Originally a blog post at https://tics.wustl.edu/tics-in-adhd, 27 Feb 2019.ADHD is very common in people with tics: at least 50% of children with tics also have ADHD [1]. What about the other side? That is, how common are tics in children with ADHD? Previously I would have said, “well, more common than in kids without ADHD” [2]. That statement is true, but dramatically understates the situation.The best data we have comes from two randomized, controlled treatment studies of ADHD, because they observed the children prospectively for tics, blind to treatment assignment. Law and Schachar [3] carried out a careful, randomized controlled trial of methylphenidate for ADHD, lasting 1 year, in 91 children with tics (age 8). They monitored carefully for tics. Children who at the beginning of the study had “a severe motor or vocal tic disorder or Tourette’s disorder,” or who had been treated for tics, were not allowed to participate. Still, mild to moderate tics were observed in 30% of children at the start of the study (27 of 91). During the next year, 12 of the children without tics at the start of the study developed “clinically significant tics for the first time (i.e., moderate or worse).” This rate was essentially the same in children on or off methylphenidate—in other words, the risk factor is ADHD, not the stimulant. By the end of the study, more than 43% of children with ADHD had tics. We can say “more than” for at least three reasons. First, children with “severe” chronic tics or a history of treatment for tics were excluded from participation. Second, children who developed mild tics for the first time during the year of follow-up were not counted. Third, they diagnosed tics based on reports from parents and teachers–with careful questioning by trained research staff–but only supplemented by direct examination at the research visits if tics were reported to be “moderate,” “severe,” or “Tourette-like.” We know from our recent New Tics study and previous research that many tics not recognized by parents or teachers are identified when the child is observed by clinicians or trained research staff [4]. For all these reasons, probably even more children with ADHD had tics than the 43% reported by Law and Schchar.  Spencer and colleagues [5] reported on a large sample of boys with ADHD. 34% had a tic disorder at the start of the study, and 20% of the remaining boys developed tics at follow-up, so that by the end of the study half of the boys (64 of 128) had a current or past tic disorder. (In boys without ADHD, only 10 of 110 had a tic disorder by the end of the study.) The positive news was that tic disorders remitted faster than ADHD did. These diagnoses were based on DSM-III-R, which required impairment in a life role or marked distress to diagnose a tic disorder. Presumably rates would have been even higher if less bothersome tics were counted.A cross-sectional study performed face-to-face, semi-structured diagnostic interviews in children that teachers and parents identified as having possible ADHD or tics, and found a  chronic tic disorder in 57% of children diagnosed with ADHD [6]. A more recent report found tics to be 4-6 times more common in children with vs. without ADHD, and the children with tics tended to have more clinical problems and lower quality of life [7]. Interestingly, over 3 decades ago, Comings et al. concluded from clinical experience that about half of children seen for ADHD (only) either had motor or vocal tics or a relative with TS [8,9].
Many (though not all) of my patients who have tried marijuana have felt that their tics improved after using it. Such self-treatment is not rare (poster P94 here), and other doctors report similar results (see for example poster P6 here). Pharmacological benefits from cannabis products are plausible, since cannabinoid receptors in the brain's basal ganglia are well positioned to affect movement . Of course, in addition to any real benefit from marijuana, there could be expectation effects, or one could simply care less about tics when high. Random allocation clinical trials with blind rating of benefit (RCTs) are essential to demonstrating whether marijuana has any true benefit for tics. Müller-Vahl and colleagues carried out two RCTs about 15 years ago in Tourette syndrome (TS) using THC (tetrahydrocannabinol), the main intoxicating ingredient in cannabis . Both trials showed benefit, but the trials were relatively small. Two to 3 years ago, the Tourette Association of America funded two pilot studies in this field, but results have not yet been reported. One trial, at Yale, was to study the FAAH (fatty acid amide hydrolase) inhibitor PF-04457845 in TS , but the trial was placed on clinical hold pending results from a different trial. Investigators at Toronto Western Hospital were funded for a trial in TS of medical cannabis products with varying concentrations of THC and cannabidiol . Cannabidiol is being studied in several brain disorders, including epilepsy, with hopes that it may provide benefit without the psychological side effects of THC. Not surprisingly, the paucity of data has led to different viewpoints. Müller-Vahl has argued that THC may be appropriate in some TS patients , whereas an American Academy of Neurology review and a Cochrane-style review in JAMA concluded that the evidence was insufficient to recommend THC for tic disorders . The clinical utility of cannabinoids in TS was one of two clinical controversies debated at the 2015 First World Congress on Tourette Syndrome and Tic Disorders .
BackgroundIt was getting hard to find reviewers for the F1000Research Highlights papers, since one of us seemed to have collaborated with nearly everyone doing GTS research. Here are suggestions on how to find non-conflicted expert reviewers.Via PubMedFollow these steps in order: Search PubMed for (subject of article) NOT (OR'ed list of authors of this paper). Example: (Tourette [MAJR] NOT Tourette [AU]) NOT (Hartmann A [au] OR Andrén P [au] OR Atkinson-Clement C [au] OR Czernecki V [au] OR Delorme C [au] OR Debes N [au] OR Mol Debes, N [au] OR Debes, N [au] OR Szejko N [au] OR Ueda K [au] OR Black KJ) Filters: in the last 5 years Sort by: Publication Date   Then pick from the results 10+ authors I've heard of.        Then for potential reviewer names, perhaps a few at a time, search PubMed as follows to identify anyone who's published with us in the past 5 years: (list of OR'ed names from Step 2) AND (list of author names from Step 1). Example: (Emily J Ricketts [fau] OR Flint M Espil [fau] OR Douglas W Woods [fau] OR Shannon M Bennett [fau] OR John T Walkup [fau] OR Joseph F McGuire [fau] OR Jordan T Stiede [fau]) AND (Hartmann A [au] OR Andrén P [au] OR Atkinson-Clement C [au] OR Czernecki V [au] OR Delorme C [au] OR Debes N [au] OR Mol Debes, N [au]  OR Debes, N [au]  OR Szejko N [au] OR Ueda K [au] OR Black KJ) Filters: in the last 5 years Sort by: Publication Date    Results are highlighted as shown in Fig. \ref{885437}, showing that we have to scratch Szejko, McGuire, and Woods. But also we can keep the others above, namely Ricketts, Espil, Bennett, Walkup and Stiede. Note: the [fau] tag will not catch publications that don't submit the author's full name to NLM, e.g. it may miss a publication by Walkup JT [au]. I used the [fau] tag so I could just copy and paste from the PubMed search output in step 1, and I think journals are mostly submitting full author names now. Use the "Walkup J [au]" style instead to catch a few more potential conflicts.  Repeat as needed with other groups of potential reviewers.

Shan H. Siddiqi

and 5 more

ABSTRACT OBJECTIVE: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies. BACKGROUND: While safe intravenous use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data. METHODS: Over 200 articles referring to intravenous levodopa (IVLD) were examined for details of administration, pharmacokinetics, benefit and side effects. RESULTS: We identified 144 original reports describing IVLD use in humans, beginning with psychiatric research in 1959-1960 before the development of peripheral decarboxylase inhibitors. At least 2781 subjects have received IVLD, and reported outcomes include parkinsonian signs, sleep variables, hormones, hemodynamics, CSF amino acid composition, regional cerebral blood flow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis. CONCLUSION: At least 2781 patients have received i.v. levodopa with a safety profile comparable to that seen with oral administration.