Cannabinoid formulations have been increasingly proposed as therapeutic potential options for anxiety disorders (ADs). Several countries have expanded regulatory frameworks facilitating access to these compounds due to their alleged therapeutic benefits, including their application in ADs. Given its public health significance, we evaluated existing evidence regarding the efficacy of different medical cannabinoids as interventions for ADs and related mental conditions.
Methods:
A comprehensive search was conducted in PubMed, Embase, PsycInfo, Web of Science, Scielo, and Lilacs databases. We included randomized controlled trials (RTCs) assessing the effects of various cannabinoid formulations on patients with ADs and related conditions. Distinct meta-analyses were performed for cannabinoid subtypes. Analyses were conducted using Jamovi software, relying on standardized mean difference (SMD) calculations of pre/post-intervention score changes for both intervention and control groups.
Results:
We incorporated 21 placebo-controlled RCTs, examining cannabinoid interventions in social anxiety disorder (SAD = 5), generalized anxiety disorder (GAD = 1), post-traumatic stress disorder (PTSD = 7), obsessive-compulsive disorder (OCD = 1), and Tourette syndrome (TS = 7). Data extraction indicated considerable heterogeneity across outcomes, including clinical symptoms, neuroimaging findings, well-being, psychosocial functioning, safety, and tolerability. In studies utilizing pure or enriched CBD, the meta-analytic measure indicated a nonsignificant difference (SMD = −0.40; 95% CI: −0.84/0.03). However, a subgroup analysis of pure CBD compounds yielded a moderate, statistically significant effect size (SMD: −0.61, 95% CI: −1.15/−0.07). For studies investigating pure or enriched delta-9-tetrahydrocannabinol (Δ9-THC), the meta-analytic measure was −0.65 (95% CI: −1.06/−0.24), suggesting a moderate, significant effect favoring Δ9-THC-dominant compounds. In meta-analyses of studies with Δ9-THC and cannabidiol (CBD) mixtures, the effects were not significant (SMD = −0.73, 95% CI: −2.00/0.55). Although suggesting a potential superior efficacy of pharmaceutically pure formulations of Δ9-THC and CBD over alternative versions, these results must be interpreted with caution due to heterogeneous study designs and small sample sizes.
Discussion:
The current evidence is limited. Low-quality evidence suggests that pharmaceutical-grade CBD may have limited efficacy for SAD and GAD. In addition, low-quality evidence supports Δ9-THC’s efficacy for the reduction of nightmares in PTSD and tic severity in TS. Further double-blind, randomized, placebo-controlled trials with larger and heterogeneous samples are required to investigate the clinical outcomes of pharmaceutical-grade cannabinoids and standardized cannabis extracts in the treatment of ADs.
de SouzaMR, HenriquesAT, LimbergerRP. Medical cannabis regulation: An overview of models around the world with emphasis on the Brazilian scenario. J Cannabis Res, 2022; 4(1):33.
2.
JinD, DaiK, XieZ, et al.Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Sci Rep, 2020; 10(1):3309.
3.
CrocqM-A. History of cannabis and the endocannabinoid system. Dialogues Clin Neurosci, 2020; 22(3):223–228.
4.
VolkowND, BalerRD, ComptonWM, et al.Adverse health effects of marijuana use. N Engl J Med, 2014; 370(23):2219–2227.
5.
ZuardiAW, ShirakawaI, FinkelfarbE, et al.Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl), 1982; 76(3):245–250.
6.
ColizziM, BhattacharyyaS. Cannabis use and the development of tolerance: A systematic review of human evidence. Neurosci Biobehav Rev, 2018; 93:1–25.
7.
PertweeRG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol, 2008; 153(2):199–215.
8.
WhitingPF, WolffRF, DeshpandeS, et al.Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA, 2015; 313(24):2456–2473.
9.
BergamaschiMM, QueirozRHC, ZuardiAW, et al.Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf, 2011; 6(4):237–249.
10.
