%PDF-1.3
%
4 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
7 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
5 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
8 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
6 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
1 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
3 0 obj
<>>>/BBox[0 0 612 792]/Length 53>>stream
xs
w3T0WI2P0T5T R
Ɩf
!\!Y\ !p
o
endstream
endobj
10 0 obj
<>stream
Arbortext Advanced Print Publisher 9.0.114/W
2019-05-11T20:36:23-07:00
2019-03-11T23:42:02+05:30
application/pdf
CAN-2018-0053-ver9-Tartaglia_2P 3..9
Acrobat Distiller 8.1.0 (Windows); modified using iText 4.2.0 by 1T3XT
uuid:79182971-4831-4844-98f1-79b046fe784d
uuid:716c4617-b312-4e37-a2db-d0c3d788ce2c
endstream
endobj
11 0 obj
<>stream
x+ |
endstream
endobj
12 0 obj
<>stream
xS**T0T0 Bi yJ%
endstream
endobj
13 0 obj
<>stream
x+ |
endstream
endobj
14 0 obj
<>stream
xS**T0T0 Bi yS&
endstream
endobj
15 0 obj
<>stream
x+ |
endstream
endobj
16 0 obj
<>stream
xS**T0T0 Bi y8#
endstream
endobj
17 0 obj
<>stream
x+ |
endstream
endobj
18 0 obj
<>stream
xS**T0T0 Bi yA$
endstream
endobj
19 0 obj
<>stream
x+ |
endstream
endobj
20 0 obj
<>stream
xS**T0T0 Bi y\'
endstream
endobj
21 0 obj
<>stream
x+ |
endstream
endobj
22 0 obj
<>stream
xS**T0T0 Bi ye(
endstream
endobj
23 0 obj
<>stream
x+ |
endstream
endobj
24 0 obj
<>stream
xS**T0T0 Bi yn)
endstream
endobj
26 0 obj
<>stream
/GS1 gs
BT
/F6 1 Tf
10.959 0 0 10.959 62.022 697.8896 Tm
0 0 0 rg
0 Tc
0 Tw
[(t)12.3(h)0(e)15.8(s)12.2(e)-225.5(p)13(at)19.9(ie)19(nt)20.5(s)-225.7(m)10.2(a)12.8(y)-224.9(i)11.7(n)0(v)16.1(o)13.7(lv)20(e)-225.5(m)10.2(e)12.5(d)0(i)19.5(c)0(a)20.1(t)0(i)18.8(o)0(n)21.9(s)-225.7(t)12.3(o)-224.2(ad)20.7(dr)20.1(es)19.5(s)-225.7(i)11.7(ss)19.3(ue)20.3(s)]TJ
0 -1.1847 TD
[(with)-232(sleep)-232.6(\(melatonin)-233.2(and)-229.9(clonidine\),)-235.7(anxiety)-232.3(\(selective)]TJ
0 -1.1795 TD
[(serotonin)-526.5(reuptake)-524.6(inhibitors)-525.6(and)-524.7(benzodiazepines\),)]TJ
0 -1.1847 TD
[(hy)21.6(pe)20.3(ra)19.8(ct)19.6(iv)19.6(it)18.8(y)-519.7(a)12.8(nd)-511.7(d)13(e)0()15.8(c)12.5(i)11.7(t)0(s)-513.5(i)11.7(n)-519.5(a)12.8(tt)19.4(en)20.7(ti)18.8(on)-511(\()11.9(p)0(s)20.1(y)0(c)20.4(h)0(o)22.2(s)0(t)19.3(i)0(m)16.7(u)13(-)]TJ
0 -1.1795 TD
[(l)12(a)0(n)15.8(t)12.3(s)12.2(\))0(,)-339.1(a)12.8(nd)-340.9(s)12.2(e)0(i)19(z)12.5(ur)20.1(es)-337.4(\(c)19.2(ar)19.8(ba)21.3(m)10.2(a)0(z)20.1(e)0(p)20.3(i)0(n)19.8(e)0(,)-338.6(v)13.1(al)19.7(pr)20.1(oi)20.2(c)-349.6(a)12.8(ci)19(d,)-338(a)12.8(n)0(d)]TJ
0 -1.1847 TD
(lamotrigine\).)Tj
8.2191 0 0 7.3052 118.6015 637.9652 Tm
(12)Tj
10.959 0 0 10.959 131.074 633.0896 Tm
[(Yet,)-425.5(for)-422.8(many)-421.4(patients)-422.4(with)-423.4(FXS,)-425.2(the)]TJ
-6.3009 -1.1795 TD
-.0001 Tc
[(aforementioned)-383.4(pharmacotherapies,)-385.5(when)-380.3(used)-383.9(alone)]TJ
T*
0 Tc
[(or)-274.1(in)-275(combination,)-269.1(have)-273.8(suboptimal)-273.7(efcacy)-273.4(and)-271.2(toler-)]TJ
0 -1.1847 TD
(ability,)Tj
8.2191 0 0 7.3052 91.4456 599.1306 Tm
(1113)Tj
10.959 0 0 10.959 113.7826 594.2549 Tm
[(suggesting)-214.9(a)-214.8(persistent)-212(unmet)-218.1(medical)-215.4(need)]TJ
-4.7231 -1.1795 TD
[(for)-303.8(novel,)-307.1(interventional)-304.3(treatment)-303.5(approaches)-306.1(for)-303.8(pa-)]TJ
0 -1.1847 TD
[(tients)-365.4(with)-361.4(FXS.)-363.1(Because)-360.6(the)-365(clinical)-361.9(abnormalities)-361.4(in)]TJ
0 -1.1795 TD
[(these)-309.3(patients)-313.7(\(and)-311.1(most)-308.6(recently)-313.4(in)-311.2(children)-307.7(with)-309.6(au-)]TJ
0 -1.1847 TD
[(tism)-439.9(spectrum)-440.1(disorder)]TJ
8.2191 0 0 7.3052 167.6409 547.3132 Tm
(14)Tj
10.959 0 0 10.959 175.5212 542.4377 Tm
[(\))-443.3(have)-439.4(been)-439.4(linked,)-441(at)-440.5(least)]TJ
-10.3567 -1.1795 TD
-.0001 Tc
[(in)-218.2(part,)-212.9(with)-216.6(dysregulation)-212.7(of)-217.9(the)-215.1(endocannabinoid)-218.5(sys-)]TJ
0 -1.1847 TD
[(tem,)-414.5(we)-412.5(briey)-409.5(review)-414.7(recent)-411.1(research)-416.8(characterizing)]TJ
0 -1.1795 TD
[(the)-520.3(involvement)-524.6(of)-517.9(the)-525.5(endocannabinoid)-523.7(system)-522.5(in)]TJ
T*
0 Tc
[(FXS)-441.5(and)-436.8(present)-439.6(the)-437.5(cases)-439.6(of)-435(three)-438.6(individuals)-441.8(\(one)]TJ
0 -1.1847 TD
[(child)-268.2(and)-266.1(two)-269.5(adults\))-269.6(with)-263.1(FXS)-270.7(who)-268.2(experienced)-265(func-)]TJ
0 -1.1795 TD
[(tional)-281.1(benet)-279(after)-280(treatment)-282.8(with)-278.6(cannabidiol)-278.4(\(CBD\)-)]TJ
0 -1.1847 TD
[(enriched)-302.1(\(CBD)]TJ
/F5 1 Tf
6.1043 0 TD
(+)Tj
/F6 1 Tf
.5794 0 TD
[(\))-303.6(preparations.)]TJ
/F4 1 Tf
10.4607 0 0 10.4607 62.022 425.877 Tm
[(Endocannabinoids)-301.2(and)-298.4(FXS)]TJ
/F6 1 Tf
10.959 0 0 10.959 62.022 412.9511 Tm
[(The)-373.8(endocannabinoid)-374.6(system)-372.4(consists)-375.8(of)-373(receptors)-378.3(in)]TJ
0 -1.1847 TD
-.0178 Tc
[(the)-693.3(b)1.1(rain)-697.7(and)-692.8(p).4(eripheral)-693.8(t)-.3(issues)-693.6(that)-693.5(are)-693.3(i)-.9(nvolved)]TJ
0 -1.1795 TD
[(in)-263.2(numerous)-264.3(physiological)-264.5(p).3(rocesses)-264.3(a).1(s)-264.3(w)-3.1(e)4.9(l)-.7(l)-264.5(a).1(s)-269.5(t)-.4(he)-264.1(endo-)]TJ
0 -1.1847 TD
-.0181 Tc
[(cannabinoids,)-876.1(N-arachidonoylethanolamine)-879.9(\(ananda-)]TJ
0 -1.1795 TD
0 Tc
[(m)20.5(i)16.9(d)18.2(e)17.7(;)-501.1(A)19.7(E)18.8(A)19.7(\))-500.2(a)18(n)18.5(d)-499.1(2)18.6(-)17.7(a)18(r)17.4(a)18(c)17.7(h)18.9(i)16.9(d)18.2(o)18.9(n)18.5(o)18.9(y)18.3(l)17.2(g)18.3(l)22.4(y)18.3(c)17.7(e)17.7(r)17.4(o)18.9(l)-500.1(\(2-AG\).)-515.1(The)]TJ
T*
-.0001 Tc
[(endocannabinoids)-225.8(bind)-217.3(to)-222.4(the)-220.3(G)19.9(-)17.6(p)18.1(r)17.3(o)18.8(t)17.4(e)17.6(i)16.8(n)18.4(-)17.6(c)17.6(o)18.8(u)18.1(p)18.1(l)17.1(e)17.6(d)-199.2(r)]TJ
19.7667 0 TD
-.0178 Tc
(ecep-)Tj
-19.7667 -1.1847 TD
-.0176 Tc
[(tors,)-208.3(cannabinoid)-206.3(1)-205.9(a).4(nd)-206.3(2)-211.1(\()4.7(CB)]TJ
8.2191 0 0 7.3052 186.3495 333.4109 Tm
0 Tc
(1)Tj
10.959 0 0 10.959 192.359 335.2251 Tm
.018 Tc
[(and)-212.1(C)1.5(B)]TJ
8.2191 0 0 7.3052 225.6377 333.4109 Tm
0 Tc
(2)Tj
10.959 0 0 10.959 229.7763 335.2251 Tm
.0191 Tc
(\),)Tj
8.2191 0 0 7.3052 236.3527 340.1007 Tm
.0314 Tc
[(15)6.9(,)8(1)6.9(6)]TJ
10.959 0 0 10.959 257.2723 335.2251 Tm
.0178 Tc
[(and)-207.1(m)-3.1(od-)]TJ
-17.8164 -1.1795 TD
0 Tc
[(u)-18(l)-19(a)-18.2(t)-18.7(e)-525.5(s)-18.8(y)-17.9(n)-17.7(a)-18.2(p)-18(t)-18.7(i)-19.4(c)-525.5(t)-18.7(r)-18.8(a)-18.2(n)-17.7(s)-18.8(m)-20.9(i)-19.4(s)-18.8(s)-18.8(i)-19.4(o)-17.3(n)-519.5(throughout)-500.4(the)-499.5(central)]TJ
0 -1.1847 TD
[(nervous)-220.3(system.)]TJ
8.2191 0 0 7.3052 131.244 314.192 Tm
(17,18)Tj
10.959 0 0 10.959 151.2566 309.3164 Tm
[(Receptors)-221.4(are)-221.2(distributed)-219.3(through-)]TJ
-8.1426 -1.1795 TD
[(out)-240.3(the)-235.7(body,)-240.6(with)-237.2(CB)]TJ
8.2191 0 0 7.3052 157.6629 294.5763 Tm
(1)Tj
10.959 0 0 10.959 164.2393 296.3904 Tm
[(receptors)-238.6(abundantly)-237.9(expressed)]TJ
-9.3272 -1.1847 TD
[(in)-352.6(the)-349.5(brain)-350.1(and)-354(present)-351.7(at)-352.5(lower)-348.6(concentrations)-349.3(in)-352.6(a)]TJ
0 -1.1795 TD
[(variety)-212.4(of)-217.8(peripheral)-210.6(tissues)-213.9(and)-214.3(cells)-218.1(and)-214.3(CB)]TJ
8.2191 0 0 7.3052 254.7212 268.6677 Tm
(2)Tj
10.959 0 0 10.959 261.0141 270.4818 Tm
(receptors)Tj
-18.1578 -1.1847 TD
[(expressed)-280.2(primarily)-279.1(in)-275(the)-277.1(immune)-275.8(and)-281.6(hematopoietic)]TJ
0 -1.1795 TD
[(systems,)-302.6(as)-295.7(well)-300.4(as)-300.9(in)-300.9(the)-297.8(brain,)-297.7(pancreas,)-301.4(and)-302.3(bone.)]TJ
8.2191 0 0 7.3052 291.5716 249.4488 Tm
(16)Tj
10.959 0 0 10.959 72.9637 231.6472 Tm
[(CBD,)-400.6(the)-401.3(primary,)-395.2(noneuphoric)-400.5(exogenous)-400.5(phyto-)]TJ
-.9984 -1.1847 TD
[(cannabinoid)-494.4(in)-492.3(cannabis,)-491.8(may)-496.8(attenuate)-491.4(the)-494.4(loss)-493(of)]TJ
0 -1.1795 TD
-.0001 Tc
[(endogenous)-428.4(cannabinoid)-422.1(\(i.e.,)-432.6(endocannabinoid\))-429.1(sig-)]TJ
0 -1.1847 TD
0 Tc
[(naling)-285.8(observed)-279.8(in)-285.4(preclinical)-282.8(models)-283.3(of)-285(FXS,)-285.5(allowing)]TJ
0 -1.1795 TD
[(a)-302.8(component)-304.5(of)-305.7(the)-303(FMRP)-300.5(deciency)-309.4(inherent)-302(in)-306.1(FXS)]TJ
0 -1.1847 TD
[(to)-372.3(be)-372.1(bypassed.)-372.6(Specically,)-372.9(many)-374.8(abnormalities)-371.7(seen)]TJ
0 -1.1795 TD
[(in)-461.3(FXS)-462.2(appear)-456.5(to)-460.3(be)-460.1(rooted)-460.5(in)-461.3(dysregulation)-455.8(of)-460.9(the)]TJ
0 -1.1847 TD
[(endocannabinoid)-281.5(pathways)-278.1(in)-280.2(the)-282.3(central)-279.6(nervous)-282.4(sys-)]TJ
0 -1.1795 TD
[(tem,)-445.4(with)-444.1(a)-447.6(reduction)-444.4(of)-445.4(endogenous)-449(stimulation)-444.2(of)]TJ
0 -1.1847 TD
[(endocannabinoid)-276.3(receptors.)]TJ
8.2191 0 0 7.3052 183.5149 119.9055 Tm
(1921)Tj
10.959 0 0 10.959 206.5322 115.0299 Tm
[(CBD)-282.3(has)-276.9(the)-277.1(capacity)]TJ
-13.1864 -1.1795 TD
[(t)12.3(o)-250.1(i)11.7(n)0(t)20.5(e)0(r)19.5(a)0(c)20.1(t)-246.4(wi)21.3(th)-237.9(a)12.8(n)-250.5(F)13(X)0(S)16.3(-)12.6(co)21(m)10.2(p)0(r)20.1(o)0(m)18.7(i)11.7(se)19.5(d)-245.6(e)0(n)15.5(d)13(oc)21(an)21(na)15.8(b)13.7(i)0(n)19.8(o)0(i)20.2(d)]TJ
T*
[(sy)20.2(st)19.4(e)12.5(m)10.2(.)-201(I)12.3(nd)16(e)12.5(e)0(d)20.3(,)-201(de)20.3(l)12(e)0(t)19.6(i)0(o)20.2(n)-198.8(of)-191.9(F)13(M)10.7(RP)-189.7(wi)21.3(t)12.3(h)0(i)20.2(n)-198.8(a)-199.3(m)10.2(ou)21.6(se)-192.6(m)10.2(o)13.7(de)20.3(l)]TJ
0 -1.1847 TD
[(of)-295.4(FXS)-296.6(led)-293.5(to)-294.7(reduced)-299.2(production)-295.7(of)-295.4(2-AG,)-290.6(decreasing)]TJ
0 -1.1795 TD
[(activation)-298(of)-295.4(CB)]TJ
8.2191 0 0 7.3052 133.6252 61.3984 Tm
(1)Tj
10.959 0 0 10.959 140.8251 63.2692 Tm
[(receptors)-300.7(in)-295.7(the)-297.8(central)-295.2(nervous)-297.9(sys-)]TJ
15.7161 57.9085 TD
(tem.)Tj
8.2191 0 0 7.3052 332.2204 702.7651 Tm
(20)Tj
10.959 0 0 10.959 342.4251 697.8896 Tm
[(CBD)-209.9(has)-209.6(been)-211.8(shown)-206.4(to)-211.9(increase)-210.7(2-AG)-208.6(availabil-)]TJ
-2.6797 -1.1847 TD
(ity,)Tj
8.2191 0 0 7.3052 326.6645 689.7825 Tm
(22)Tj
10.959 0 0 10.959 339.4204 684.9069 Tm
[(potentially)-440.6(attenuating)-445.1(or)-444.8(reversing)-440.7(one)-446.7(of)-445.4(the)]TJ
-2.4055 -1.1795 TD
[(biological)-426.6(mechanisms)-427.2(of)-424.7(abnormal)-426.9(cellular)-423.4(function)]TJ
0 -1.1847 TD
[(in)-275(FXS.)]TJ
