Food additives and hyperactivity: the University of Southampton studies Jim Stevenson 30 March 2011

Hyperactivity

3 A pattern of behaviour showing marked individual differences in the general population and comprises overactive, impulsive and inattentive behaviour. Children with an extreme degree of hyperactivity may be diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD). Increased hyperactivity is associated with later educational difficulties and antisocial behaviour

4 ADHD and hyperactivity – disorder/normal variation. ADHD

5 Genetic influences Quantitative genetic studies twin study heritability c 0.66 Molecular genetic studies genes within dopamine system e.g. DRD4

6 Experiential/environmental influences on hyperactivity Institutional care Tizard and Hodges (1978) Romanian adoptees into UK (Kreppner et al., 2001) Brain damage prematurity 2.64 relative risk for ADHD (Bhutta et al., 2002) hydrocephalus (Stevenson & Pit-ten Cate, 2004)

7 So a wide range of contributing factors act in concert to increase the degree of hyperactivity shown by a child. Are food colours one of these factors?

Previous work on food colours and hyperactivity

Pharmacological effect of artificial food colours, flavours and natural salicylates. “No consistent evidence of effect” NIH (1983) Feingold hypothesis

10 Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta- analysis of double-blind placebo-controlled trials. Schab, D.W. & Trinh, N-A. (2004). Journal of Developmental and Behavioral Pediatrics, 25, Meta-analysis

11 “…in Sept 2002…. 15 unique double-blind placebo-controlled trials evaluating the behavioural effect of AFCs among subjects whose baseline diagnosis of hyperactivity has been graded.” Schab, D.W. & Trinh, N-A. (2004). Journal of Developmental and Behavioral Pediatrics, 25,

12 Sig. effect of additives Schab, D.W. & Trinh, N-A. (2004). Journal of Developmental and Behavioral Pediatrics, 25,

University of Southampton studies

Isle of Wight study

15

Design of I.o.W. Study All 3 year olds children on IoW N = 2677 Screen for HA Screen for Atopy HAAtopy Controls 60 HA+ AT+60 HA+ AT-60 HA- AT+60 HA- AT- Bateman et al. (2004) Archives of Disease in Childhood, 89,

On measures at home rated by parents food additives are having a detrimental effect on activity and possibly inattention. No detectable effect on behaviour at clinics. – parallels finding by Shulte-Korne et al (1996) Bateman et al. (2004) Archives of Disease in Childhood, 89, The UK Food Standards Agency decided that these results needed replication and extending

Southampton study

19

20 Design of Southampton Study Randomised, double-blind, placebo controlled, crossover trial. 3-year-olds (N= 153) and 8/9-year-olds (N = 144) from the general population. Baseline week on usual diet, then additives withdrawn. Over subsequent 6 weeks series of placebo or additive mix drinks given daily in a randomised sequence. Hyperactivity measured using parent and teacher ratings, observations of child in preschool setting or classroom and a computerised test of attention for 8/9-year-olds Combined to form Global Hyperactivity Aggregate (GHA) McCann et al. (2007) Lancet, 370,

Distribution of the Global Hyperactivity Aggregate at baseline for 8/9 year olds 21

22 Normal diet AFCPs withdrawn + placebo Active or placebo Washout + placebo Active or placebo Washout + placebo Active or placebo Week 0Week 1Week 2Week 3Week 4Week 5Week 6 Test 0Test 1Test 2Test 3Test 4Test 5Test 6 Week 2Week 4 Week 6 PlaceboMix AMix B PBA APB ABP BAP BPA x 20 for each age group McCann et al. (2007) Lancet, 370,

23 Mix contents E NumberUS LabelName of AdditiveMix AMix B E102 ColourYellow 5 (FD&C)Tartrazine  E104 ColourYellow10 (FD&C)Quinoline yellow  E110 ColourYellow6 (FD&C)Sunset Yellow E122 Colour14720 (CI#)Carmoisine E124 Colour16255 (CI#)Ponceau 4R  E129 ColourRed40 (FD&C)Allura Red AC  E211 PreservativeSodium benzoate Mix A was the same as the active challenge employed in the Isle of Wight study published in Mix B reflected a high average daily consumption of the additives by 3 and 8/9 year old UK children at the time the study was commissioned (2004). McCann et al. (2007) Lancet, 370,