HuestisMA, SoliminiR, PichiniS, et al.Cannabidiol adverse effects and toxicity. Curr Neuropharmacol, 2019; 17(10):974–989.
11.
KarniolIG, CarliniEA. Pharmacological interaction between cannabidiol and delta 9-tetrahydrocannabinol. Psychopharmacologia, 1973; 33(1):53–70.
12.
LattanziS, BrigoF, TrinkaE, et al.Efficacy and safety of cannabidiol in epilepsy: A systematic review and meta-analysis. Drugs, 2018; 78(17):1791–1804.
13.
GuerriniR, ChironC, VandameD, et al.Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first-line add-on therapies for seizures in dravet syndrome: A network meta-analysis. Epilepsia Open, 2024; 9(2):689–703.
14.
CrippaJA, GuimarãesFS, CamposAC, et al.Translational investigation of the therapeutic potential of cannabidiol (cbd): toward a new age. Front Immunol, 2018; 9:2009.
15.
TalwarA, EstesE, AparasuR, et al.Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis. Exp Neurol, 2023; 359:114238.
16.
HillKP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: A clinical review. JAMA, 2015; 313(24):2474–2483.
17.
BilbaoA, SpanagelR. Medical cannabinoids: A pharmacology-based systematic review and meta-analysis for all relevant medical indications. BMC Med, 2022; 20(1):259.
18.
KesslerRC, PetukhovaM, SampsonNA, et al.Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res, 2012; 21(3):169–184.
19.
GBD 2021 Causes of Death Collaborators. Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990-2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet, 2024; 403(10440):2100–2132.
20.
BarryMJ, NicholsonWK, SilversteinM, et al.; US Preventive Services Task Force. Screening for Anxiety Disorders in Adults: US Preventive Services Task Force Recommendation Statement. JAMA, 2023; 329(24):2163–2170.
21.
COVID-19 Mental Disorders Collaborators. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet, 2021; 398(10312):1700–1712.
22.
JavaidSF, HashimIJ, HashimMJ, et al.Epidemiology of anxiety disorders: Global burden and sociodemographic associations. Middle East Curr Psychiatr, 2023; 30(1); doi: 10.1186/s43045-023-00315-3
23.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR®): Test Questions for the Diagnostic Criteria. (MuskinPR, DickermanAL, DrysdaleAet al. eds). American Psychiatric Association Publishing: Arlington, TX; 2022.
24.
American Psychiatric Association (APA). DSM-5: Manual Diagnóstico e Estatístico de Transtornos Mentais. Artmed Editora, 2014.
25.
FerrãoYA, RadinsRB, FerrãoJVB. Psychopathological intersection between obsessive-compulsive disorder and post-traumatic stress disorder: Scoping review of similarities and differences. Trends Psychiatry Psychother, 2023; 45:e20210370.
26.
RobertsonMM, EapenV. Tourette’s: Syndrome, disorder or spectrum? Classificatory challenges and an appraisal of the DSM criteria. Asian J Psychiatr, 2014; 11:106–113.
27.
ShitovaAD, ZharikovaTS, KovalevaON, et al.Tourette syndrome and obsessive-compulsive disorder: A comprehensive review of structural alterations and neurological mechanisms. Behav Brain Res, 2023; 453:114606; doi: 10.1016/j.bbr.2023.114606
28.
SzuhanyKL, SimonNM. Anxiety disorders: A review. JAMA, 2022; 328(24):2431–2445.
29.
EddyCM, RickardsHE, CavannaAE. Treatment strategies for tics in Tourette syndrome. Ther Adv Neurol Disord, 2011; 4(1):25–45; doi: 10.1177/1756285610390261
30.
JohnsonKA, WorbeY, FooteKD, et al.Tourette syndrome: Clinical features, pathophysiology, and treatment. Lancet Neurol, 2023; 22(2):147–158; doi: 10.1016/S1474-4422(22)00303-9
31.
PenninxBW, PineDS, HolmesEA, et al.Anxiety disorders. Lancet, 2021 Mar 6;397(10277):914–927. doi: 10.1016/S0140-6736(21)00359-7 Epub 2021 Feb 11. Erratum in: Lancet. 2021 Mar 6;397(10277):880. doi: 10.1016/S0140-6736(21)00473-6
32.