8.2191 0 0 7.3052 345.1464 663.8738 Tm
(20)Tj
10.959 0 0 10.959 356.0314 658.9983 Tm
[(Importantly,)-270.7(CB)]TJ
8.2191 0 0 7.3052 427.7479 657.1841 Tm
(1)Tj
10.959 0 0 10.959 434.7211 658.9983 Tm
[(protein)-273.4(expression)-272.2(appears)]TJ
-11.1016 -1.1795 TD
[(unaffected)-386.9(in)]TJ
/F7 1 Tf
5.7215 0 TD
(FMR1)Tj
/F6 1 Tf
2.8401 0 TD
[(knockout)-381.6(\(KO\))-381.8(mice,)-387(suggesting)]TJ
-8.5616 -1.1847 TD
[(that)-233.5(the)-230.5(downstream)-235.1(elements)-228.4(of)-233.3(endocannabinoid)-234.9(sig-)]TJ
0 -1.1795 TD
[(naling)-254.8(can)-256.3(be)-248(engaged,)-255.6(even)-253.8(in)-254.3(the)-251.2(absence)-251.9(of)-254(FMRP.)]TJ
8.2191 0 0 7.3052 544.3085 625.0392 Tm
(19)Tj
10.959 0 0 10.959 324.0566 607.2377 Tm
[(In)-440(addition)-441.6(to)-439.6(the)-442.6(role)-441(of)-440.2(2-AG,)-440.7(recent)-442(work)-442.8(has)]TJ
-1.0036 -1.1847 TD
[(begun)-420.6(to)-418.9(highlight)-417.9(the)-416.8(potential)-419.2(importance)-419(of)-419.5(AEA)]TJ
0 -1.1795 TD
[(in)-378.5(addressing)-380.9(social)-375.1(impairment)-376.8(as)-378.5(well)-372.8(as)-378.5(decits)-377.7(in)]TJ
0 -1.1847 TD
[(learning)-421.5(and)-421.3(memory)-419.6(among)-418(those)-416.7(with)-418.3(FXS.)-425.2(In)-419.3(an)]TJ
/F7 1 Tf
0 -1.1795 TD
(FMR1)Tj
/F6 1 Tf
2.8918 0 TD
[(KO)-431.5(mouse)-435(model)-430(of)-435(FXS,)-435.6(Qin)-431(et)-435.6(al.)-434.9(demon-)]TJ
-2.8918 -1.1847 TD
[(strated)-435.1(that)-435.2(increased)-435.6(levels)-432.6(of)-435.1(AEA)-433.3(were)-434.3(associated)]TJ
0 -1.1795 TD
[(with)-449.3(greater)-450.4(cognitive)-450(performance.)]TJ
8.2191 0 0 7.3052 475.0298 534.3873 Tm
(23)Tj
10.959 0 0 10.959 487.8424 529.5117 Tm
[(Similarly,)-449.5(Wei)]TJ
-15.9489 -1.1847 TD
[(et)-549.4(al.)-543.5(utilized)-547.9(mouse)-543.7(models)-547.2(of)-543.7(FXS)-544.9(to)-548.2(show)-540.5(that)]TJ
0 -1.1795 TD
[(AEA-mediated)-426.3(signaling)-424.7(at)-419.8(CB)]TJ
8.2191 0 0 7.3052 453.2597 501.7888 Tm
(1)Tj
10.959 0 0 10.959 461.8204 503.603 Tm
[(receptors,)-424.1(driven)-425.9(by)]TJ
-13.5744 -1.1795 TD
[(oxytocin,)-346.3(controls)-342.9(social)-344.1(reward)]TJ
8.2191 0 0 7.3052 454.8471 495.4959 Tm
(24)Tj
10.959 0 0 10.959 466.5258 490.677 Tm
[(and)-343.7(that)-347.3(increasing)]TJ
-14.0038 -1.1847 TD
[(AEA)-402.3(activity)-397.2(resulted)-402(in)-399.2(reductions)-401.2(in)-399.2(social)-401(impair-)]TJ
0 -1.1795 TD
(ment.)Tj
8.2191 0 0 7.3052 338.1731 469.644 Tm
(25)Tj
10.959 0 0 10.959 349.3416 464.7684 Tm
[(Much)-301.9(like)-302.5(its)-300.1(impact)-300(on)-304(2-AG,)-301(CBD)-297.9(has)-302.7(been)]TJ
-3.3108 -1.1847 TD
[(shown)-408.2(to)-408.5(increase)-412.4(levels)-406.7(of)-409.2(AEA)-412.6(by)-407.7(binding)-406.7(to)-408.5(fatty)]TJ
0 -1.1795 TD
[(acid-binding)-240.7(proteins,)-239.7(which)-233.7(transport)-237.7(AEA)-236.8(to)-237.8(the)-235.7(cat-)]TJ
0 -1.1847 TD
[(abolic)-347.8(enzyme)-350.2(fatty)-346.5(acid)-348.3(amide)-348.5(hydrolase,)-344.4(an)-351.5(enzyme)]TJ
0 -1.1795 TD
[(that)-533.5(breaks)-533.9(down)-529.7(AEA.)]TJ
8.2191 0 0 7.3052 424.0629 417.8267 Tm
(2628)Tj
10.959 0 0 10.959 449.8582 412.9511 Tm
[(Binding)-530.7(to)-532.7(fatty)-532.8(acid-)]TJ
-12.4829 -1.1847 TD
[(binding)-210.2(proteins)-204.2(is)-208.9(thought)-203.1(to)-206.8(increase)-205.5(AEA)-205.7(availability)]TJ
0 -1.1795 TD
[(and)-302.3(CB)]TJ
8.2191 0 0 7.3052 346.3369 385.2283 Tm
(1)Tj
10.959 0 0 10.959 353.5936 387.0424 Tm
(activation.)Tj
/F4 1 Tf
10.4607 0 0 10.4607 313.0582 361.1338 Tm
[(CBD)-300.3(and)-303.8(FXS:)-295.3(Other)-300.7(Mechanisms)-297.8(of)-303.6(Action)]TJ
/F6 1 Tf
10.959 0 0 10.959 313.0582 348.2078 Tm
[(The)-394.5(mechanisms)-385.8(underlying)-390(the)-390.9(potential)-388.1(benets)-390.9(of)]TJ
0 -1.1847 TD
-.0001 Tc
[(CBD)-427.3(for)-428.1(FXS)-431.2(span)-429.8(far)-429(beyond)-422.5(the)-432.4(endocannabinoid)]TJ
0 -1.1795 TD
0 Tc
[(system.)-599.3(Beyond)-592.9(providing)-593.8(benet)-594.5(to)-594.8(patients)-593.1(with)]TJ
0 -1.1847 TD
[(FXS)-348.3(through)-342.8(increases)-343.3(in)-347.5(2-AG)-343.1(and)-343.7(AEA)-345.4(availability,)]TJ
0 -1.1795 TD
[(CBD)-380.6(may)-377.8(positively)-376.4(affect)-376.7(synaptic)-380.2(plasticity.)-377.5(Studies)]TJ
0 -1.1847 TD
(of)Tj
/F7 1 Tf
1.1381 0 TD
(FMR1)Tj
/F6 1 Tf
2.8039 0 TD
[(KO)-343.5(mice)-346.4(have)-346.3(identied)-346.7(discrete)-346(alterations)]TJ
-3.942 -1.1795 TD
[(in)-207.8(synaptic)-204.3(plasticity)-207.5(in)-202.6(specic)-206.8(brain)-205.3(regions,)-205.4(including)]TJ
0 -1.1847 TD
[(an)-289.4(increase)-288.3(in)-285.4(long-term)-281.3(depression)-287.4(\(LTD\))-285.3(in)-290.5(the)-282.3(hip-)]TJ
0 -1.1795 TD
(pocampus,)Tj
8.2191 0 0 7.3052 360.2834 249.4488 Tm
(23,29)Tj
10.959 0 0 10.959 380.6361 244.5731 Tm
[(and)-260.9(preclinical)-256.9(data)-254.3(suggest)-258.2(that)-254.2(reduc-)]TJ
-6.1664 -1.1795 TD
[(ing)-525.8(LTD)-526.4(in)]TJ
/F7 1 Tf
5.5094 0 TD
(FMR1)Tj
/F6 1 Tf
2.9849 0 TD
[(KO)-524.6(mice)-522.2(requires)-526.2(activation)-525.6(of)]TJ
-8.4943 -1.1847 TD
[(endocannabinoid)-276.3(receptors.)]TJ
8.2191 0 0 7.3052 434.5511 223.5401 Tm
(19)Tj
10.959 0 0 10.959 445.3794 218.6645 Tm
[(Therefore,)-272.4(it)-276.1(is)-271(hypothe-)]TJ
-12.0742 -1.1795 TD
[(sized)-533(that)-528.3(CBD)-530.7(may)-533(increase)-531.4(synaptic)-530.2(plasticity)-528.2(in)]TJ
0 -1.1847 TD
[(FXS,)-347.6(facilitating)-348.8(one)-343.3(of)-347.1(the)-349.5(basic)-345.8(cellular)-345.8(mechanisms)]TJ
0 -1.1795 TD
[(thought)-389.3(to)-387.8(be)-392.8(associated)-386.4(with)-387.2(learning)-390.5(and)-390.2(improve-)]TJ
0 -1.1847 TD
[(ments)-301.6(in)-300.9(cognition.)]TJ
8.2191 0 0 7.3052 398.8912 171.7228 Tm
(29)Tj
10.959 0 0 10.959 324.0566 153.9212 Tm
[(More)-271.6(recent)-276.5(work)-272.1(has)-276.9(also)-270(begun)-275.8(to)-274(identify)-273.2(decits)]TJ
-1.0036 -1.1847 TD
[(in)-342.3(GABA)-335.5(receptor)-333.6(expression)-339.4(among)-335.2(those)-339.1(with)-335.5(FXS.)]TJ
0 -1.1795 TD
[(As)-211.3(FMRP)-207.4(has)-209.6(been)-206.6(shown)-206.4(in)-207.8(animal)-206.6(models)-205.7(to)-211.9(enhance)]TJ
0 -1.1847 TD
.0185 Tc
[(e)-5.2(x).2(pression)-480.3(of)-476.8(GABA)-479.2(receptors,)-477.4(the)-476(l)-.5(ac)-5.2(k)-475.4(o)1.2(f)-476.8(F).5(MRP)]TJ
0 -1.1795 TD
0 Tc
[(among)-299(those)-302.9(with)-299.3(FXS)-301.8(has)-297.6(been)-299.8(associated)-303.6(with)-299.3(fewer)]TJ
T*
.0195 Tc
[(GABA)-617.8(receptors.)]TJ
8.2191 0 0 7.3052 394.5826 93.9968 Tm
.0314 Tc
(30)Tj
10.959 0 0 10.959 409.6629 89.1779 Tm
.0204 Tc
[(Indeed,)-615.2(p)2.4(reclinical)-609(studies)-614(i)1(n)]TJ
/F7 1 Tf
-8.8151 -1.1847 TD
0 Tc
(FMR1)Tj
/F6 1 Tf
2.7676 0 TD
[(KO)-307.3(mice)-310.1(have)-304.9(consistently)-309.2(shown)-304.7(downregula-)]TJ
-2.7676 -1.1795 TD
[(tion)-300.7(of)-300.5(the)-303(GABA)-299.3(system.)]TJ
8.2191 0 0 7.3052 427.5211 68.1449 Tm
(11)Tj
10.959 0 0 10.959 438.6896 63.2692 Tm
[(As)-299.2(CBD)-297.9(acts)-302(as)-300.9(a)-302.8(positive)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 62.022 754.3557 Tm
(4)Tj
41.0345 0 TD
[(TARTA)-9.7(GLIA)-305.5(ET)-299.4(AL.)]TJ
ET
endstream
endobj
36 0 obj
<>stream
/GS1 gs
BT
/F6 1 Tf
10.959 0 0 10.959 59.7543 697.8896 Tm
0 0 0 rg
0 Tc
0 Tw
[(allosteric)-217.5(modulator)-212.9(of)-212.6(GABA-A)-215.3(receptors,)]TJ
8.2191 0 0 7.3052 246.0472 702.7651 Tm
(31)Tj
10.959 0 0 10.959 256.2519 697.8896 Tm
[(CBD)-215.1(may)]TJ
-17.9302 -1.1847 TD
[(also)-301(act)-298.7(to)-299.9(enhance)-302.6(the)-297.8(binding)-298.1(afnity)-299.5(for)-298.7(GABA.)]TJ
1.0036 -1.1795 TD
[(The)-234.1(impact)-238(of)-233.3(CBD)-235.8(on)-236.8(serotonin)-236.8(represents)-237.1(a)-235.5(mech-)]TJ
-1.0036 -1.1847 TD
[(anism)-389.9(by)-387(which)-383.7(CBD)-385.8(may)-388.2(aid)-386.7(in)-388.8(reduction)-387.5(of)-383.3(social)]TJ
0 -1.1795 TD
[(anxiety)-496.1(and)-493.7(resulting)-487.7(avoidance)-495(experienced)-492.7(by)-490.5(pa-)]TJ
0 -1.1847 TD
[(tients)-334.4(with)-330.3(FXS.)-332.1(Indeed,)-331.4(the)-334(anxiolytic)-329.4(effects)-333.8(of)-331.6(CBD)]TJ
0 -1.1795 TD
[(have)-589.4(been)-584.3(reported)-586.6(in)-590.6(over)-584.8(30)-588.8(preclinical)-588(studies,)]TJ
T*
[(using)-267.7(multiple)-260.2(models)-262.6(of)-264.3(anxiety)-263.3(\(i.e.,)-261.8(generalized)-265.4(anx-)]TJ
0 -1.1847 TD
[(iety,)-389.4(stress-induced)-388.6(anxiety,)-391.9(panic)-386.7(disorder,)-390.1(and)-390.2(con-)]TJ
0 -1.1795 TD
[(textual)-336.5(fear)-333.7(conditionin)5.8(g\),)]TJ
8.2191 0 0 7.3052 175.181 586.2046 Tm
(32,33)Tj
10.959 0 0 10.959 196.3842 581.329 Tm
[(as)-331.9(well)-331.4(as)-331.9(in)-331.9(a)-333.8(growing)]TJ
-12.4673 -1.1847 TD
[(number)-225.1(of)-228.1(human)-226.7(studies,)-222.7(including)-227.7(within-social)-223(anx-)]TJ
0 -1.1795 TD
(iety.)Tj
8.2191 0 0 7.3052 77.896 560.2959 Tm
(32,34)Tj
10.959 0 0 10.959 99.1559 555.4203 Tm
[(Several)-336.3(preclinical)-334.5(studies)-337.2(have)-335.9(identied)-336.4(the)]TJ
-3.5954 -1.1847 TD
[(serotonin)-588.5(1A)-582.5(receptor)-587.1(as)-585.4(one)-586.4(mechanism)-584.2(through)]TJ
0 -1.1795 TD
[(which)-300.9(CBD)-297.9(exerts)-298(its)-300(anxiolytic)-298.3(effects.)]TJ
8.2191 0 0 7.3052 232.2708 534.3873 Tm
(35,36)Tj
/F4 1 Tf
10.4607 0 0 10.4607 59.7543 503.603 Tm
[(Case)-302.9(Reports)]TJ
/F6 1 Tf
10.959 0 0 10.959 59.7543 490.677 Tm
[(We)-374.9(report)-368.9(the)-375.4(cases)-372.3(of)-367.8(three)-376.5(patients)-370.6(with)-371.7(diagnosed)]TJ
0 -1.1847 TD
[(FXS)-467.3(who)-459.6(received)-463.9(oral)-461.4(forms)-462.5(of)-460.9(botanically)-460.1(derived)]TJ
0 -1.1795 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
1.0346 0 TD
[(solutions)-454.8(and)-452.3(reported)-452.1(clinical)-455(symptom)-448.2(im-)]TJ
-3.0315 -1.1847 TD
(provement.)Tj
/F9 1 Tf
10.4607 0 0 10.4607 59.7543 425.877 Tm
[(Patient)-300.5(1)]TJ
/F6 1 Tf
10.959 0 0 10.959 59.7543 412.9511 Tm
[(Patient)-273.6(1)-276.3(i)0(s)-276.1(a)-271.7(3-year)-275.2(6-month-old)-268.2(male)-273.3(with)-273.4(FXS)-275.9(diag-)]TJ
T*
[(nosed)-287(at)-290.5(age)-287.5(15)-283.6(months)-286.7(with)-283.8(250)-290.9(to)-284.4(650)-285.7(CGG)-287(repeats.)]TJ
0 -1.1795 TD
-.0001 Tc
[(He)-515.7(was)-513.8(born)-516.2(full-term)-512.4(following)-515.1(an)-517.2(uncomplicated)]TJ
0 -1.1847 TD
0 Tc
[(pregnancy)-437.7(and)-436.8(delivery)-437.9(at)-435.3(seven)-438.2(pounds)-439(six)-439.3(ounces.)]TJ
0 -1.1795 TD
