking, nor does it influence food preferences in humans. Keywords: cannabidiol; food preferences; phytocannabinoids; sweet taste; tetrahydrocannabinol Introduction energy deficit.1 More specifically, the ECS seems to Downloaded by 62.72.192.93 from online.liebertpub.com at 06/23/17. For personal use only. There is growing evidence that the endocannabinoid modulate palatability-dependent appetite,2–5 although system (ECS) plays an important role in the regulation the underlying mechanisms are far from clear. of hedonic hunger, that is, consuming foods for the ex- It is important to note that palatability, or pleasant- perience of reward and not for the compensation of any ness, is not a fixed function of the sensory properties Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. Parts of this study have previously been submitted as an abstract to the International Cannabinoid Research Society 2015 and to the Society for the Study of Ingestive Behavior 2015. *Address correspondence to: Dr. Gerry Jager, Division of Human Nutrition, Wageningen University, P.O. Box 17, Wageningen 6700 AA, The Netherlands, E-mail: [email protected] ª Suzanne E.M. de Bruijn et al. 2017; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mary Ann Liebert, Inc. offers reprint services for those who want to order professionally produced copies of articles published under the Creative Commons Attribution (CC BY) license. To obtain a price quote, email [email protected]. Please include the article’s title or DOI, quantity, and delivery destination in your email. 114 de Bruijn, et al.; Cannabis and Cannabinoid Research 2017, 2.1 115 http://online.liebertpub.com/doi/10.1089/can.2017.0018 (e.g., taste, smell, texture) of a food, but also depends on THC bioavailability varied widely and THC could the hedonic evaluation of more qualitative (liking) and not be detected in plasma of all participants.28 Based contextual (eating occasion) characteristics.6,7 on the limited number of studies performed in hu- Considering taste, there seem to be two ways in which mans, the aim of this study was to further investigate taste intensity perception and liking can be modulated. whether modulating the ECS by administering phyto- One is through alterations in quantitative taste intensity cannabinoid preparations affects sweet taste intensity perception, reflected by a shift in the psychophysical perception and liking in humans, and whether this re- (concentration intensity) function. In case of, for exam- sults in altered food preferences. ple, sweet taste, the same sugar concentration is per- ceived as more or less intensely sweet. The other way Methods is related to changes in hedonic evaluation, reflected Participants by a shift in the psychohedonic (intensity pleasantness) Ten healthy, normal weight (body mass index = 21.7 – function, where for example, the perceived sweetness in- 1.2 kg/m2)malesaged23.4– 1 years participated in this tensity of a sugar concentration is unchanged, but the study. Participants were incidental Cannabis users to en- perceived sweetness is liked more or less.8 sure familiarity with the psychotropic effects of Cannabis In rodents, endocannabinoid activity modulates sweet use. Frequency of use ranged from four times a year to taste palatability. Endocannabinoid stimulation en- once a week. To limit the risk of adverse events, males hances liking of sweet taste9,10 and motivational behav- were excluded from participation when they had ever ex- ior aimed at obtaining a sucrose solution,11 whereas perienced negative effects from using Cannabis (e.g., bad endocannabinoid inhibition reduces liking and motiva- trip, Cannabis-induced psychosis). Other exclusion crite- tional behavior.9,11 Some studies suggest that adminis- ria were restraint eating (Dutch eating behavior question- tration of cannabidiol (CBD) decreases food naire: score >2.9),29 lack of appetite, difficulties swallowing intake,12,13 possibly through indirect antagonism of the or eating, having taste or smell disorders (self-report), fol- ECS,14,15 whereas other studies do not find an effect of lowing an energy-restricted diet 2 months before the CBD on food intake.16,17 Taken together, it is clear study, weight change >5 kg during the 2 months before that CBD is far from being a classical ligand for the the study, and being allergic or intolerant to the products CB1 or CB2 receptor. The molecule displays a wide spec- under study. Participants were instructed to abstain from trum of activities on various molecular targets and pro- Cannabis from 2 weeks before the first test session until duces multiple pharmacological effects.15,18 study completion. Compliance was tested by means of a Administration of endocannabinoids was found to urine sample (SureScreen Diagnostics Ltd.) at the begin- specifically increase responses to sweet taste in the ning of each test session. Participants were also asked Chorda tympani, the nerve that innervates the tongue, not to use alcohol in the 2 days before a test session 19 in wild-type mice, but not in CB1 knockout mice. and not to eat or drink anything except water or Administration of a CB1 antagonist decreased re- weak tea during the 2 h before a test session. Partici- sponses to sweet taste in the Chorda tympani.20 pants gave written informed consent before the start Together, these results suggest that modulating the of the study and they received financial compensation ECS selectively changes the psychophysical function at the end of the study. The study was approved by the for sweet taste in mice. Medical Ethics Committee of Wageningen University Downloaded by 62.72.192.93 from online.liebertpub.com at 06/23/17. For personal use only. In humans, anecdotal evidence suggests that the use andwasconductedinaccordancewiththeHelsinki of Cannabis preparations increases food palatability declaration of 1975, as revised in 2008. The study and intake,21–25 a phenomenon colloquially known as was registered on clinicaltrials.gov as NCT02112292. ‘‘the munchies.’’ Furthermore, the CB1 inverse agonist rimonabant decreases food intake.26,27 Thus far, Design and procedures only one study examined the effects of oral adminis- The study had a randomized, placebo-controlled, double- tration of D9-tetrahydrocannabinol (THC) on taste blind crossover design. All participants completed one intensity and liking in humans. In a double-blind practice session (familiarization with the test procedures) placebo-controlled study, acute Cannabis administra- and three test sessions after administration of Cannabis tion was found not to affect taste intensity perception rich in THC, CBD, or placebo (for details see section and liking for sweet, sour, salty, and bitter food stimuli ‘‘Study drugs and administration’’). Test sessions were at baseline, and 2, 4, and 6 h postdosing. However, 2 weeks apart to allow for complete clearance of drugs. de Bruijn, et al.; Cannabis and Cannabinoid Research 2017, 2.1 116 http://online.liebertpub.com/doi/10.1089/can.2017.0018 Each test session
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