BreilmannJ, GirlandaF, GuaianaG, et al.Benzodiazepines versus placebo for panic disorder in adults. Cochrane Database Syst Rev, 2019; 3(3):CD010677.
33.
AgarwalSD, LandonBE. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw Open, 2019; 2(1):e187399.
34.
BandelowB, ReittM, RöverC, et al.Efficacy of treatments for anxiety disorders: A meta-analysis. Int Clin Psychopharmacol, 2015; 30(4):183–192.
35.
BlackN, StockingsE, CampbellG, et al.Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: A systematic review and meta-analysis. Lancet Psychiatry, 2019; 6(12):995–1010.
36.
SkelleyJW, DeasCM, CurrenZ, et al.Use of cannabidiol in anxiety and anxiety-related disorders. J Am Pharm Assoc (2003), 2020; 60(1):253–261.
37.
FliegelDK, LichensteinSD. Systematic literature review of human studies assessing the efficacy of cannabidiol for social anxiety. Psychiatry Res Commun, 2022; 2(4):100074; doi: 10.1016/j.psycom.2022.100074
38.
NarayanAJ, DowneyLA, ManningB, et al.Cannabinoid treatments for anxiety: A systematic review and consideration of the impact of sleep disturbance. Neurosci Biobehav Rev, 2022; 143:104941.
39.
Coelho C deF, VieiraRP, Araújo-JuniorOS, et al.The impact of cannabidiol treatment on anxiety disorders: A systematic review of randomized controlled clinical trials. Life (Basel), 2024; 14(11):1373; doi: 10.3390/life14111373
40.
KweeCM, van GervenJM, BongaertsFL, et al.Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool. J Psychopharmacol, 2022; 36(12):1299–1314.
41.
HaneyM. Cannabis use and the endocannabinoid system: A clinical perspective. Am J Psychiatry, 2022; 179(1):21–25.
42.
HanK, WangJ-Y, WangP-Y, et al.Therapeutic potential of cannabidiol (CBD) in anxiety disorders: A systematic review and meta-analysis. Psychiatry Res, 2024; 339:116049.
43.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Bmj, 2021; 372:n71.
44.
da Costa SantosCM, de Mattos PimentaCA, NobreMRC. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem, 2007; 15(3):508–511.
45.
OuzzaniM, HammadyH, FedorowiczZ, et al.Rayyan-a web and mobile app for systematic reviews. Syst Rev, 2016; 5(1):210.
46.
Armijo-OlivoS, StilesCR, HagenNA, et al.Assessment of study quality for systematic reviews: A comparison of the Cochrane Collaboration Risk of Bias Tool and the Effective Public Health Practice Project Quality Assessment Tool: Methodological research. J Eval Clin Pract, 2012; 18(1):12–18.
47.
PennypackerSD, CunnaneK, CashMC, et al.Potency and therapeutic THC and CBD Ratios: U.S. cannabis markets overshoot. Front Pharmacol, 2022; 13:921493.
48.
HigginsJPT, ThomasJ, ChandlerJ, et al.Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons; 2019.
49.
Bonn-MillerMO, SisleyS, RiggsP, et al.The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: A randomized cross-over clinical trial. PLoS One, 2021; 16(3):e0246990.
50.
DerSimonianR, LairdN. Meta-analysis in clinical trials. Control Clin Trials, 1986; 7(3):177–188.
51.
BorensteinM, HedgesLV, HigginsJPT, et al.Introduction to Meta-Analysis. John Wiley & Sons; 2011.
52.
Anonymous. Jamovi - open statistical software for the desktop and cloud. n.d. Available from: http://www.jamovi.org [Last accessed: February14, 2025].
53.
Müller-VahlKR, KoblenzA, JöbgesM, et al.Influence of treatment of Tourette syndrome with delta9-tetrahydrocannabinol (delta9-THC) on neuropsychological performance. Pharmacopsychiatry, 2001; 34(1):19–24.