[(In)-522.8(the)-520.2(newborn)-522(period,)-523.2(he)-522.2(began)-519.1(having)-522.4(problems)]TJ
T*
[(latching)-503.9(for)-500.4(breastfeeding,)-498(and)-504(he)-501.5(was)-498.2(fed)-500.9(pumped)]TJ
0 -1.1847 TD
[(breast)-255.3(milk)-247.9(and)-255.7(formula)-250.7(from)-252.3(a)-251(bottle;)-248.6(he)-253.2(had)-250.2(frequent)]TJ
0 -1.1795 TD
[(gagging)-199.5(and)-204(spitting)-200.4(up.)-200.8(By)-200.6(6)-198.7(months)-204(of)-197.1(age,)-204(with)-195.8(intro-)]TJ
0 -1.1847 TD
[(duction)-448.4(of)-445.4(soft)-446.7(baby)-443.3(foods,)-447.1(he)-444.6(was)-446.4(often)-443.5(dysphagic,)]TJ
0 -1.1795 TD
[(choked)-216.4(easily,)-219.8(and)-219.5(was)-213.6(intolerant)-215.2(of)-217.8(chunky)-216.2(or)-217.2(textured)]TJ
0 -1.1847 TD
[(foods.)-333.3(Testing)-330(for)-334.9(food)-330.7(allergies)-328.7(was)-332.6(negative,)-332.5(and)-333.3(his)]TJ
0 -1.1795 TD
[(formula)-561.1(was)-555.1(changed)-560.9(multiple)-560.3(times)-556.8(over)-558.9(his)-557.3(rst)]TJ
0 -1.1847 TD
[(year)-265(of)-259.2(life.)-267(He)-257(grew)-262.9(slowly)-263.5(at)-259.4(the)-261.6(third)-263(to)-258.5(fth)-264.3(percen-)]TJ
0 -1.1795 TD
[(tile)-318.8(for)-314.2(weight)-309.9(and)-317.8(the)-313.3(50th)-309.3(percentile)-315.2(for)-314.2(length)-316.2(until)]TJ
T*
[(15)-340.5(months)-338.5(of)-336.8(age.)-338.5(He)-339.7(was)-337.8(also)-337.2(hypotonic)-338.2(with)-335.5(delays)]TJ
0 -1.1847 TD
[(in)-321.6(gross)-319.3(motor)-315.5(skills.)-319.2(He)-319.1(had)-317.4(behavioral)-316.7(concerns,)-321.2(in-)]TJ
0 -1.1795 TD
[(cluding)-278.6(atypical)-277.4(motor)-274.2(movements,)-277.3(frequent)-276.8(repetitive)]TJ
0 -1.1847 TD
[(moving,)-317.4(stiffening)-311.1(and)-317.8(shaking)-313.6(of)-316.1(his)-314.2(legs,)-311.6(body)-313.7(rock-)]TJ
0 -1.1795 TD
[(ing,)-416.4(and)-410.9(repetitive)-414.2(nger)-411.1(stereotypies)-413.6(while)-411.2(touching)]TJ
0 -1.1847 TD
[(his)-433.2(ears.)-430.7(He)-432.9(displayed)-429.8(difculty)-430.2(adjusting)-429.7(to)-429.2(new)-430.1(or)]TJ
0 -1.1795 TD
[(noisy)-298.1(places)-297.4(and)-297.1(changes)-292.7(in)-295.7(routine,)-298.5(as)-295.7(well)-295.2(as)-295.7(trouble)]TJ
0 -1.1847 TD
[(making)-313.9(eye)-313.7(contact)-308.9(and)-312.6(a)-313.1(short)-308.3(attention)-315.1(span)-310.8(during)]TJ
0 -1.1795 TD
[(play)-435.3(and)-436.8(in)-435.4(social)-437.2(interactions;)-433.3(he)-439.4(would)-430(sometimes)]TJ
0 -1.1847 TD
[(stare)-300.1(off)-299.2(and)-302.3(seem)-299.2(disconnected)-302.7(for)-298.7(10)-299.1(to)-299.9(30)-164.6(sec.)]TJ
1.0036 -1.1795 TD
[(At)-345.7(15)-340.5(months)-343.6(of)-347.1(age,)-348.9(he)-341.1(was)-348.1(evaluated)-346.4(and)-343.7(under-)]TJ
-1.0036 -1.1795 TD
[(went)-257.4(a)-261.4(brain)-257(magnetic)-258.6(resonance)-257.4(imaging)-260.8(\()-81.2(MRI\),)-260.9(elec-)]TJ
0 -1.1847 TD
[(troencephalography)-605.9(\(EEG\),)-605.9(creatine)-608.9(kinase,)-606.6(plasma)]TJ
0 -1.1795 TD
[(amino)-579.8(acids,)-583.7(and)-581.6(thyroid)-582.8(and)-581.6(genetic)-579.5(testing.)-579.2(His)]TJ
22.912 57.9085 TD
[(MRI,)-609(EEG,)-609(microarray,)-610.5(and)-607.5(laboratory)-606(parameters)]TJ
0 -1.1847 TD
[(were)-325.6(normal.)-323.4(His)-328.3(FXS)-322.5(DNA)-328.1(test)-323.2(results)-327.4(showed)-323.6(a)-328.6(full)]TJ
0 -1.1795 TD
[(mutation)-459.4(for)-464.2(FXS)-462.2(with)-464.8(260)-461.6(to)-460.3(650)-461.6(fully)-465.8(methylated)]TJ
0 -1.1847 TD
[(CGG)-297.3(repeats.)]TJ
.9984 -1.1795 TD
[(At)-516.4(this)-519.2(time,)-516.5(the)-520.2(patients)-519.9(parents)-516.9(independently)]TJ
-.9984 -1.1847 TD
.0184 Tc
[(obtaine)-5.3(d)-211.7(a).2(nd)-216.9(bega)-5(n)-211.4(a).2(dministerin)-4.5(g)-211.6(an)-216.6(oral)-212.7(pa)-5(ste)-212.2(c)-.1(om-)]TJ
0 -1.1795 TD
.0178 Tc
[(prising)-662.3(18%)-660(to)-661.7(23)-5(.5)-5(%)-660(C)1.3(BD)-660.3(an)-5.1(d)-662.4(t)-.9(race)-662.9(amou)-5.4(nts)]TJ
T*
-.0001 Tc
[(\(0.03%\))-478.6(of)-481.7(delta-9-tetrahydrocannabinol)-478.3(\(THC\))-481.2(that)]TJ
0 -1.1847 TD
0 Tc
[(delivered)-301.3(50)-164.6(mg)-297.5(of)-300.5(CBD)-297.9(per)-303.7(day)-297.3(\(RSHO)]TJ
/F5 1 Tf
16.2127 0 TD
()Tj
/F6 1 Tf
1.1847 0 TD
[(Blue)-300.3(Label;)]TJ
-17.3974 -1.1795 TD
[(Naturewell,)-330.7(Inc.,)-338.1(San)-333.6(Diego,)-331.5(CA\).)-336(They)-334.8(combined)-334(the)]TJ
0 -1.1847 TD
[(CBD)-339.3(paste)-340.7(with)-340.7(coconut)-343.5(oil,)-339.5(heated)-342.3(the)-344.3(mixture)-339.6(until)]TJ
0 -1.1795 TD
[(it)-317.4(liqueed,)-321.7(and)-323(then)-315.5(used)-321.7(a)-323.5(syringe)-320.5(to)-315.4(administer)-323(the)]TJ
0 -1.1847 TD
[(liquid)-458(preparation)-455.3(orally.)-456.2(During)-459.6(the)-458.2(rst)-456.6(month)-454.2(of)]TJ
0 -1.1795 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
1.0553 0 TD
[(treatment,)-473.5(the)-473.7(family)-471.8(noticed)-474.8(behavioral)-471.9(im-)]TJ
-3.0522 -1.1847 TD
(provements.)Tj
.9984 -1.1795 TD
[(After)-283.5(1)-286.6(month)-283.4(of)-285(CBD)]TJ
/F5 1 Tf
9.1513 0 TD
(+)Tj
/F6 1 Tf
.8639 0 TD
[(monotherapy,)-283(the)-287.4(then)-284.5(16-)]TJ
-11.0137 -1.1795 TD
[(month-old)-206.2(patient)-207(began)-208.7(specialized)-205(care)-208.7(in)-212.9(the)-204.7(form)-205.8(of)]TJ
0 -1.1847 TD
[(speech)-249.5(and)-245.4(language)-249.1(therapy)-246.7(and)-250.5(occupational)-245(therapy)]TJ
0 -1.1795 TD
[(for)-402.1(FXS.)-409.7(A)-404.5(baseline)-406.2(measure)-406.1(of)-404(adaptive)-405.8(functioning)]TJ
0 -1.1847 TD
[(was)-441.3(obtained)-445.3(\(Table)-440.5(1\).)-444.7(Over)-444.1(the)-442.6(next)-445.8(3)-441.8(months)-441.9(of)]TJ
0 -1.1795 TD
[(daily)-284(50-mg)-284(CBD)]TJ
/F5 1 Tf
7.0717 0 TD
(+)Tj
/F6 1 Tf
.8639 0 TD
[(treatment)-282.8(with)-283.8(adjunctive)-287.6(therapy,)]TJ
-7.9356 -1.1847 TD
[(the)-411.6(family)-414.9(noted)-411.1(continued)-412.3(improvements)-411.9(in)-414.7(a)-411.4(wide)]TJ
0 -1.1795 TD
[(range)-313.7(of)-316.1(clinical)-315.3(parameters.)-316.3(Feeding)-314.4(improved)-314.5(mark-)]TJ
0 -1.1847 TD
[(edly)-342.5(with)-345.8(increased)-347.7(willingness)-347.3(to)-341.3(eat)-345.2(solid)-346(foods)-344.4(and)]TJ
0 -1.1795 TD
[(increased)-451.1(intake)-452(overall.)-448.9(His)-452.5(parents)-454.8(also)-451(noted)-452.5(im-)]TJ
0 -1.1847 TD
[(provements)-283.7(in)-290.5(motor)-284.5(coordination,)-290.2(more)-287.7(frequent)-287.1(vo-)]TJ
0 -1.1795 TD
[(calizations,)-229.1(less)-230.4(rocking)-226(and)-229.9(kicking)-227.1(during)-228.8(feeds,)-232.3(more)]TJ
T*
[(frequent)-240.6(and)-245.4(longer)-238.7(eye)-241.3(contact,)-241(an)-242.9(increase)-241.7(in)-244(positive)]TJ
0 -1.1847 TD
[(interactions)-294.3(with)-294.1(other)-297.7(children,)-296.7(greater)-295.2(willingness)-295.6(to)]TJ
0 -1.1795 TD
[(explore)-299.3(new)-300.8(places,)-307.1(and)-302.3(less)-297.6(self-stimulatory)-300.1(behavior.)]TJ
0 -1.1847 TD
[(Many)-234.6(of)-238.5(the)-235.7(parental)-240.5(observations)-234.5(were)-237.7(also)-238.9(conrmed)]TJ
0 -1.1795 TD
[(by)-485.3(the)-484(patients)-483.7(occupational)-488.1(and)-483.3(speech)-487.5(therapists,)]TJ
0 -1.1847 TD
[(some)-582.6(of)-579.9(whom)-578.8(were)-584.3(unaware)-581(of)-585.1(the)-582.3(initiation)-579.1(of)]TJ
0 -1.1795 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
.8122 0 TD
[(treatment.)-230.4(CBD)]TJ
/F5 1 Tf
6.3371 0 TD
(+)Tj
/F6 1 Tf
.8174 0 TD
[(solution)-229.1(was)-234.3(the)-230.5(only)-232.3(medica-)]TJ
-9.9635 -1.1847 TD
[(tion)-295.6(used)-301(in)-300.9(treatment)-298.3(during)-301.3(this)-301.9(time.)]TJ
ET
310.847 198.652 239.074 .28348 re
f
310.847 93.09 239.074 .28348 re
f
376.838 180.397 84.189 .22676 re
f
465.789 180.397 84.132 .22676 re
f
310.847 154.715 239.074 .28348 re
f
BT
/F4 1 Tf
8.9663 0 0 8.9663 310.8472 215.3196 Tm
[(Table)-300.2(1.)-500.5(Patient)-303.6(1:)-304.5(Adaptive)-299.9(Functioning)]TJ
6.7246 0 0 5.9768 475.1999 219.2881 Tm
(a)Tj
8.9663 0 0 8.9663 481.3794 215.3196 Tm
[(at)-304.7(1)-301.6(Year)]TJ
-19.0193 -1.1128 TD
[(4)-301.6(Months)-301.6(of)-296.4(Age)-306.9(and)-295.7(3)-301.6(Years)-302.8(0)-301.6(Months)-301.6(of)-302.7(Age)]TJ
/F2 1 Tf
7.9702 0 0 7.9702 390.2172 186.7464 Tm
[(1)-336.8(year)-326.9(4)-329.7(months)-3739.8(3)-336.8(years)-323.4(0)-336.8(months)]TJ
-1.6787 -2.1268 TD
(Standardized)Tj
1.4795 -1.1239 TD
(score)Tj
5.9774 0 0 5.3127 406.8282 164.3527 Tm
(b)Tj
7.9702 0 0 7.9702 426.8975 169.7952 Tm
[(Percentile)-591.6(Standar)12(dized)]TJ
6.3591 -1.1239 TD
(score)Tj
5.9774 0 0 5.3127 495.7794 164.3527 Tm
(b)Tj
7.9702 0 0 7.9702 515.792 169.7952 Tm
(Percentile)Tj
/F9 1 Tf
-25.714 -3.2365 TD
[(Communica)12.2(tion)-3954(84)-4122.8(14th)-4116.6(87)-4122.8(19th)]TJ
0 -1.1239 TD
[(Daily)-293.5(living)-297.8(skills)-3745.5(71)-4620.7(3rd)-4118.7(77)-4635(6th)]TJ
T*
[(Socializatio)10.3(n)-5430.1(8)0(6)-4122.8(18th)-4116.6(79)-4635(8th)]TJ
T*
[(Motor)-295.9(skills)-5843.9(78)-4627.8(7th)-4121.6(70)-4393.1(2nd)]TJ
T*
[(Adaptive)-289.1(behavior)]TJ
.9958 -1.1239 TD
(composite)Tj
9.617 1.1239 TD
[(76)-4627.8(5th)-4121.6(75)-4635(5th)]TJ
5.9774 0 0 5.3127 319.8046 84.8692 Tm
(a)Tj
7.9702 0 0 7.9702 322.6393 81.2976 Tm
[(Vineland)-292.8(adaptive)-293.1(behavior)-290.9(scales,)-295.7(second)-296.4(editionpar)12.9(ent)-297.6(survey.)]TJ
5.9774 0 0 5.3127 319.8046 75.9118 Tm
(b)Tj
7.9702 0 0 7.9702 323.1495 72.3401 Tm
(Mean)Tj
/F5 1 Tf
2.4967 0 TD
()Tj
/F9 1 Tf
.7113 0 TD
(SD)Tj
/F5 1 Tf
1.3088 0 TD
(=)Tj
/F9 1 Tf
.7184 0 TD
(100)Tj
/F5 1 Tf
1.6929 0 TD
()Tj
/F9 1 Tf
.7184 0 TD
(15.)Tj
-8.0663 -1.1239 TD
[(SD,)-294(standard)-296.1(deviation.)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 59.7543 753.8455 Tm
[(TREA)-10.3(TMENT)-305.4(OF)-302.7(FX)-8.4(S)-299.8(WITH)-303.3(CBD)]TJ
48.6485 0 TD
(5)Tj
ET
endstream
endobj
42 0 obj
<>stream
/GS1 gs
BT
/F6 1 Tf
10.959 0 0 10.959 72.9637 697.8896 Tm
0 0 0 rg
0 Tc
0 Tw
[(At)-299.1(the)-297.8(4-month)-298.8(follow-up)-297.3(visit,)-295.2(the)-303(patients)-297.5(weight)]TJ
-.9984 -1.1847 TD
[(had)-358.8(increased)-352.9(to)-356.8(the)-354.7(15th)-355.9(percentile,)-361(while)-354.3(his)-355.6(length)]TJ
0 -1.1795 TD
[(remained)-320.9(at)-316.3(the)-318.5(50th)-319.7(percentile.)-319.6(Developmental)-316.1(prog-)]TJ
0 -1.1847 TD
[(ress)-256.1(included)-250.7(improved)-252.4(ne)-250.2(and)-255.7(gross)-252.1(motor)-248.3(skills,)-251.9(de-)]TJ
0 -1.1795 TD
[(creased)-512.4(repetitive)-512.5(rocking,)-514.9(improved)-511(social)-509.6(interest/)]TJ
0 -1.1847 TD