24 Results – 3 year olds * * p<.05 McCann et al. (2007) Lancet, 370,

25 Results – 3 year olds * * p<.05 McCann et al. (2007) Lancet, 370,

26 Results – 3 year olds * * p<.05 McCann et al. (2007) Lancet, 370,

27 Results – 8/9 year olds * * p<.05 McCann et al. (2007) Lancet, 370,

28 Results – 8/9 year olds ** ** p<.01 McCann et al. (2007) Lancet, 370,

29 Results – 8/9 year olds * p<.05 ** p<.01 *** McCann et al. (2007) Lancet, 370,

30 European Food Standards Authority “The Panel concludes that the McCann et al. study provides limited evidence that the two different mixtures of synthetic colours and sodium benzoate tested had a small and statistically significant effect on activity and attention in children selected from the general population excluding children medicated for ADHD…..” The EFSA Journal (2008) 660, 1-53

What might be the mechanisms underlying these effects of food additives on behaviour?

32 Stevenson et al. (2010) American Journal of Psychiatry, 370,

33 histamine histamine N-methyltranferase gene Thr105Ile (rs ) and T939C (rs ) dopamine catechol-o-methyltransferase Val108Met (rs4680) adrenergic adrenergic receptor alpha 2A ADRA2A C1291G (rs ). dopamine dopamine receptor D4 (DRD4) DRD4 (rs ) dopamine transporter gene (DAT1, 10-repeat) Possible genetic moderators Stevenson et al. (2010) American Journal of Psychiatry, 370,

34 Possible genetic moderators Variable number tandem repeat (VNTR) dopamine dopamine receptor D4 (DRD4) dopamine transporter gene (DAT1, 10-repeat)) Stevenson et al. (2010) American Journal of Psychiatry, 370,

35 3 year olds8/9 year olds Stevenson et al. (2010) American Journal of Psychiatry, 370,

36 Histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistency between previous studies. Stevenson et al. (2007) American Journal of Psychiatry, 370,

How important are these effects?

Impact on mean hyperactivity scores McCann et al. (2007), Lancet, 370, ; Schab & Trinh (2004) J.Dev.Behav. Ped., 25, ; Kreppner et al. (2004). J Ab. Ch. Psych., 29, ; Aarnoudse-Moens et al. (2009). Ped., 124, ; Fabiano et al. (2009). Clin. Psych. Rev., 29, ; Faraone et al. (2010) Eur.Ch.Ad. Psychiat., 19,

39 0 Changes in mean hyperactivity scores Hyperactivity or ADHD symptom severity score.2.7 McCann et al. (2007) food additives vs placebo Conners et al. (2001) MTA trial Combined treatment vs community comparison population meanADHD mean 2

* * * * * p <.05 from reference category 0 McGee (2002) J Child Psychol Psychiat, 43, “There were strong linear relationships between early hyperactivity and later adverse outcomes. Adjustment for other childhood variables suggested that early hyperactivity was associated with continuing school difficulties, problems with attention and poor reading in adolescence.”

41 Conclusions Mixtures of certain artificial colours together with a sodium benzoate preservative in the diet increased the average level of hyperactivity in 3 and 8/9 year old children in the general population. The mean effect in these general population samples (0.18) is similar to that found by Schab and Trinh in well designed studies of clinic samples (0.21). Although the results of the study suggest that some mixtures of certain artificial food colours and benzoate preservative may affect the level of hyperactive behaviour in children, removal of these additives from the diet would not be a panacea for ADHD. McCann et al. (2007) Lancet, 370,

Prof. Jim StevensonPsychologist Prof. John WarnerPaediatrician Prof. Edmund Sonuga-BarkePsychologist Dr. Donna McCannPsychologist Kate GrimshawDietitian Yuet-Wan Lok Dietitian Debbie CrumplerSecretary Research assistant psychologists: Angelina Barrett Alison Cooper Lyndy Dalen Elizabeth Kitchin Lucy Porteous Emily Prince Catherine Varcoe-Baylis