54.
Müller-VahlKR, SchneiderU, KoblenzA, et al.Treatment of tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): A randomized crossover trial. Pharmacopsychiatry, 2002; 35(2):57–61.
55.
Müller-VahlKR, SchneiderU, PrevedelH, et al.Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: A 6-week randomized trial. J Clin Psychiatry, 2003; 64(4):459–465.
56.
Müller-VahlKR, PrevedelH, TheloeK, et al.Treatment of tourette syndrome with delta-9-tetrahydrocannabinol (delta 9-THC): no influence on neuropsychological performance. Neuropsychopharmacology, 2003; 28(2):384–388.
57.
BergamaschiMM, QueirozRHC, ChagasMHN, et al.Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology, 2011; 36(6):1219–1226.
58.
CrippaJAS, DerenussonGN, FerrariTB, et al.Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: A preliminary report. J Psychopharmacol, 2011; 25(1):121–130.
59.
JetlyR, HeberA, FraserG, et al.The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology, 2015; 51:585–588.
60.
MasatakaN. Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders. Front Psychol, 2019; 10:2466.
61.
KayserRR, HaneyM, RaskinM, et al.Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: A human laboratory study. Depress Anxiety, 2020; 37(8):801–811.
62.
RabinakCA, BlanchetteA, ZabikNL, et al.Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: A preliminary study. Psychopharmacology (Berl), 2020; 237(6):1813–1826.
63.
Abi-JaoudeE, BhikramT, ParveenF, et al.A double-blind, randomized, controlled crossover trial of cannabis in adults with tourette syndrome. Cannabis Cannabinoid Res, 2023; 8(5):835–845.
64.
BolsoniLM, CrippaJAS, HallakJEC, et al.Effects of cannabidiol on symptoms induced by the recall of traumatic events in patients with posttraumatic stress disorder. Psychopharmacology (Berl), 2022; 239(5):1499–1507.
65.
BolsoniLM, CrippaJAS, HallakJEC, et al.The anxiolytic effect of cannabidiol depends on the nature of the trauma when patients with post-traumatic stress disorder recall their trigger event. Braz J Psychiatry, 2022; 44(3):298–307.
66.
KweeCM, BaasJM, van der FlierFE, et al.Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial. Eur Neuropsychopharmacol, 2022; 59:58–67.
67.
PacittoR, PetersC, IadipaoloA, et al.Cannabinoid modulation of brain activation during volitional regulation of negative affect in trauma-exposed adults. Neuropharmacology, 2022; 218:109222.
68.
Müller-VahlKR, PisarenkoA, SzejkoN, et al.CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study. Psychiatry Res, 2023; 323:115135.
69.
ZabikNL, RabinakCA, PetersCA, et al.Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder. Neurobiol Learn Mem, 2023; 201:107758.
70.
GundugurtiPR, BandaN, YadlapalliSSR, et al.Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial. Asian J Psychiatr, 2024; 97:104073.
71.
KweeCMB, van der FlierFE, DuitsP, et al.Effects of cannabidiol on fear conditioning in anxiety disorders: Decreased threat expectation during retention, but no enhanced fear re-extinction. Psychopharmacology (Berl), 2024; 241(4):833–847.
72.
Müller-VahlKR, PisarenkoA, RinglstetterR, et al.The effect of nabiximols on driving ability in adults with chronic tic disorders: Results of a substudy analysis of the double-blind, randomized, placebo-controlled CANNA-TICS trial. Cannabis Cannabinoid Res, 2024; 9(5):1349–1359.
73.
RussoEB, BurnettA, HallB, et al.Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res, 2005; 30(8):1037–1043.
74.
BisognoT, HanusL, De PetrocellisL, et al.Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol, 2001; 134(4):845–852.
75.
CamposAC, GuimarãesFS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry, 2009; 33(8):1517–1521.
76.
HurdYL. Leading the next CBD wave-safety and efficacy. JAMA Psychiatry, 2020; 77(4):341–342.