[(engagement,)-556.6(improved)-557.6(vocalizations,)-554(and)-555.8(decreased)]TJ
0 -1.1795 TD
[(hyperactivity.)-218.1(The)-213.4(patient)-217.3(began)-219.1(a)-214.8(regimen)-219.8(of)-217.8(sertraline)]TJ
T*
[(\(2.5)-167.5(mg)-400.9(per)-402(day\))-399.2(due)-401.2(to)-398.2(preliminary)-403.3(evidence)-400.7(of)-398.8(im-)]TJ
0 -1.1847 TD
[(proved)-382.8(language)-383.6(and)-385(development)-379.2(in)-383.7(young)-383.8(children)]TJ
0 -1.1795 TD
[(with)-759.7(FXS)-757(treated)-760.8(with)-759.7(sertraline.)]TJ
8.2191 0 0 7.3052 225.2976 586.2046 Tm
(37,38)Tj
10.959 0 0 10.959 251.2062 581.329 Tm
(Subsequent)Tj
-17.2629 -1.1847 TD
[(follow-up)-328.3(visits)-325.1(\(at)-330.3(21)-325(and)-333.3(27)-325(months)-328.1(of)-326.4(age\))-327.3(showed)]TJ
0 -1.1795 TD
[(continued)-277.8(improvement)-274(in)-280.2(language)-275(and)-276.4(developmen-)]TJ
0 -1.1847 TD
[(tal)-345.7(skills.)-339.9(The)-342.7(patient)-346.6(started)-342(walking)-343.7(and)-343.7(self-feeding)]TJ
0 -1.1795 TD
[(independently,)-252.7(exhibited)-253.5(more)-246.3(frequent)-256.1(and)-250.5(varied)-250.6(vo-)]TJ
0 -1.1847 TD
[(calizations,)-223.9(fewer)-226(repetitive)-228(and)-224.7(motor)-222.4(behaviors,)-225.1(fewer)]TJ
0 -1.1795 TD
[(sensory)-334.9(sensitivities)-332.1(\(e.g.,)-332.8(tolerated)-331.5(noise)-334.9(and)-333.3(lights)-333.7(of)]TJ
T*
[(reworks\),)-343.4(a)12.8(n)13.3(d)-328.4(m)10.2(o)13.7(r)12.2(e)-328.9(f)11.6(r)12.2(e)12.5(qu)21.2(e)12.5(n)13.3(t)-329.1(i)11.7(n)13.3(i)11.7(t)12.3(i)11.7(at)19.9(i)16.9(o)0(n)-319.6(o)13.7(f)-329.8(j)12(o)13.7(i)11.7(nt)-321(a)12.8(t)12.3(t)12.3(e)12.5(n)13.3(-)]TJ
0 -1.1847 TD
-.0127 Tc
[(tion)-237.3(with)-237(pointin)-12.7(g)8.6(.)-234.4(W)-1.7(eight)-238.4(i)-1(ncrease)-12.7(d)-225.2(to)-236.9(the)-233(2)-12.7(5)8.9(t)-.4(h)-231.8(p)-12.7(e)7.6(r)-.5(cen-)]TJ
0 -1.1795 TD
0 Tc
[(t)12.3(i)11.7(l)12(e)12.5(.)-340.7(H)0(e)-329.4(c)12.5(on)21.9(t)12.3(i)11.7(n)13.3(u)13(ed)-331.4(u)13(s)12.2(i)11.7(n)0(g)-330.5(C)14.5(BD)]TJ
/F5 1 Tf
11.9035 0 TD
(+)Tj
/F6 1 Tf
.9208 0 TD
[(so)20.8(l)12(u)13(t)12.3(i)11.7(o)13.7(n)-343.6(a)12.8(n)13.3(d)-343.9(r)12.2(e)12.5(m)15.3(ai)19.3(n)13.3(e)12.5(d)]TJ
-12.8243 -1.1847 TD
-.0127 Tc
[(in)-314.9(a)-310.3(s)-12.7(t)6.6(r)-.5(ong)-315.2(e)-.2(arly)-315.2(interven)-12.7(t)7.8(i)-1(on)-314.9(progra)-12.7(m)10.3(:)-317.2(1)-164.8(h)-314.6(per)-316(w)2.1(eek)-315.2(of)]TJ
0 -1.1795 TD
-.013 Tc
[(occ)-13(u)7.3(pation)-13(a)8(l)-1(,)-612.4(s)-.8(pe)-13(e)6.8(c)-.5(h,)-617.5(and)-615.6(p)0(hysica)-13(l)-603.8(t)-.7(he)-13(r)6.5(a)-.2(py;)-617.5(6)-165.1(h)-614.9(p)0(er)]TJ
0 -1.1847 TD
[(we)-12.9(e)6.9(k)-418.9(of)-420.3(Early)-418.8(S)-12.9(t)7(a)-.1(rt)-419.6(Den)-12.9(v)8.4(er)-419.7(Model)-419.9(b).8(eh)-12.9(a)8.4(v).2(ioral)-419.9(t)-.6(her)-12.9(a)6.9(py)]TJ
0 -1.1795 TD
.2908 Tc
[(a)303.6(n)304.1(da)303.6(p)303.8(p)303.8(l)302.8(i)302.5(e)303.3(db)304.5(e)303.3(h)304.5(a)303.6(v)303.9(i)302.5(o)290.8(r)311.6(a)303.6(la)303.6(n)304.1(a)303.6(l)302.8(y)303.9(s)290.8(i)314.7(s)290.8(.)]TJ
.9984 -1.1847 TD
0 Tc
[(When)-270.3(the)-271.9(patient)-269(was)-270.5(30)-268(months)-271.2(of)-269.5(age,)-271.3(his)-272.8(parents)]TJ
-.9984 -1.1795 TD
[(chose)-401(to)-398.2(discontinue)-398.7(CBD)]TJ
/F5 1 Tf
10.8637 0 TD
(+)Tj
/F6 1 Tf
.9829 0 TD
[(treatment)-401.8(to)-398.2(instead)-398.4(ex-)]TJ
-11.8466 -1.1847 TD
[(plore)-215.9(minocycline,)-209.4(shown)-211.6(to)-211.9(improve)-213.7(behavioral)-213.2(symp-)]TJ
0 -1.1795 TD
[(toms)-432.7(in)-430.2(some)-432.5(patients)-427.5(with)-433.8(FXS.)]TJ
8.2191 0 0 7.3052 213.1653 366.0094 Tm
(39)Tj
10.959 0 0 10.959 225.7511 361.1338 Tm
[(The)-430.7(initiation)-434.2(of)]TJ
-14.9401 -1.1795 TD
[(25)-164.6(mg)-364.7(per)-360.6(day)-364.6(of)-362.6(minocycline)-360.1(coupled)-365.4(with)-361.4(cessation)]TJ
0 -1.1847 TD
[(of)-626.5(CBD)]TJ
/F5 1 Tf
3.4143 0 TD
(+)Tj
/F6 1 Tf
1.2105 0 TD
[(treatment)-629.4(resulted)-629.6(in)-626.8(increased)-627(anxiety,)]TJ
-4.6248 -1.1795 TD
[(more)-354.9(frequent)-359.6(meltdowns,)-356(and)-359.2(more)-354.9(difculty)-357.8(falling)]TJ
0 -1.1847 TD
[(and)-302.3(maintaining)-298.4(sleep.)]TJ
.9984 -1.1795 TD
[(During)-278.5(a)-271.7(clinic)-278.1(visit)-270.1(when)-276.8(the)-271.9(patient)-274.2(was)-275.7(3)-276.3(years)-273.4(of)]TJ
-.9984 -1.1847 TD
[(age,)-317.8(it)-312.3(was)-311.9(noted)-318(that)-311.1(the)-313.3(patient)-315.6(continued)-314(to)-315.4(engage)]TJ
0 -1.1795 TD
[(and)-473(make)-468.8(slow)-469.7(progress,)-467.1(although)-469.9(anxiety,)-469.5(frequent)]TJ
0 -1.1847 TD
[(meltdowns,)-433.6(and)-436.8(difculties)-432.8(with)-439(sleep)-434.4(persisted,)-436(and)]TJ
0 -1.1795 TD
[(increasing)-516.1(challenges)-514.8(with)-516.6(transitions)-514(and)-519.6(attention)]TJ
T*
[(span)-341.8(were)-341.1(observed.)-336(The)-342.7(patients)-338.9(medical)-339.5(treatments)]TJ
0 -1.1847 TD
[(included)-504.2(a)-504.5(daily)-506.4(regimen)-504.3(of)-502.3(4)-167.6(m)0(g)-504.4(o)0(f)-502.3(sertraline)-507.4(and)]TJ
0 -1.1795 TD
[(25)-164.6(mg)-261.3(of)-264.3(minocycline.)-261.1(He)-262.2(also)-264.8(continued)-262.3(to)-263.7(receive)-259.6(in-)]TJ
0 -1.1847 TD
[(tensive)-233.1(early)-227.1(intervention)-230.8(services)-232.2(\(as)-232.1(described)-233.3(above\).)]TJ
0 -1.1795 TD
[(At)-257.7(3)-255.6(years)-252.7(of)-254(age,)-255.8(an)-258.4(updated)-256.9(adaptive)-255.7(behavior)-253.6(assess-)]TJ
0 -1.1847 TD
[(ment)-262.1(was)-265.4(obtained)-259.1(\(Table)-264.6(1\).)-263.6(After)-262.8(discussion)-262.4(with)-257.9(his)]TJ
0 -1.1795 TD
[(family)-311.4(and)-312.6(medical)-308.5(team,)-308.5(the)-313.3(patient)-310.4(was)-311.9(restarted)-307(on)]TJ
0 -1.1847 TD
.009 Tc
(CBD)Tj
/F5 1 Tf
2.0227 0 TD
0 Tc
(+)Tj
/F6 1 Tf
.9726 0 TD
.0086 Tc
[(treatment,)-378.7(50)-169.4(m)8.6(g)-387.2(per)-382.7(d).9(ay.)-383.8(F).9(ollowing)-381.8(reinitia-)]TJ
-2.9953 -1.1795 TD
.0092 Tc
[(tion)-251.6(of)-248.2(CBD)]TJ
/F5 1 Tf
4.9714 0 TD
0 Tc
(+)Tj
/F6 1 Tf
.8432 0 TD
.0088 Tc
[(treatm)8.8(e)-9.9(n)1.4(t,)-254.3(his)-253.2(p)1.1(arents)-253.2(noted)-247.2(r)-4.8(eductions)]TJ
-5.8146 -1.1847 TD
[(in)-453.9(anxiety,)-456.2(fewer)-455(m)8.7(e)-10(l)0(tdowns,)-456.2(a).8(nd)-454.2(improvements)-455(in)]TJ
0 -1.1795 TD
.009 Tc
[(his)-496.1(a)1.1(bilit)-4.6(y)-490(to)-494.6(fall)-491.1(and)-490.1(s)-4.6(tay)-490(a)-4.1(sleep.)-492.1(T)2.2(he)-490.7(patient)-496(h)2(as)]TJ
T*
.0088 Tc
[(now)-364.4(t).4(ransitioned)-366.2(i)-.2(nto)-365.5(a)-366.4(small)-367.2(p)1.1(r)-4.8(e).6(school)-367.2(where)-366.7(h)1.8(e)-366.7(i)-.2(s)]TJ
0 -1.1847 TD
0 Tc
[(co)21(nt)20.5(in)19.8(ui)19.5(ng)-325.3(t)12.3(o)-332.9(do)-325(we)22.1(ll)-327.7(a)12.8(n)0(d)-325.4(h)0(a)21.3(s)-334.4(re)19.5(m)10.2(a)0(i)19.3(n)0(e)20.6(d)-333.6(on)-324.7(hi)20.2(s)-334.4(C)0(B)23.3(D)]TJ
/F5 1 Tf
21.2359 0 TD
(+)Tj
/F6 1 Tf
-21.2359 -1.1795 TD
[(t)12.3(r)0(e)19.5(a)0(t)19.9(m)10.2(en)20.7(t.)]TJ
/F9 1 Tf
10.4607 0 0 10.4607 313.0582 698.2297 Tm
[(Patient)-300.5(2)]TJ
/F6 1 Tf
10.959 0 0 10.959 313.0582 685.2471 Tm
[(Pa)16.1(t)12.3(i)11.7(en)15.5(t)-225.7(2)-229.7(i)11.7(s)-230.9(a)-225.2(2)0(6)16.5(-)12.6(ye)20.4(ar)19.8(-o)21.1(l)12(d)-230.1(m)10.2(a)0(l)19.7(e)-230.6(w)14.8(i)0(t)18.8(h)-229.5(f)11.7(u)0(l)19.9(l)0(-)19.4(m)10.2(ut)20.1(at)19.9(i)11.7(o)0(n)-221.3(\()]TJ
/F5 1 Tf
19.8339 0 TD
(>)Tj
/F6 1 Tf
.569 0 TD
[(20)16.5(0)]TJ
-20.403 -1.1795 TD
[(CG)19(G)-456(r)12.2(ep)20.3(ea)20.1(ts)19.3(\))-458.8(F)13(XS)-449.3(a)12.8(n)0(d)-444.4(a)0(n)-449.8(I)12.3(Q)-456(s)12.2(co)21(re)-446(in)-445.7(th)20.8(e)-458.3(m)10.2(i)11.7(d)0(-)20.4(5)0(0)21.7(s)0(.)]TJ
0 -1.1847 TD
[(De)17.2(s)12.2(p)0(i)19.5(t)0(e)-389.1(a)-401.1(m)10.2(e)12.5(di)19.5(ca)20.1(ti)18.8(on)-392(r)12.2(e)0(g)20.4(i)11.7(m)10.2(e)0(n)-393.2(t)12.3(ha)21.3(t)-401.6(i)11.7(nc)20.6(lu)19.9(de)20.3(d)-400.8(6)0(0)-143.9(m)10.2(g)-400.7(o)0(f)]TJ
0 -1.1795 TD
[(m)10.2(e)0(t)19.6(h)0(y)21.6(l)0(p)19.9(h)0(e)15.8(n)13.3(id)19.5(at)19.9(e)-360(h)13.7(yd)21(ro)20.8(ch)15.8(l)12(o)13.7(ri)18.7(de)-347(\(o)20.5(nc)20.6(e)-360(d)0(a)20.6(i)11.7(ly)20(\),)-349.5(2.)19.3(5)-157.3(m)10.2(g)-354.2(o)0(f)]TJ
0 -1.1847 TD
[(ar)19.8(ip)19.5(ip)19.5(ra)19.8(zo)21(le)19.4(,)-444.2(1)13.4(00)-143.9(m)10.2(g)-442.1(o)13.7(f)-443.6(s)12.2(e)0(r)19.5(t)0(r)19.3(a)0(l)19.7(i)11.7(ne)20.6(,)-444.2(2)13.4(00)-149.1(m)15.3(g)-442.1(of)-429.9(m)10.2(i)11.7(no)21.9(cy)20.4(-)]TJ
0 -1.1795 TD
[(cl)19.3(in)19.8(e,)-317.9(a)12.8(n)0(d)-315.1(0)0(.)19.3(2)-157.3(m)10.2(g)-323.2(of)-316.1(c)12.5(l)0(o)20.6(n)0(i)19.8(d)0(i)19.5(n)0(e)-315.6(\()11.9(at)-316.3(be)21(dt)20.1(im)21.8(e\))19.2(,)-325.2(t)0(h)20.8(e)-328.9(p)13(a)0(t)19.9(i)0(e)19(n)0(t)]TJ
T*
[(ex)14.9(p)13(e)0(r)19.5(i)11.7(en)15.5(c)12.5(e)0(d)-424.5(s)0(i)18.7(g)0(n)21.3(i)0()20.2(c)0(a)20.1(n)0(t)-424.4(s)0(y)15(m)15.3(pt)20.1(om)18.7(s)-437.8(o)13.7(f)-438.4(a)12.8(t)12.3(t)0(e)19.6(n)0(t)20.5(i)0(o)20.2(n)0(-)20.7(d)0(e)15.2()13.7(ci)19(t)12.3(/)]TJ
0 -1.1847 TD
[(hy)16.4(p)13(e)0(r)19.5(a)0(c)20.1(t)0(i)18.8(v)0(i)19.6(t)12.3(y)-318(d)0(i)19.5(s)0(o)20.8(r)0(d)20.1(e)0(r)19.5(,)-320(i)11.7(n)0(c)20.6(l)0(u)19.9(d)0(i)19.5(n)0(g)-309.8(h)0(y)21.6(p)0(e)20.3(r)0(a)19.8(c)0(t)19.6(i)11.7(vi)19.6(ty)20.2(,)-320(i)11.7(na)21(tt)19.4(en)20.6(-)]TJ
0 -1.1795 TD
[(ti)18.8(on)21.9(,)-464.9(a)12.8(nd)-449.6(im)16.7(p)13(u)0(l)19.9(s)0(i)18.7(v)0(i)19.6(t)12.3(y.)-451.8(He)-448.4(al)19.7(so)-450(su)20.1(ff)18.1(e)12.5(r)0(e)19.5(d)-462.9(f)11.6(r)0(o)20.8(m)-460.6(an)21(xi)19.3(et)19.6(y,)]TJ
0 -1.1847 TD
[(wh)18.2(i)11.7(c)0(h)-304.9(l)12(ed)-305.6(to)-305.1(av)20.7(oi)20.2(da)20.6(nt)-305.5(b)13.7(e)0(h)15.8(a)12.8(vi)19.6(or)-305.1(a)12.8(n)0(d)-304.7(s)0(l)19.1(e)0(e)19.8(p)-312.9(di)19.5(st)19.3(ur)20.1(ba)21.3(nc)15.5(e)12.5(s)0(,)]TJ
0 -1.1795 TD
[(an)15.8(d)-245.6(s)12.2(om)18.7(e)-246.2(s)12.2(ig)19.6(ni)19.8(c)21(an)21(t)-246.4(f)0(e)19(a)0(t)19.9(u)0(r)20.1(e)0(s)-239.1(o)13.7(f)-247(a)0(u)20.7(t)0(i)18.8(s)12.2(m)10.2(,)-247.6(in)19.8(cl)19.3(ud)20.9(in)19.8(g)-245.6(s)0(o)20.8(c)0(i)19(a)0(l)]TJ
0 -1.1847 TD
[(av)15.6(o)13.7(i)0(d)19.5(a)0(n)21(c)0(e)19.8(,)-573.5(p)13(o)0(o)22.3(r)-572.3(e)12.5(y)0(e)-559(c)0(o)21(n)0(t)20.5(a)0(c)20.1(t)0(,)-561.2(p)0(e)20.3(r)0(s)19.3(e)0(v)20.4(e)0(r)19.5(a)0(t)19.9(i)11.7(ve)-559(be)15.9(h)13.7(a)0(v)20.7(i)0(o)20.2(r)0(,)]TJ
0 -1.1795 TD
[(ha)16.1(n)13.3(d)-292.2(s)12.2(t)0(e)19.6(r)0(e)19.5(o)0(t)20.8(y)0(p)21(i)0(e)19(s)0(,)-281.9(a)12.8(nd)-284(t)12.3(a)0(c)20.1(t)0(i)18.8(l)12(e)-292.7(d)13(ef)19(en)20.6(si)18.7(ve)20.4(ne)20.6(ss)19.3(.)]TJ
1.0036 -1.1847 TD
[(Due)-306(to)-299.9(ongoing)-306.4(symptomatolog)7.1(y,)-306.9(the)-303(patient)-305.2(began)]TJ
-1.0036 -1.1795 TD
[(taking)-513.5(a)-509.7(liquid)-514.9(preparation)-512.2(containing)-508.5(63.9%)-512.7(CBD,)]TJ
0 -1.1847 TD
-.0001 Tc
[(4%)-307.5(cannabichromene,)-304.6(3.4%)-303.7(THC,)-302.5(and)-302.4(0.7%)-303.8(phenylbi-)]TJ
0 -1.1795 TD
0 Tc
[(guanide,)-385.8(delivered)-378.9(orally)-379.3(by)-381.9(a)-380.4(1-mL)-379.6(syringe.)-381.9(The)-379(pa-)]TJ
T*
[(tients)-457.8(parents)-454.8(obtained)-450.5(the)-458.2(solution)-451.5(independent)-454.4(of)]TJ
0 -1.1847 TD
[(their)-418.7(physician.)-418.1(Between)-415.1(0.05)-414.3(and)-416.1(0.1)-163.9(mL)-415.9(\(i.e.,)-422.2(32.0)]TJ
0 -1.1795 TD
[(63.9)-166(mg)-463(CBD\))-461.8(of)-460.9(the)-458.2(oral)-461.4(solution)-461.9(was)-462(delivered)-461.7(in)]TJ
0 -1.1847 TD
[(the)-334(morning,)-336(once)-330.8(per)-334.7(day)-333.5(for)-329.7(6)-333.2(weeks,)-332.5(during)-332.3(which)]TJ
0 -1.1795 TD
[(time)-300(other)-302.9(therapies)-295.8(remained)-300.2(unchanged.)]TJ
1.0036 -1.1847 TD
[(During)-356.1(the)-359.9(rst)-353.1(week)-361(of)-357.5(treatment)-355.2(with)-356.2(the)-359.9(CBD)]TJ
/F5 1 Tf
20.2323 0 TD
(+)Tj
/F6 1 Tf
-21.2359 -1.1795 TD
[(solution,)-383.5(the)-385.7(patients)-385.4(family)-378.7(noticed)-386.9(that)-383.5(his)-381.4(anxiety)]TJ
0 -1.1847 TD
[(level)-294.8(was)-296.4(reduced)-294.1(and)-297.1(he)-294.6(was)-291.2(able)-295.6(to)-294.7(explore)-294.1(and)-291.9(par-)]TJ
0 -1.1795 TD
[(ticipate)-423.7(in)-419.9(more)-422.2(activities)-420.4(with)-418.3(less)-421.8(social)-416.5(avoidance.)]TJ
T*
[(His)-597.3(facility)-590.3(with)-594.2(language)-590.5(increased,)-595.3(as)-595.8(shown)-589.2(by)]TJ
0 -1.1847 TD
[(greater)-336.6(capacity)-333.9(to)-336.1(engage)-331.4(in)-337.1(longer)-331.8(more)-334.2(meaningful)]TJ
0 -1.1795 TD
[(conversations.)-428.6(The)-425.5(quality)-429(and)-426.4(duration)-425.6(of)-424.7(his)-428(sleep)]TJ
0 -1.1847 TD
[(also)-373.4(improved;)-370.6(he)-372.2(no)-371.3(longer)-373.2(awoke)-367.7(and)-374.7(wandered)-371.7(in)]TJ
0 -1.1795 TD
[(the)-308.1(middle)-305.2(of)-305.7(the)-308.1(night.)-307.7(His)-302.5(symptoms)-306.6(of)-305.7(anxiety)-304.7(and)]TJ
0 -1.1847 TD
[(linguistic)-321.4(skills)-325.1(continued)-319.2(to)-320.6(improve)-322.3(over)-315.8(the)-323.7(6-week)]TJ
0 -1.1795 TD
[(course)-306.7(of)-305.7(treatment)-308.7(with)-304.5(the)-303(CBD)]TJ
/F5 1 Tf
13.8072 0 TD
(+)Tj
/F6 1 Tf
.8898 0 TD
[(solution.)-300.8(His)-307.6(par-)]TJ
-14.697 -1.1847 TD
[(ents)-415.2(have)-413.5(continued)-412.3(him)-409.4(on)-412.7(a)-411.4(stable)-415.9(dose)-409(of)-414.4(0.1)-163.9(mL)]TJ
0 -1.1795 TD
[(daily)-490.9(now)-485.8(for)-484.9(2)-488.4(years)-490.7(and)-488.5(have)-486(observed)-486.8(sustained)]TJ
0 -1.1847 TD
[(symptom)-298.2(improvement.)]TJ
/F9 1 Tf
10.4607 0 0 10.4607 313.0582 206.0787 Tm
[(Patient)-300.5(3)]TJ
/F6 1 Tf
10.959 0 0 10.959 313.0582 193.096 Tm
[(Patient)-382.2(3)-374.6(i)0(s)-379.6(a)-380.4(22-year-old)-376(female)-378.5(who)-376.8(was)-379.2(diagnosed)]TJ
0 -1.1795 TD
.0226 Tc
[(with)-382.7(FXS)-383.7(a)-.8(t)-384.1(9)-383(years)-384.2(o).1(f)-384.8(a)-.8(g)4.7(e)-389.1(with)-382.7(a)-383.6(f)-2(ull)-384.4(m)1.7(utatio)5.3(n)-388.3(o)5.3(f)]TJ
/F5 1 Tf
.1707 -1.1847 TD
0 Tc
(>)Tj
/F6 1 Tf
.5794 0 TD
[(200)-265(CGG)-266.3(repeats.)-263.5(She)-266.3(met)-265.1(all)-268.4(of)-264.3(her)-266.8(early)-268.4(milestones)]TJ
-.7501 -1.1795 TD
[(appropriately,)-238.4(but)-235.1(at)-233.6(around)-237.5(3)-234.9(t)0(o)-232.6(4)-234.9(years)-237.2(of)-238.5(age,)-235.1(she)-235.8(de-)]TJ
0 -1.1847 TD
[(veloped)-520.6(quite)-516.5(signicant)-514.9(anxiety)-516.8(and)-514.4(panic)-521.2(attacks.)]TJ
0 -1.1795 TD
[(There)-462.9(was)-456.8(mild)-460.1(benet)-460(associated)-458.8(with)-454.5(initiation)-460.1(of)]TJ
0 -1.1847 TD
[(psychological)-216.8(therapies,)-222.6(although)-216.4(her)-220.3(mother)-215.2(described)]TJ
0 -1.1795 TD
[(difculties)-396.6(with)-397.6(new)-393.9(settings,)-396.3(social)-395.8(anxiety,)-391.9(frequent)]TJ
T*
[(negative)-266(perseverative)-266.8(thoughts,)-262.6(and)-266.1(ongoing)-265(panic)-267.8(at-)]TJ
0 -1.1847 TD
[(tacks)-351(that)-347.3(would)-342.1(vary)-347.1(in)-347.5(frequency)-351.4(depending)-344.9(on)-350.6(her)]TJ
0 -1.1795 TD
[(routine)-304.4(and)-297.1(social)-297.5(supports.)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 62.022 754.3557 Tm
(6)Tj
41.0345 0 TD
[(TARTA)-9.7(GLIA)-305.5(ET)-299.4(AL.)]TJ
ET
endstream
endobj
46 0 obj
<>stream
/GS1 gs
BT
/F6 1 Tf
10.959 0 0 10.959 70.7527 697.8896 Tm
0 0 0 rg
0 Tc
0 Tw
[(Starting)-292.7(in)-295.7(the)-292.6(fourth)-295.9(grade,)-297.8(she)-292.7(had)-296.8(mild)-294.5(academic)]TJ
-1.0036 -1.1847 TD
[(challenges)-292.4(that)-290.4(were)-289.4(supported)-288.5(with)-288.9(a)-287.2(504)-290.9(educational)]TJ
0 -1.1795 TD
[(plan)-305.8(through)-296.3(the)-303(end)-302.6(of)-300.5(high)-299.6(school.)-304.2(Ongoing)-300.2(anxiety)]TJ
0 -1.1847 TD
[(was)-218.8(present)-222.3(and)-214.3(trials)-221.6(of)-217.8(St.)-217.4(Johns)-219.3(Wort)-219.8(and)-219.5(other)-215(sup-)]TJ
0 -1.1795 TD
[(plements)-352(were)-346.3(minimally)-348.3(helpful.)-351.1(She)-349.1(did)-350.3(not)-348.6(receive)]TJ
0 -1.1847 TD
[(any)-390.1(other)-390.8(medication)-388.5(treatment.)-390.7(She)-390.5(graduated)-392.2(from)]TJ
0 -1.1795 TD
[(college)-206.5(with)-201(academic)-207.3(supports,)-202.8(with)-206.2(continued)-205.4(periods)]TJ
T*
[(of)-217.8(signicant)-214.8(anxiety)-216.8(symptoms,)-212.8(social)-214.8(withdrawal,)-210.5(and)]TJ
0 -1.1847 TD
[(panic)-272.9(attacks.)-268.3(After)-268(college,)-267.9(she)-266.8(began)-265.7(work)-266.9(as)-269.9(an)-268.7(edu-)]TJ
0 -1.1795 TD
[(cational)-219.6(aide)-219(in)-218.1(a)-220(public)-218.9(school,)-216.3(with)-216.5(an)-217(exacerbation)-219.7(of)]TJ
0 -1.1847 TD
[(anxiety)-273.7(due)-266.7(to)-268.9(this)-270.9(transition)-267.6(into)-269.7(adulthood)-265.5(and)-271.2(pres-)]TJ
0 -1.1795 TD
[(sures)-305.1(of)-295.4(increased)-301.1(independence.)]TJ
1.0036 -1.1847 TD
[(At)-314.6(22)-319.8(years)-320(of)-316.1(age,)-317.8(her)-318.6(parents)-320.3(provided)-316.7(her)-318.6(with)-314.8(a)]TJ
-1.0036 -1.1795 TD
[(liquid)-318.3(formulation)-313.5(of)-316.1(hemp)-312.8(oil)-314.3(containing)]TJ
/F8 1 Tf
17.3198 0 TD
(*)Tj
/F6 1 Tf
.9984 0 TD
[(43)-169.8(mg)-313(of)]TJ
-18.3182 -1.1847 TD
[(CBD)-520.3(daily)-516.8(\(Charlottes)-516.1(Web)]TJ
/F5 1 Tf
12.0121 0 TD
()Tj
/F6 1 Tf
1.4019 0 TD
[(Everyday)-517.3(Advanced;)]TJ
-13.414 -1.1795 TD
[(CWB)-405.5(Holdings,)-407.3(Inc.,)-405.4(Denver,)-406.8(CO\),)-403(which)-409.6(she)-401.3(began)]TJ
T*
[(taking.)-223.1(She)-219.7(described)-222.9(feeling)-223.6(calmer,)-222(with)-221.7(fewer)-220.9(persev-)]TJ
0 -1.1847 TD
[(erative)-347.5(worries,)-344.5(and)-348.8(a)-344.1(cessation)-347.2(of)-347.1(panic)-345.4(attacks.)-345.9(This)]TJ
0 -1.1795 TD
[(led)-340.1(to)-341.3(more)-339.4(interactions)-335.7(and)-343.7(activities)-337.7(with)-335.5(peers)-341.1(and)]TJ
0 -1.1847 TD
[(improved)-650.7(performance)-649.8(at)-647.4(work.)-649(Her)-648.3(mother)-644.5(also)]TJ
0 -1.1795 TD
[(noted)-333.5(that)-331.7(she)-328.9(became)-329.4(more)-334.2(engaged)-328.7(socially,)-333.8(calmed)]TJ
0 -1.1847 TD
[(more)-204.9(easily)-205(when)-199.2(frustrated,)-206.1(and)-204(was)-203.3(less)-204.5(likely)-199.8(to)-206.8(xate)]TJ
0 -1.1795 TD
[(on)-397.1(negative)-390.2(aspects)-393.6(of)-393.7(various)-397.5(situations.)-391.3(She)-395.6(missed)]TJ
0 -1.1847 TD
[(about)-462.1(1)-462.5(week)-459.3(of)-460.9(dosing)-460.9(when)-457.8(on)-464.4(a)-458(family)-461.4(vacation)]TJ
0 -1.1795 TD
[(out)-374.8(of)-373(town,)-374.5(and)-369.5(after)-373.1(a)-375.2(few)-374.9(days)-373.1(without)-368.9(treatment,)]TJ
0 -1.1847 TD
[(she)-370.3(experienced)-373.7(recurrence)-371.2(of)-367.8(anxiety)-366.8(symptoms)-368.7(and)]TJ
0 -1.1795 TD
[(reemergence)-303.8(of)-300.5(panic)-298.8(attacks.)-299.3(These)-302.5(resolved)-297(after)-300.7(she)]TJ
T*
[(was)-456.8(home)-451.8(and)-452.3(able)-455.9(to)-455.1(restart)-451.5(her)-453.1(CBD)]TJ
/F5 1 Tf
16.6731 0 TD
(+)Tj
/F6 1 Tf
1.0346 0 TD
(treatment.)Tj
-17.7078 -1.1847 TD
[(She)-307.7(is)-312.3(currently)-305.8(working)-306.4(full)-308.2(time)-310.3(and)-307.5(living)-307.9(indepen-)]TJ
0 -1.1795 TD
[(dently.)-466.2(She)-462.9(has)-463.1(continued)-464(CBD)]TJ
/F5 1 Tf
13.3209 0 TD
(+)Tj
/F6 1 Tf
1.045 0 TD
[(treatment)-463.9(for)-464.2(two)]TJ
-14.3659 -1.1847 TD
[(and)-302.3(a)-297.6(half)-301.6(years)-299.3(with)-299.3(sustained)-300.8(therapeutic)-301.2(benet.)]TJ
/F4 1 Tf
10.4607 0 0 10.4607 59.7543 283.4078 Tm
(Discussion)Tj
/F6 1 Tf
10.959 0 0 10.959 59.7543 270.4818 Tm
[(Based)-328.7(on)-329.9(its)-331.1(morbidity)-323(and)-328.1(prevalence,)-333.2(its)-325.9(association)]TJ
T*
[(with)-325.2(a)-323.5(number)-323.4(of)-321.2(co-occurring)-322.9(problems,)-323.9(such)-326.2(as)-321.6(sei-)]TJ
0 -1.1795 TD
[(zures,)-350.7(anxiety,)-350.5(and)-343.7(sleep)-351.6(disturbances,)]TJ
8.2191 0 0 7.3052 229.3795 249.4488 Tm
(13)Tj
10.959 0 0 10.959 241.1149 244.5731 Tm
[(and)-343.7(the)-349.5(pau-)]TJ
-16.549 -1.1795 TD
[(city)-343.6(of)-341.9(efcacious)-339.4(therapeutic)-342.6(options,)-343.8(FXS)-343.2(represents)]TJ
0 -1.1847 TD
[(an)-248(important)-245.4(public)-249.9(health)-243.8(problem.)]TJ
8.2191 0 0 7.3052 218.8346 223.5401 Tm
(6)Tj
10.959 0 0 10.959 225.5243 218.6645 Tm
[(The)-244.5(present)-248.2(arti-)]TJ
-15.1264 -1.1795 TD
[(cle)-288.9(provides)-281.3(a)-287.2(brief)-284.9(review)-280.1(of)-285(recent)-286.8(research)-282.2(that)-285.2(doc-)]TJ
0 -1.1847 TD
[(uments)-288.6(the)-287.4(promise)-287(of)-290.2(CBD)-287.5(as)-285.4(a)-287.2(therapeutic)-290.9(agent)-287.8(for)]TJ
0 -1.1795 TD
[(patients)-308.5(with)-309.6(FXS.)-306.2(Also)-304.5(described)-310.9(are)-309.1(the)-303(cases)-310.3(of)-305.7(one)]TJ
0 -1.1847 TD
[(pediatric)-390.1(and)-390.2(two)-383.4(adult)-386.9(patients)-386.1(with)-387.2(FXS)-389.7(for)-386.6(whom)]TJ
0 -1.1795 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
.9001 0 TD
[(treatment)-313.8(appears)-314.9(to)-315.4(have)-315.2(contributed)-315(to)-315.4(posi-)]TJ
-2.897 -1.1847 TD