77.
KalsoomI, ShehzadiK, LiH-S, et al.Unraveling the mechanisms of cannabidiol’s pharmacological actions: A comprehensive research overview. Top Curr Chem (Cham), 2024; 382(2):20.
78.
GuimarãesFS, ChiarettiTM, GraeffFG, et al.Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl), 1990; 100(4):558–559.
79.
GuimarãesFS, de AguiarJC, MechoulamR, et al.Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze. Gen Pharmacol, 1994; 25(1):161–164.
80.
ZuardiAW, RodriguesNP, SilvaAL, et al.Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol, 2017; 8:259.
81.
LinaresIM, ZuardiAW, PereiraLC, et al.Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry, 2019; 41(1):9–14.
82.
Metna-LaurentM, MondésirM, GrelA, et al.Cannabinoid-Induced Tetrad in Mice. Curr Protoc Neurosci, 2017; 80:9.59.1–9.59.10.
83.
AndreaeMH, CarterGM, ShaparinN, et al.Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J Pain, 2015; 16(12):1221–1232.
84.
PhanKL, AngstadtM, GoldenJ, et al.Cannabinoid modulation of amygdala reactivity to social signals of threat in humans. J Neurosci, 2008; 28(10):2313–2319.
85.
GorkaSM, FitzgeraldDA, de WitH, et al.Cannabinoid modulation of amygdala subregion functional connectivity to social signals of threat. Int J Neuropsychopharmacol, 2014; 18(3):pyu104; doi: 10.1093/ijnp/pyu104
86.
BhattacharyyaS, MorrisonPD, Fusar-PoliP, et al.Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 2010; 35(3):764–774.
87.
BhattacharyyaS, EgertonA, KimE, et al.Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors. Sci Rep, 2017; 7(1):15025.
RussoEB. The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain. Front Plant Sci, 2018; 9:1969.
91.
CoganPS. The “entourage effect” or “hodge-podge hashish”: the questionable rebranding, marketing, and expectations of cannabis polypharmacy. Expert Rev Clin Pharmacol, 2020; 13(8):835–845.
92.
ChristensenC, RoseM, CornettC, et al.Decoding the Postulated Entourage Effect of Medicinal: What It Is and What It Isn’t. Biomedicines, 2023; 11(8):2323; doi: 10.3390/biomedicines11082323
93.
FreemanAM, PetrilliK, LeesR, et al.How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. Neurosci Biobehav Rev, 2019; 107:696–712.
94.
HallerJ, BakosN, SzirmayM, et al.The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci, 2002; 16(7):1395–1398.
95.
MarsicanoG, WotjakCT, AzadSC, et al.The endogenous cannabinoid system controls extinction of aversive memories. Nature, 2002; 418(6897):530–534.
96.
TrezzaV, CampolongoP. The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Front Behav Neurosci, 2013; 7:100.
97.
PatelS, HillMN, CheerJF, et al.The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev, 2017; 76(Pt A):56–66.
98.
HerkenhamM, LynnAB, LittleMD, et al.Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A, 1990; 87(5):1932–1936.
99.
SzejkoN, SaramakK, Müller-VahlKR. The Use of Cannabis-Based Medicine in Selected Neurological Disorders. Curr Top Behav Neurosci. 2024; doi: 10.1007/7854_2024_564
100.
McPartlandJM, GlassM, PertweeRG. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: Interspecies differences. Br J Pharmacol, 2007; 152(5):583–593.
101.
ThamM, YilmazO, AlaverdashviliM, et al.Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol, 2019; 176(10):1455–1469.
102.
ArndtDL, de WitH. Cannabidiol does not dampen responses to emotional stimuli in healthy adults. Cannabis Cannabinoid Res, 2017; 2(1):105–113.
103.
GrotenhermenF. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet, 2003; 42(4):327–360.
104.
EichlerM, SpinediL, Unfer-GrauwilerS, et al.Heat exposure of cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med, 2012; 78(7):686–691.
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