[(tive)-483.3(changes)-484.1(in)-476.8(anxiety)-485.8(and/or)-482(language)-476.7(skills,)-484.7(with)]TJ
0 -1.1795 TD
[(no)-298.9(observed)-300.5(adverse)-299.7(events.)]TJ
1.0036 -1.1847 TD
[(Before)-404.6(starting)-407(CBD)]TJ
/F5 1 Tf
8.4012 0 TD
(+)Tj
/F6 1 Tf
.9881 0 TD
[(treatment,)-406.2(Patient)-408.1(1)-405.6(experi-)]TJ
-10.3929 -1.1795 TD
[(enced)-355.2(heightened)-347.7(symptoms)-348(of)-352.3(anxiety,)-350.5(frequent)-349.2(tan-)]TJ
T*
[(trums,)-399.8(and)-395.4(sleep)-393(difculties.)-395.9(Over)-397.5(the)-396.1(rst)-394.5(month)-392.1(of)]TJ
0 -1.1847 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
1.1433 0 TD
[(monotherapy,)-562.3(and)-560.9(subsequent)-565(3)-560.8(months)-560.9(of)]TJ
-3.1401 -1.1795 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
1.1847 0 TD
[(treatment)-598.4(combined)-597.8(with)-599.3(speech,)-600.6(language,)]TJ
19.7305 57.9085 TD
[(and)-338.5(occupational)-338.1(therapy,)-333.9(the)-339.2(patient)-336.3(made)-339.5(consider-)]TJ
0 -1.1847 TD
[(able)-352.5(progress)-348.9(with)-351(feeding)-352(and)-354(weight)-351.3(gain,)-351.9(exhibited)]TJ
0 -1.1795 TD
[(better)-405.6(oralmotor)-406.6(coordination,)-404(had)-410.6(decreased)-409.3(social)]TJ
0 -1.1847 TD
[(avoidance)-432.9(and)-436.8(sensory)-433.2(sensitivities,)-440(and)-431.6(showed)-437.4(im-)]TJ
0 -1.1795 TD
[(provements)-568.2(in)-569.9(attention)-568.6(span/engagement,)-571.2(the)-572(fre-)]TJ
0 -1.1847 TD
[(quency)-537.8(and)-540.2(severity)-541.9(of)-538.5(atypical)-536.1(motor)-538(movements,)]TJ
0 -1.1795 TD
[(and)-359.2(general)-356.4(level)-362.1(of)-357.4(hyperactivity.)-357.8(Upon)-358.7(discontinua-)]TJ
T*
[(tion)-280(of)-285(CBD)]TJ
/F5 1 Tf
4.9559 0 TD
(+)Tj
/F6 1 Tf
.8691 0 TD
[(treatment,)-282.1(the)-282.3(patients)-287.1(prior)-283.7(symptoms)]TJ
-5.825 -1.1847 TD
[(reemerged.)-323.2(While)-327.2(a)-323.5(strong)-326.6(therapy)-324.2(program)-326.6(and)-323(later)]TJ
0 -1.1795 TD
[(addition)-529.6(of)-528.2(other)-530.5(medications)-531.5(likely)-530.9(contributed)-527.1(to)]TJ
0 -1.1847 TD
[(this)-296.7(patients)-297.5(overall)-299.6(developmental)-297.5(progress,)-296.4(the)-297.8(tem-)]TJ
0 -1.1795 TD
[(porally)-314.6(related)-321.3(improvements)-318.7(in)-316.4(anxiety,)-319.5(feeding,)-320.2(tan-)]TJ
0 -1.1847 TD
[(trums,)-306.7(and)-302.3(sleepevident)-309.4(when)-302.6(CBD)]TJ
/F5 1 Tf
15.2557 0 TD
(+)Tj
/F6 1 Tf
.8846 0 TD
[(treatment)-308.7(was)]TJ
-16.1403 -1.1795 TD
[(initially)-448.1(started)-450.7(as)-450.9(monotherapy)-449.2(and)-452.3(then)-450(reinstated)]TJ
0 -1.1847 TD
[(following)-484(cessationare)-490.4(compelling)-486.4(support)-489.9(for)-490.1(the)]TJ
0 -1.1795 TD
[(benets)-302.9(of)-305.7(CBD)]TJ
/F5 1 Tf
6.4665 0 TD
(+)Tj
/F6 1 Tf
.8846 0 TD
[(treatment)-303.5(for)-303.8(this)-301.9(patient.)-304.5(By)-304(main-)]TJ
-7.3511 -1.1795 TD
[(taining)-465.3(his)-469.4(adaptive)-462.7(functioning)-470.8(scores)-462.7(from)-469.6(1)-467.7(t)0(o)-465.4(3)]TJ
0 -1.1847 TD
[(years)-247.6(of)-243.6(age,)-245.4(the)-246.1(patient)-243.2(demonstrated)-248.3(a)-245.9(signicant)-245.9(im-)]TJ
0 -1.1795 TD
[(provement)-383.8(over)-383(the)-385.7(characteristic)-384.9(developmental)-380.2(tra-)]TJ
0 -1.1847 TD
[(jectory)-516.9(of)-523(young)-523.5(male)-516.4(children)-525(with)-516.6(FXS,)-523.5(where)-524(a)]TJ
0 -1.1795 TD
[(decrease)-277.4(in)-275(adaptive)-276.4(functioning)-279.4(scores)-276.4(is)-276.1(typically)-275.4(ob-)]TJ
0 -1.1847 TD
[(served)-296.9(between)-301.5(2)-297(and)-302.3(6)-297(years)-304.5(of)-295.4(age.)]TJ
8.2191 0 0 7.3052 472.1385 430.7527 Tm
(40)Tj
10.959 0 0 10.959 321.7889 412.9511 Tm
[(Patient)-201.2(2)-203.9(showed)-204.6(a)-204.5(similarly)-202.5(encouraging)-200.2(response)-203.5(to)]TJ
-.9984 -1.1847 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
1.0502 0 TD
[(treatment,)-468.3(experiencing)-474.9(reduced)-469.9(anxiety,)-474.7(im-)]TJ
-3.047 -1.1795 TD
[(proved)-548.4(use)-552(of)-548.9(language,)-548.4(and)-550.6(better)-550.4(sleep)-553.4(within)-548.5(1)]TJ
0 -1.1847 TD
[(week)-417.9(of)-414.4(beginning)-417.1(treatment)-417.3(with)-418.3(a)-416.6(CBD)]TJ
/F5 1 Tf
17.3612 0 TD
(+)Tj
/F6 1 Tf
1.0036 0 TD
(solution.)Tj
-18.3648 -1.1795 TD
[(It)-223.8(is)-219.2(also)-223.4(remarkable)-222.6(that)-223.1(the)-225.4(patient)-222.5(continued)-220.9(to)-222.3(dem-)]TJ
T*
[(onstrate)-214.2(symptom)-215.4(improvement)-217.1(over)-217.5(the)-215(initial)-214.5(6-week)]TJ
0 -1.1847 TD
[(treatment)-515.6(period,)-518(with)-516.6(longer-term)-520.4(follow-up)-514.6(high-)]TJ
0 -1.1795 TD
[(lighting)-494(continued)-495.1(use)-495.1(of)-492(CBD)]TJ
/F5 1 Tf
13.1399 0 TD
(+)Tj
/F6 1 Tf
1.0812 0 TD
[(solution)-492.9(with)-490.7(sus-)]TJ
-14.221 -1.1847 TD
[(tained)-296.8(benet.)]TJ
.9984 -1.1795 TD
[(In)-305.5(Patient)-304.6(3,)-306.6(the)-303(use)-308.9(of)-305.7(CBD)]TJ
/F5 1 Tf
11.562 0 TD
(+)Tj
/F6 1 Tf
.8846 0 TD
[(solution)-306.7(was)-301.6(also)-306.2(a)-18.2(s)-18.8(-)]TJ
-13.4451 -1.1847 TD
.0186 Tc
[(soci)4.4(ated)-242.5(wit)5(h)-241.9(a)-242.8(p).6(osi)4.4(t)-.1(ive)-237.9(e).1(ffect)-238.1(in)-242.2(a)-237.6(h)1.2(igher)-243.4(f)4.4(unc)5.2(t)-.1(ioning)]TJ
0 -1.1795 TD
0 Tc
[(female)-254.3(with)-257.9(FXS)-255.2(and)-255.7(long-standing)-257.7(anxiety)-258.2(symptoms.)]TJ
0 -1.1847 TD
[(Similar)-263.3(to)-268.9(Patient)-263.2(1,)-265.2(treatment)-267.3(discontinuation)-264.6(was)-265.4(as-)]TJ
0 -1.1795 TD
[(sociated)-339(with)-335.5(a)-339(recurrence)-340.1(of)-341.9(anxiety)-335.8(symptoms,)-337(with)]TJ
T*
[(reinitiation)-440.5(of)-445.4(CBD)]TJ
/F5 1 Tf
8.1167 0 TD
(+)Tj
/F6 1 Tf
1.0243 0 TD
[(treatment)-443.2(leading)-444.4(to)-444.7(symptom)]TJ
-9.141 -1.1847 TD
[(improvement)-294.7(and)-302.3(resulting)-301.5(long-term)-296.8(use.)]TJ
.9984 -1.1795 TD
[(The)-234.1(present)-237.8(ndings,)-234.8(coupled)-230.9(with)-237.2(the)-235.7(available)-233.2(pre-)]TJ
-.9984 -1.1847 TD
[(clinical)-294.6(data,)-295(highlight)-293.8(the)-297.8(potential)-295(for)-293.5(CBD)-297.9(as)-295.7(an)-294.6(in-)]TJ
0 -1.1795 TD
[(tervention)-654.2(for)-650.5(individuals)-653.9(with)-656.2(FXS.)-652.8(The)-653.1(existing)]TJ
0 -1.1847 TD
[(literature)-228.2(combines)-231.3(to)-232.6(demonstrate)-230.3(that)-233.5(CBD)-230.6(may)-227.8(pos-)]TJ
0 -1.1795 TD
[(itively)-570.6(impact)-569(individuals)-571.1(with)-568.3(FXS)-570.8(through)-570.5(many)]TJ
0 -1.1847 TD
[(mechanisms,)-442(including)-439.8(the)-442.6(endocannabinoid)-441.9(system,)]TJ
0 -1.1795 TD
[(GABA,)-319.2(and)-317.8(serotonin.)-318.8(While)-322(a)-318.3(number)-318.2(of)-321.2(drugs)-319.2(have)]TJ
0 -1.1847 TD
[(been)-330.8(developed)-329.5(to)-325.8(target)-328.3(specic)-331(systems)-329.2(\(e.g.,)-332.8(GABA)]TJ
0 -1.1795 TD
[(agonists\),)-232.6(CBD)-230.6(has)-235.5(the)-235.7(potential)-232.9(to)-232.6(yield)-232.5(a)-235.5(multifaceted)]TJ
T*
[(benet)-496.2(to)-501.6(individuals)-503.9(with)-495.9(FXS)-503.5(due)-499.5(to)-501.6(its)-501.8(multiple)]TJ
0 -1.1847 TD
[(mechanisms)-313.4(of)-316.1(action.)-316.1(CBD)-313.4(has)-318.3(not)-312.4(only)-315.1(been)-315.3(shown)]TJ
0 -1.1795 TD
-.0178 Tc
[(to)-278.3(be)-279.5(generally)-278.9(well)-279.9(tole)5(rated)-278.9(r)-.4(elative)-279.5(t)-.3(o)-278.3(o)1.1(ther)-279.8(treatments)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 59.7543 753.8455 Tm
0 Tc
[(TREA)-10.3(TMENT)-305.4(OF)-302.7(FX)-8.4(S)-299.8(WITH)-303.3(CBD)]TJ
48.6485 0 TD
(7)Tj
ET
endstream
endobj
51 0 obj
<>stream
/GS1 gs
BT
/F6 1 Tf
10.959 0 0 10.959 62.022 697.8896 Tm
0 0 0 rg
-.0178 Tc
0 Tw
[(used)-460(in)-454.5(this)-460.8(population,)]TJ
8.2191 0 0 7.3052 167.6976 702.7651 Tm
-.0237 Tc
(41)Tj
10.959 0 0 10.959 180.2267 697.8896 Tm
0 Tc
[(but)-457.6(also)-461.4(numerous)-458.5(studies)]TJ
-10.7861 -1.1847 TD
[(have)-356.6(documented)-360.3(its)-362.1(benets)-354.7(in)-357.8(terms)-359.7(of)-362.6(sleep)-356.8(quali-)]TJ
0 -1.1795 TD
(ty,)Tj
8.2191 0 0 7.3052 72.737 676.8565 Tm
(42,43)Tj
10.959 0 0 10.959 93.4866 671.981 Tm
[(anxiety)-294.4(\(including)-288.2(social)-292.4(anxiety\),)]TJ
8.2191 0 0 7.3052 241.8519 676.8565 Tm
(34,44)Tj
10.959 0 0 10.959 262.6015 671.981 Tm
[(and)-291.9(cog-)]TJ
-18.3027 -1.1847 TD
[(nitive)-535.8(impairment)]TJ
8.2191 0 0 7.3052 144.17 663.8738 Tm
(45)Tj
10.959 0 0 10.959 152.0504 658.9983 Tm
[(symptom)7.4(s)-536.1(experienced)-534(by)-531.9(the)]TJ
-8.215 -1.1795 TD
[(individuals)-302.1(proled)-297.8(in)-300.9(the)-297.8(present)-299.9(case)-301.8(series.)]TJ
.9984 -1.1847 TD
[(These)-514.6(data)-513(serve)-516.9(as)-513(stepping)-514.4(stones)-513.5(upon)-516(which)]TJ
-.9984 -1.1795 TD
[(proof-of-concept)-561(open-label)-565(trials)-563(should)-563.8(be)-563.5(based.)]TJ
T*
[(As)-206.1(with)-201(many)-204.1(patients,)-204.4(however,)-201.6(those)-204.6(discussed)-203.2(herein)]TJ
0 -1.1847 TD
[(used)-249.3(orally)-250(administered)-250.9(botanical)-247.3(CBD)]TJ
/F5 1 Tf
15.9282 0 TD
(+)Tj
/F6 1 Tf
.8329 0 TD
[(solution)-249.8(that)]TJ
-16.7611 -1.1795 TD
[(is)-276.1(not)-276.2(regulated)-274.5(by)-278.4(the)-271.9(Food)-277.6(and)-276.4(Drug)-272.5(Administration)]TJ
0 -1.1847 TD
-.0001 Tc
[(and,)-213.7(thus,)-217.2(inconsistencies)-215.5(i)-.1(n)-213(availability,)-211.8(quality,)-216.3(purity,)]TJ
0 -1.1795 TD
0 Tc
[(and)-462.6(labeling)]TJ
8.2191 0 0 7.3052 117.6378 560.2959 Tm
(46,47)Tj
10.959 0 0 10.959 140.2582 555.4203 Tm
[(make)-463.7(research,)-467.7(interpretations,)-463(and)]TJ
-7.139 -1.1847 TD
[(clinical)-630.9(recommendations)-631.3(challenging.)-630(The)-632.4(present)]TJ
0 -1.1795 TD
[(case)-343.2(series)-345.7(is)-348.6(limited)-340.8(by)-345.6(its)-346.6(reliance)-345.4(on)-340.2(manufacturer-)]TJ
0 -1.1847 TD
[(reported)-452.1(cannabinoid)-453(content)-453.2(as)-450.9(well)-450.4(as)-456.1(the)-447.8(lack)-456.6(of)]TJ
0 -1.1795 TD
[(multimethod)-439.7(assessment)-436.3(of)-440.2(patient)-439.7(symptomatology,)]TJ
T*
[(including)-201.9(clinimetric)-203.7(data.)-201.9(The)-197.9(observed)-202.2(clinical)-201.5(benet)]TJ
0 -1.1847 TD
[(of)-212.6(CBD)]TJ
/F5 1 Tf
2.9953 0 TD
(+)Tj
/F6 1 Tf
.7915 0 TD
[(treatment)-210.4(in)-212.9(case)-208.7(studies,)-212.4(particularly)-207.2(with)-206.2(re-)]TJ
-3.7868 -1.1795 TD
[(spect)-294.4(to)-289.5(caregiver-reported)-290.7(behavioral)-290.8(outcomes,)-292.3(must)]TJ
0 -1.1847 TD
[(also)-383.8(be)-387.6(interpreted)-384.9(with)-382.1(caution)-386.6(given)-381.2(the)-385.7(signicant)]TJ
0 -1.1795 TD
[(placebo)-344.3(effects)-344.1(that)-342.1(have)-341.1(been)-346.3(documented)-339.6(in)-342.3(clinical)]TJ
0 -1.1847 TD
[(trials)-340.6(of)-341.9(CBD.)]TJ
8.2191 0 0 7.3052 123.7606 430.7527 Tm
(48)Tj
10.959 0 0 10.959 135.3826 425.877 Tm
[(Only)-340(placebo-contr)6.5(olled)-340.2(trials)-340.6(will)-342.6(be)]TJ
-6.6941 -1.1795 TD
[(able)-368(to)-372.3(elucidate)-368.8(the)-370.2(true)-374.2(therapeutic)-368.5(effects)-375.1(of)-367.8(CBD/)]TJ
0 -1.1847 TD
(CBD)Tj
/F5 1 Tf
1.9968 0 TD
(+)Tj
/F6 1 Tf
.8174 0 TD
[(treatment)-231.1(on)-236.8(FXS)-234.5(symptomatolog)7.1(y.)-239.7(Until)-230.4(rigor-)]TJ
-2.8142 -1.1795 TD
[(ous)-468(clinical)-470.5(trials)-469.9(have)-470.4(demonstrated)-470.7(the)-468.5(efcacy)-470(of)]TJ
0 -1.1847 TD
(CBD/CBD)Tj
/F5 1 Tf
4.2834 0 TD
(+)Tj
/F6 1 Tf
1.1588 0 TD
[(treatment)-572.5(for)-578(FXS,)-575.2(current)-574.1(treatments)]TJ
-5.4422 -1.1795 TD
[(for)-583.2(the)-587.5(many)-581.7(behavioral)-580.5(problems)-583.3(associated)-588.2(with)]TJ
T*
[(FXS)-400.1(should)-398.2(be)-398(utilized)-403.1(before)-399.7(off-label)-394.3(use)-402(of)-398.8(CBD)]TJ
/F5 1 Tf
21.2359 0 TD
(+)Tj
/F6 1 Tf
-21.2359 -1.1847 TD
(products.)Tj
.9984 -1.1795 TD
[(In)-305.5(an)-305(effort)-303.6(to)-305.1(overcome)-303.1(existing)-303.9(limitations,)-305.1(future)]TJ
-.9984 -1.1847 TD
[(studies)-425.2(should)-429.3(independently)-424.1(test)-426.6(patient)-429.4(samples)-427.2(to)]TJ
0 -1.1795 TD
[(conrm)-477.9(actual)-483.3(constituents)-479.7(of)-481.6(each)-481.4(CBD)]TJ
/F5 1 Tf
17.3405 0 TD
(+)Tj
/F6 1 Tf
1.0657 0 TD
(prepara-)Tj
-18.4061 -1.1847 TD
(tion)Tj
8.2191 0 0 7.3052 79.5968 288.2834 Tm
(47)Tj
10.959 0 0 10.959 90.822 283.4078 Tm
[(and)-307.5(utilize)-302.3(well-validated)-303.9(caregiver-reported)-306.2(as-)]TJ
-2.628 -1.1795 TD
[(sessments)-345.6(of)-347.1(anxiety)-340.9(and)-348.8(other)-344.3(FXS)-343.2(symptomatology,)]TJ
0 -1.1847 TD
[(in)-425(addition)-426.1(to)-424(unstructured)-422.6(caregiver-)-428.4(and)-421.3(clinician-)]TJ
0 -1.1795 TD
[(based)-303.1(reports,)-304.3(in)-300.9(an)-305(attempt)-302.6(to)-299.9(more)-303.2(completely)-300.4(track)]TJ
T*
[(each)-502.1(patients)-499.2(course)-498.1(while)-499.2(in)-497.5(clinical)-501.6(care.)-497.6(Due)-502.6(to)]TJ
0 -1.1847 TD
[(inconsistencies)-252.1(observed)-254(in)-254.3(many)-250.7(oral)-254.5(botanical)-252.4(p)13(r)0(e)19.5(p)0(a)20.6(-)]TJ
0 -1.1795 TD
[(ra)19.8(t)12.3(i)0(o)20.2(n)0(s)15.2(,)-289(r)12.2(i)0(g)19.6(o)0(r)20.8(o)0(u)21.6(s)-293(e)12.5(x)0(a)20.4(m)10.2(in)19.8(at)19.9(io)20.2(ns)-279.7(of)-279.9(ph)21.5(ar)19.8(m)10.2(a)0(c)20.1(e)0(u)20.3(t)0(i)18.8(c)0(a)20.1(l)0(-)19.4(g)0(r)20.2(a)0(d)20.7(e)]TJ
0 -1.1847 TD
[(pr)20.1(ep)20.3(ar)19.8(at)19.9(io)20.2(ns)-419.3(of)-424.7(C)14.5(B)0(D)-421(s)12.2(ho)17(u)13(l)0(d)-419.8(b)0(e)-423.9(e)12.5(xp)20.6(lo)20.6(re)19.5(d)-431.9(a)0(s)-419.9(p)0(o)21.6(t)0(e)19.6(n)0(t)20.5(i)0(a)19.3(l)]TJ
0 -1.1795 TD
[(t)12.3(r)0(e)19.5(a)0(t)19.9(m)10.2(en)20.7(ts)-280.7(fo)20.2(r)-293(c)12.5(hi)20.2(ld)19.9(re)19.5(n)-291.9(a)12.8(nd)-278.9(ad)15.5(o)13.7(l)0(e)19.3(s)0(c)19.5(e)0(n)20.6(t)0(s)-280.7(w)0(i)21.3(t)0(h)-279.2(F)0(X)16.5(S)12.8(.)]TJ
/F4 1 Tf
10.4607 0 0 10.4607 62.022 154.885 Tm
(Acknowledgment)Tj
/F6 1 Tf
10.959 0 0 10.959 62.022 141.959 Tm
[(Writing)-390.7(services)-392.5(for)-397(some)-391.1(components)-390.6(of)-388.5(the)-396.1(manu-)]TJ
0 -1.1847 TD
[(script)-298.5(were)-299.8(provided)-301.2(by)-299.1(Christopher)-298(Caiazza.)]TJ
/F4 1 Tf
10.4607 0 0 10.4607 62.022 102.1039 Tm
[(Author)-303.3(Disclosure)-299.8(Statement)]TJ
/F6 1 Tf
10.959 0 0 10.959 62.022 89.1779 Tm
[(N.T.)-626.9(has)-623.5(received)-624.3(funding)-624.8(from)-624.8(Neuren,)-624.5(Alcobra,)]TJ
T*
[(Roche,)-486.5(and)-493.7(Seaside)-486.8(to)-491.3(carry)-485.5(out)-488.6(treatment)-489.7(trials)-490.6(in)]TJ
0 -1.1795 TD
[(FXS.)-414.9(She)-416.3(has)-416.5(also)-409.6(consulted)-418.2(with)-413.1(Novartis,)-413.8(Zynerba,)]TJ
22.9068 57.9085 TD
[(and)-426.4(Ovid)-418.2(regarding)-424.1(treatment)-417.3(in)-425(FXS.)-420.1(M.B.M.)-422.9(is)-421(an)]TJ
0 -1.1847 TD
-.0001 Tc
[(employee)-485.2(of)-486.9(Zynerba)-488.3(Pharmaceuticals.)-490(R.H.)-481.8(has)-489.1(re-)]TJ
0 -1.1795 TD
0 Tc
[(ceived)-266.2(funding)-262.6(from)-267.8(Novartis,)-258.6(Marinus,)-265.1(Neuren,)-267.6(Alco-)]TJ
0 -1.1847 TD
[(bra,)-270.9(Seaside,)-263.6(and)-266.1(Roche)-264.8(to)-268.9(carry)-263.1(out)-266.2(treatment)-267.3(trials)-263(in)]TJ
0 -1.1795 TD
[(FXS.)-420(She)-416.3(has)-421.7(also)-414.8(consulted)-418.2(with)-418.3(Fulcrum,)-415.1(Zynerba,)]TJ
0 -1.1847 TD
[(and)-302.3(Ovid)-299.2(regarding)-299.9(treatment)-298.3(in)-300.9(FXS.)]TJ
/F4 1 Tf
10.4607 0 0 10.4607 313.0582 602.2487 Tm
(References)Tj
/F9 1 Tf
7.4718 0 0 7.4718 316.7999 592.2708 Tm
[(1.)-507(Hagerman)-205.8(RJ,)-213.1(Berry-Kravis)-214.1(E,)-201.8(Hazlett)-209.7(HC,)-209.8(et)-202.3(al.)-202.8(Fra)-9.9(gile)-204.8(X)-204.3(syndrome.)-213(Nat)-204.7(Rev)]TJ
1.214 -1.1988 TD
[(Dis)-298.2(Primers.)-313.1(2017;3:17065.)]TJ
-1.214 -1.1988 TD
[(2.)-507(Darnell)-257.8(JC,)-255.5(Richter)-253.5(JD.)-255(Cytoplasmi)-13.7(c)-251.1(RNA-binding)-261.2(proteins)-257.1(and)-250.8(the)-257.3(control)]TJ
1.214 -1.2064 TD
[(of)-298.6(complex)-307.3(brain)-306.8(function.)-311.6(Cold)-304(Spring)-298.7(Harb)-306.2(Perspect)-305.9(Bio)-9.3(l.)-294.8(2012;4:)]TJ
0 -1.1988 TD
(a012344.)Tj
-1.214 -1.1988 TD
[(3.)-507(Turner)-301.5(G,)-296.2(Webb)-294.9(T,)-292.8(Wake)-297.4(S,)-300.4(et)-293.4(al.)-293.8(Preval)-9.5(ence)-292.5(of)-298.6(fragile)-296.5(X)-295.4(syndrome.)-304(Am)-293(J)]TJ
1.214 -1.1988 TD
[(Med)-298.5(Genet.)-311.5(1996;64:196197.)]TJ
-1.214 -1.1988 TD
[(4.)-507(Coffee)-302.1(B,)-301.5(Keith)-306.8(K,)-301.5(Albizua)-305.5(I,)-302.4(et)-301(al.)-301.4(Inciden)-9.6(ce)-297.4(of)-306.1(fragile)-304.1(X)-303(syndrome)-303.8(by)]TJ
1.214 -1.1988 TD
[(newborn)-210.4(screening)-222.9(for)-211.8(methylated)-210.6(FMR)-9(1)-203.2(D)0(N)-8.3(A)0(.)-208.2(A)0(m)-209.5(J)-212.7(Hum)-211.8(Genet.)-212.9(2009;85:)]TJ
T*
(503514.)Tj
-1.214 -1.2064 TD
[(5.)-507(H)15.2(u)0(n)15.6(t)0(e)25.3(r)-292.6(J)15(,)-288.6(Ri)24(ve)23(ro)20.8(-A)18.2(ri)27.5(as)-279.3(O,)-276.9(An)17.9(ge)27.7(lo)18.8(v)-287.3(A)0(,)-276.5(e)0(t)-278.2(a)0(l)25.1(.)-296.2(Ep)26.7(id)24.6(em)20.3(io)18.8(l)16.5(o)0(g)15.6(y)-283.2(of)-283.4(fr)21.2(a)16.2(g)0(i)22.2(l)0(e)-280.1(X)-287.8(sy)20.8(n-)]TJ
1.214 -1.1988 TD
[(d)15.7(r)0(o)20.8(m)0(e)20.3(:)-288.6(a)-287.3(s)0(y)20.8(s)0(t)18.9(e)0(m)20.3(a)16.2(ti)19.9(c)-289(r)0(e)25.3(v)0(i)17.5(e)0(w)-273.3(a)0(n)21.8(d)-287.8(me)20.3(ta)19.5(-a)22.2(na)21.8(l)16.5(y)0(s)20.8(i)0(s)24.6(.)-288.6(Am)-277.8(J)-296.1(M)0(e)27.3(d)-287.8(Ge)22(ne)20.1(t)-292.6(A)0(.)-276.5(2)16.8(01)18.4(4;)]TJ
T*
[(16)26(4a)17.8(:)14.9(1)0(6)18.4(4)0(8)26()0(1)23.6(6)0(5)18.4(8)0(.)]TJ
-1.214 -1.1988 TD
[(6.)-507(Crawford)-309.7(DC,)-305(Acuna)-298.3(JM,)-306.3(Sherman)-302.1(SL.)-310.4(FMR1)-303.3(and)-296.3(the)-302.9(fragile)-304.1(X)-303(syndrome:)]TJ
1.214 -1.1988 TD
[(human)-305.7(genome)-300.7(epidemiol)-11(ogy)-298(review)-10.5(.)-296.2(Genet)-303.6(Med.)-306.4(2001;3:35937)-15.5(1.)]TJ
-1.214 -1.1988 TD
[(7.)-507(Tassone)-215.2(F,)-211.8(Hagerman)-213.4(RJ,)-213.1(Taylor)-211.2(AK,)-213.5(et)-209.9(al.)-210.4(Elevated)-211.1(levels)-217.5(of)-207.5(FMR1)-212.3(mRNA)-213.8(in)]TJ
1.214 -1.2064 TD
[(carrier)-307.9(males:)-303.5(a)-302.5(new)-298(mechanis)-11.7(m)-297.5(o)0(f)-306.1(involvement)-307.9(in)-296.4(the)-302.9(fragile-X)-305.1(syn-)]TJ
0 -1.1988 TD
[(drome.)-307.7(Am)-300.6(J)-303.7(Hum)-302.8(Genet.)-303.9(2000;66:615.)]TJ
-1.214 -1.1988 TD
[(8.)-507(Garber)-281(KB,)-276.5(Visootsak)-281.6(J,)-273.6(Warren)-275.1(ST.)-281.8(Fragile)-275.4(X)-272.6(syndrome.)-281.3(Eur)-279.4(J)-273.4(Hum)-272.5(Genet.)]TJ
1.214 -1.1988 TD
(2008;16:666672.)Tj
-1.214 -1.1988 TD
[(9.)-507(Farzin)-251.2(F,)-242.1(Pe)-8.5(rry)-246.2(H,)-250.6(Hessl)-248.9(D,)-247.2(et)-247.9(al.)-248.3(Autism)-255.2(spectrum)-251.2(disorders)-254.2(and)-250.8(attention-)]TJ
1.214 -1.1988 TD
[(decit/hype)-12.9(ractivity)-307.2(disorder)-307.8(in)-296.4(boys)-310.3(with)-300.1(the)-302.9(fragile)-304.1(X)-303(premutation.)-313.6(J)]TJ
T*
[(Dev)-299.9(Behav)-302(Pediat)-9.9(r.)-300.5(2006;27\(2)-307.4(Suppl\):S137)-14.1(S144.)]TJ
-1.7148 -1.2064 TD
[(10.)-505.4(Leigh)-301.6(MJS,)-310.5(Hagerman)-304.4(RJ,)-304.1(Hessl)-302(D.)-300.3(Fragi)-10.4(le)-295.3(X)-303(Syndrome.)-308.7(In:)-304.3(Hansen)-306.6(RL,)]TJ
1.7224 -1.1988 TD
[(Rogers)-300.3(SJ,)-300.6(eds.)-303.6(Autism)-300.8(and)-296.3(other)-304.9(neurodevelopmental)-308.2(disorders.)-307.6(Ameri-)]TJ
T*
[(can)-305.1(Psychiatric)-313.7(Publishing:)-302.3(Arlington)-12.3(,)-296.2(2013,)-304.9(pp.)-302.8(5776)-9.5(.)]TJ
-1.7224 -1.1988 TD
[(11.)-505.4(Lo)22.6(za)18.2(no)-189.3(R,)-197.7(Ha)23.8(re)-194.7(EB)20.8(,)-205.1(H)0(a)23.8(g)0(e)20.1(r)0(m)24.4(a)0(n)-198.2(R)15(J.)-197.8(Mo)22.7(d)15.7(u)0(l)18.8(a)16.2(ti)19.9(on)-196.9(of)-192.3(th)24.2(e)-205.6(G)0(A)19.8(B)0(A)22(e)0(r)25.3(g)0(i)22.2(c)-205.5(pa)24.3(th)16.6(w)15.8(a)0(y)-198.7(f)0(o)27.7(r)]TJ
1.7224 -1.1988 TD
[(th)16.6(e)-281.5(t)0(r)21.8(e)0(a)23(t)0(m)16.9(e)0(n)20.1(t)-285(of)-275.8(fr)21.2(ag)21.8(il)17.9(e)-281.5(X)-295.4(s)15.6(y)0(n)18.4(d)15.7(ro)20.8(me)20.3(.)-288.6(N)0(e)25.4(u)0(r)20.8(o)0(p)18(s)0(y)20.8(c)14.5(hi)22.2(at)19.5(r)-285(D)0(i)20(s)-287.9(Tr)21.9(ea)22.9(t.)-277.7(20)18.4(14)26(;1)16.5(0)16.8(:)]TJ
T*
[(17)18.4(69)26(1)23.6(77)18.4(9.)]TJ
-1.7224 -1.2064 TD
[(12.)-505.4(Fragile)-305.8(X)-303(Clinical)-304.3(and)-303.9(Research)-303.1(Consor)-13.5(tium.)-298.5(Consens)-13.7(us)-300.8(of)-298.6(the)-302.9(Fragile)-305.8(X)]TJ
1.7224 -1.1988 TD
[(Clinical)-304.3(&)-306.5(Research)-303.1(Consortiu)-14.1(m)-297.5(o)0(n)-303.1(Clinical)-304.3(Practices.)-311.9(Medications)-306.5(for)]TJ
T*
[(Individuals)-309.4(with)-300.1(Fra)-9.9(gile)-295.9(X)-303(Syndrom)-11.7(e.)-297(Available)-307.4(at:)-299.5(https://fragil)-18.9(ex.org//)]TJ
T*
[(wp-content/)-12.8(uploads/2012/0)-15.6(8/)]TJ
T*
[(Medic)-9.5(ations_for_Individual)-16(s_with_Fragile_X_S)-13(yndrome2012-O)-14.4(ct.pdf.)]TJ
T*
[(Access)-11.9(ed)-296.2(April)-307.5(11,)-300.5(2018.)]TJ
-1.7224 -1.1988 TD
[(13.)-505.4(Lozano)-307.8(R,)-303.9(Azarang)-303(A,)-299.2(Wilai)-9.3(sakditipakorn)-310.4(T,)-300.4(et)-301(al.)-301.4(Fragile)-305.8(X)-303(syndrome:)-311.6(a)]TJ
1.7224 -1.2064 TD
[(review)-268.5(of)-268.2(clinical)-270(management.)-271.2(In)-8.1(tractable)-268.4(Rare)-269.8(Dis)-267.9(Res.)-266.3(2016;5:14515)-15.5(7.)]TJ
-1.7224 -1.1988 TD
[(14.)-505.4(Karhson)-305.6(DS,)-304.5(Krasinska)-313.3(KM,)-303.8(Dallaire)-299.1(JA,)-307(et)-301(al.)-301.4(Plasma)-301.5(anan)-9.4(damide)-302.6(con-)]TJ
1.7224 -1.1988 TD
[(centra)-10.9(tions)-298(are)-307.6(lower)-304.3(in)-296.4(chi)-8.8(ldren)-301(with)-300.1(autism)-311.9(spectrum)-304.4(disorder.)-308(Mol)]TJ
T*
[(Autism.)-308.7(2018;9:18.)]TJ
-1.7224 -1.1988 TD
[(15.)-505.4(Mo)22.7(us)17.9(le)23.3(c)14.5(h)-267.5(Z,)-252.6(Va)29.4(ll)17.9(a)-257(V)0(.)-252.6(E)0(n)16.7(d)15.7(oc)16.8(a)16.2(n)0(n)19(a)16.2(bi)17.1(no)23.1(i)16.5(d)-265(sy)20.8(st)18.9(em)27.9(:)-265.8(a)0(n)-251.3(o)0(v)26(e)0(r)17.7(v)16.2(ie)23.3(w)-265(o)0(f)-253(i)0(t)19.9(s)-257.5(po)18(te)25.3(nt)24.2(ia)17.5(l)]TJ
1.7224 -1.1988 TD
[(in)-281.3(c)14.5(u)0(r)20.8(r)0(e)17.7(n)0(t)-271.7(m)0(e)20.3(d)0(i)24.6(c)0(a)23.1(l)-294.5(p)15.7(r)0(a)19.5(c)14.5(ti)19.9(ce)21.3(.)-288.6(N)0(e)17.8(u)17.5(ro)-282.7(En)24.3(do)18(c)14.5(r)0(i)19.9(n)0(o)23.1(l)-287(Le)19.5(tt)21.8(.)-288.6(2)0(0)26(0)0(9)18.4(;)14.9(30)18.4(:)14.9(1)0(5)18.4(3)0()23.6(1)0(7)18.4(9)16.8(.)]TJ
-1.7224 -1.2064 TD
[(16.)-505.4(Pacher)-219.3(P,)-212.9(Batkai)-213.6(S,)-209.3(Kuno)-10.3(s)-212(G)0(.)-212.7(The)-211.8(endocannabinoid)-218.4(system)-220.7(as)-211(an)-213.4(emerging)]TJ
1.7224 -1.1988 TD
[(target)-310.5(of)-298.6(pharmacother)-15(apy.)-304.7(Pharmacol)-306.6(Rev.)-303.7(2006;58:389462.)]TJ
-1.7224 -1.1988 TD
[(17.)-505.4(Castill)-11(o)-301.2(PE,)-300.5(Younts)-304.8(TJ,)-300.6(Chavez)-306.8(AE,)-303.4(et)-301(al.)-301.4(Endoca)-10.6(nnabinoid)-302.2(signaling)-305.6(and)]TJ
1.7224 -1.1988 TD
[(synap)-10(tic)-299.5(function.)-311.6(Neuron.)-302.8(2012;76:7081)-15.5(.)]TJ
-1.7224 -1.1988 TD
[(18.)-505.4(Ohno-S)-10.7(hosaku)-301.9(T,)-300.4(Kano)-307.5(M.)-298.5(Endoca)-10.6(nnabinoid-mediate)-12.5(d)-295.4(retro)-11.3(grade)-301.4(mod-)]TJ
1.7224 -1.1988 TD
[(ulation)-309(of)-298.6(synap)-10(tic)-299.5(transmission)-14.3(.)-296.2(Curr)-306.9(Opin)-307(Neurobiol.)-302.9(201)-10.3(4;29:18.)]TJ
-1.7224 -1.1988 TD
[(19.)-505.4(Zh)19(a)16.2(n)0(g)-276.9(L)0(,)-283.5(A)0(l)21.1(g)0(e)27.7(r)-292.6(BE)20.8(.)-288.6(E)0(n)24.3(h)0(a)21.8(n)0(c)20.2(e)0(d)-273.4(e)0(n)20.1(d)15.7(oc)16.8(a)16.2(n)0(n)19(a)0(b)24.3(i)0(n)22.2(o)0(i)18.8(d)-287.8(s)15.6(i)0(g)22.2(n)0(a)21.8(l)0(i)17.9(n)0(g)-276.9(e)0(l)23.3(e)0(v)22.9(a)16.2(te)17.7(s)-287.9(n)0(e)20.1(u)17.5(ro)20.8(-)]TJ
1.7224 -1.2064 TD
[(na)21.8(l)-287(e)0(x)17.1(c)14.5(it)19.9(a)16.2(b)0(i)17.1(l)16.5(it)19.9(y)-290.8(i)16.5(n)-290.2(f)0(r)21.2(a)0(g)21.8(i)0(l)25.5(e)-289.1(X)-287.8(s)0(y)20.8(n)0(d)21.4(r)0(o)20.8(m)0(e)20.3(.)-288.6(J)-288.5(N)0(e)25.4(u)0(r)20.8(o)0(s)17.9(c)14.5(i.)-279.6(20)18.4(1)16.8(0)0(;)16.5(3)16.8(0:)16.5(5)16.8(7)0(2)18.4(4)0()23.6(5)0(7)18.4(2)16.8(9.)]TJ
-1.7224 -1.1988 TD
[(20.)-505.4(Jung)-305.2(KM,)-303.8(Sepers)-305(M,)-298.5(Hens)-9.8(tridge)-305.3(CM,)-303.2(et)-301(al.)-301.4(Uncouplin)-11.8(g)-297.8(o)0(f)-298.6(the)-302.9(endocann)-11(-)]TJ
1.7224 -1.1988 TD
[(abinoid)-306(signalling)-304.2(complex)-307.3(in)-304(a)-302.5(mouse)-301(model)-309.4(of)-298.6(fragile)-304.1(X)-303(syndrome.)]TJ
T*
[(Nat)-303.3(Commu)-11(n.)-298.1(2012;3:1080.)]TJ
-1.7224 -1.1988 TD
[(21.)-505.4(Maccarrone)-314.2(M,)-298.5(Rossi)-306.7(S,)-300.4(Bari)-303.2(M,)-306.1(et)-301(al.)-301.4(Abnormal)-309.2(mGlu)-301.5(5)-301.9(receptor/endo-)]TJ
1.7224 -1.1988 TD
[(cannab)-9.6(inoid)-299.9(coupling)-307.8(in)-304(mice)-297.7(lacking)-306.7(FMRP)-305.1(and)-303.9(BC1)-304.3(RNA.)-303.5(Neuropsy-)]TJ
0 -1.2064 TD
[(chopharma)-13.3(cology.)-302.9(2010;35:1500)-14.7(1509.)]TJ
-1.7224 -1.1988 TD
[(22.)-505.4(Maione)-303.9(S,)-308(Piscitelli)-302.1(F,)-302.8(Gatta)-302.5(L,)-306.2(et)-301(al.)-301.4(Non-psycho)-14.7(active)-298.3(can)-9.2(nabinoids)]TJ
1.7224 -1.1988 TD
[(modul)-10.4(ate)-300(the)-302.9(descending)-308.7(pathway)-301.5(of)-306.2(antinociception)-309.8(in)-304(anaesthetized)]TJ
T*
[(rats)-303(through)-313.2(several)-305.6(mechanisms)-308.9(of)-298.6(action.)-306(Br)-305.5(J)-296.1(Pharmaco)-12(l.)-302.4(2011;162:)]TJ
T*
[(5845)-9.5(96.)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 62.022 754.3557 Tm
(8)Tj
41.0345 0 TD
[(TARTA)-9.7(GLIA)-305.5(ET)-299.4(AL.)]TJ
ET
endstream
endobj
58 0 obj
<>stream
0 0 0 rg
/GS1 gs
1 i
q 1 0 0 1 310.847 464.882 cm 0 0 m
.057 1.02 l
.614 3.657 2.295 5.339 4.932 5.896 c
5.953 5.953 l
5.953 4.989 l
5.102 4.876 l
3.24 4.756 1.286 2.726 1.077 .85 c
.964 0 l
f*
Q
q 1 0 0 1 543.968 470.835 cm 0 0 m
1.02 -.057 l
3.657 -.614 5.339 -2.296 5.896 -4.932 c
5.953 -5.953 l
4.989 -5.953 l
4.876 -5.102 l
4.667 -3.227 2.713 -1.196 .85 -1.077 c
0 -.964 l
f*
Q
316.8 469.871 227.168 .96381 re
f
q 1 0 0 1 316.8 421.058 cm 0 0 m
-1.02 .057 l
-3.663 .663 -5.328 2.256 -5.896 4.932 c
-5.953 5.953 l
-4.989 5.953 l
-4.876 5.102 l
-4.573 3.084 -2.869 1.38 -.85 1.077 c
0 .964 l
f*
Q
q 1 0 0 1 549.921 427.011 cm 0 0 m
-.057 -1.02 l
-.614 -3.658 -2.295 -5.338 -4.932 -5.896 c
-5.953 -5.953 l
-5.953 -4.989 l
-5.102 -4.876 l
-3.084 -4.573 -1.38 -2.869 -1.077 -.85 c
-.964 0 l
f*
Q
316.8 421.058 227.168 .96378 re
f
310.847 427.011 .96378 37.871 re
f
548.957 427.011 .96375 37.871 re
f
q 1 0 0 1 310.847 389.14 cm 0 0 m
.057 1.077 l
.635 3.613 2.325 5.435 4.932 5.896 c
5.953 6.009 l
5.953 4.989 l
5.102 4.932 l
3.031 4.621 1.455 2.936 1.077 .907 c
.964 0 l
f*
Q
q 1 0 0 1 543.968 395.15 cm 0 0 m
1.02 -.113 l
3.578 -.548 5.373 -2.432 5.896 -4.932 c
5.953 -6.009 l
4.989 -6.009 l
4.876 -5.102 l
4.451 -2.969 2.967 -1.505 .85 -1.077 c
0 -1.02 l
f*
Q
316.8 394.129 227.168 1.0205 re
f
q 1 0 0 1 316.8 252.17 cm 0 0 m
-1.02 .113 l
-3.595 .603 -5.357 2.391 -5.896 4.932 c
-5.953 6.009 l
-4.989 6.009 l
-4.876 5.102 l
-4.451 2.969 -2.966 1.505 -.85 1.077 c
0 1.02 l
f*
Q
q 1 0 0 1 549.921 258.18 cm 0 0 m
-.057 -1.077 l
-.635 -3.613 -2.325 -5.435 -4.932 -5.896 c
-5.953 -6.009 l
-5.953 -4.989 l
-5.102 -4.932 l
-3.031 -4.621 -1.455 -2.936 -1.077 -.907 c
-.964 0 l
f*
Q
316.8 252.17 227.168 1.0205 re
f
310.847 258.18 .96378 130.961 re
f
548.957 258.18 .96375 130.961 re
f
BT
/F9 1 Tf
7.4718 0 0 7.4718 59.7543 700.2707 Tm
0 Tc
0 Tw
[(23.)-505.4(Qin)-299.9(M,)-306.1(Zeidler)-300.4(Z,)-305.7(Moulton)-303.8(K,)-301.5(et)-308.6(al.)-301.4(Endocannabinoid-media)-18.1(ted)-300.5(improve-)]TJ
1.7224 -1.2064 TD
[(ment)-304.5(on)-303.1(a)-302.5(test)-304.8(of)-298.6(aversive)-304.6(memory)-304.4(in)-304(a)-302.5(mouse)-301(model)-309.4(of)-298.6(fragile)-304.1(X)-303(syn-)]TJ
0 -1.1988 TD
[(drome.)-307.7(Behav)-302(Brain)-305.1(Res.)-304.3(2015;291:164)-14.7(171.)]TJ
-1.7224 -1.1988 TD
[(24.)-505.4(Wei)-302.2(D,)-300.3(Lee)-307.5(D,)-300.3(Cox)-303.2(CD,)-305(et)-301(al.)-301.4(Endocannabin)-13.5(oid)-299.3(signaling)-305.6(mediates)]TJ
1.7224 -1.1988 TD
[(oxytocin-driven)-271.9(social)-259.8(reward.)-258(Pro)-9.7(c)-251.1(Natl)-264(Acad)-252.6(Sci)-261.5(U)-257.9(S)-254.6(A.)-261.3(2015;112:14084)]TJ
T*
(14089.)Tj
-1.7224 -1.1988 TD
[(25.)-505.4(Wei)-302.2(D,)-300.3(Dinh)-302.5(D,)-307.9(Lee)-299.9(D,)-300.3(et)-301(al.)-301.4(Enhan)-8.9(cement)-306(of)-298.6(anandam)-9.6(ide-mediated)]TJ
1.7224 -1.2064 TD
[(endocann)-11(abinoid)-306(signaling)-305.6(corrects)-308.2(autism-related)-313.2(social)-305.4(impairment.)]TJ
0 -1.1988 TD
[(Cannabis)-307.7(Cannabinoid)-305.9(Res.)-304.3(2016;1:8)-13.6(189.)]TJ
-1.7224 -1.1988 TD
[(26.)-505.4(Elmes)-308.3(MW,)-297.7(Kacz)-10.5(ocha)-302.8(M,)-298.5(Berger)-305.7(WT,)-307.2(et)-301(al.)-301.4(Fatty)-304.9(acid-binding)-304.8(proteins)]TJ
1.7224 -1.1988 TD
[(\(FABPs\))-310.1(are)-300(intracellular)-310(carriers)-307.4(for)-302.8(Delta9-tetr)-12.8(ahydrocannabinol)-314.9(\(THC\))]TJ
T*
[(and)-303.9(cannabidiol)-306.3(\(CBD\).)-309.8(J)-296.1(Bio)-9.3(l)-294.5(Chem)-9(.)-296.2(2015;290)-11.7(:87118721.)]TJ
-1.7224 -1.1988 TD
[(27.)-505.4(Pertwee)-306.4(RG.)-303.9(The)-302.8(diverse)-306.1(CB1)-304.3(and)-303.9(CB2)-304.3(receptor)-308.2(pharmacology)-308(of)-298.6(thr)-10.4(ee)]TJ
1.7224 -1.1988 TD
[(plant)-306.8(cannabinoids:)-309.4(delta9-tetrahydr)-15.3(ocannabinol)-11.9(,)-296.2(cannab)-9.6(idiol)-296.6(an)-8.5(d)]TJ
0 -1.2064 TD
[(delta9-tetra)-14.7(hydrocannabivarin.)-313.2(Br)-297.9(J)-303.7(Pharmaco)-12(l.)-294.8(2008;15)-13.3(3:199215.)]TJ
-1.7224 -1.1988 TD
[(28.)-505.4(Leweke)-302.6(FM,)-305.1(Piomelli)-305.9(D,)-300.3(Pahlisch)-311.6(F,)-295.2(et)-308.6(al.)-301.4(Cannabidiol)-302.7(enhances)-310.1(ananda-)]TJ
1.7224 -1.1988 TD
[(mide)-304.1(signaling)-305.6(and)-303.9(alleviates)-301.9(psych)-11.7(otic)-304.8(symptoms)-309.9(of)-298.6(schizophren)-12.4(ia.)]TJ
T*
[(Transl)-303.5(Psy)-9.7(chiatry.)-307.4(2012;2:e94.)]TJ
-1.7224 -1.1988 TD
[(29.)-505.4(Huber)-283(KM,)-273.5(Gallagher)-284.9(SM,)-272.3(Warren)-282.7(ST,)-274.3(et)-278.2(al.)-271.1(Altered)-284.4(synaptic)-279.2(plasticity)-286.4(in)-273.7(a)]TJ
1.7224 -1.1988 TD
[(mouse)-308.5(model)-301.8(of)-306.1(fragile)-304.1(X)-295.4(mental)-309.8(retardation.)-309.9(Proc)-306.3(Natl)-302(Acad)-305.7(Sci)-299.4(U)-303.4(S)-300.1(A.)]TJ
0 -1.2064 TD
[(2002;99:7746)-14.7(7750.)]TJ
-1.7224 -1.1988 TD
[(30.)-505.4(Lozano)-307.8(R,)-303.9(Martinez-Cerdeno)-308.6(V,)-305.7(Hagerman)-304.4(RJ.)-304.1(Advances)-307(in)-296.4(the)-302.9(under-)]TJ
1.7224 -1.1988 TD
[(standing)-310.2(of)-298.6(the)-302.9(gabaergic)-309.2(neurobiology)-310.1(of)-298.6(FMR)-9(1)-294.3(expanded)-309.3(alleles)-307.2(lead-)]TJ
T*
[(ing)-305.9(to)-297.9(targeted)-310.7(treatments)-309.1(for)-302.8(Fragile)-305.8(X)-295.4(Spectrum)-309(diso)-10.6(rder.)-305(Curr)-299.3(Pharm)]TJ
T*
[(Des.)-308.3(2015;21:49724979.)]TJ
-1.7224 -1.1988 TD
[(31.)-505.4(B)17.5(a)0(k)28.9(a)16.2(s)-287.9(T)0(,)-270(v)16.2(a)16.2(n)-290.2(N)18.6(i)16.6(eu)31.8(we)30.1(nh)26.6(u)17.5(i)16.5(jz)28.6(en)-268.2(P)15(S)0(,)-270(D)0(e)25.4(v)16.2(en)35.3(i)16.5(s)15.6(h)-290.2(S)18.6(O,)-269.3(et)-270.6(a)16.2(l)0(.)-272.1(T)0(h)31.8(e)-289.1(d)15.7(i)16.5(r)18.5(e)0(c)28.9(t)-285(a)16.2(c)14.5(ti)27.5(o)17.5(n)0(s)-274.6(o)17.5(f)]TJ
1.7224 -1.2064 TD
[(c)14.5(a)16.2(nn)26.6(a)16.2(b)15.7(i)16.5(d)15.7(i)16.5(o)0(l)-269.5(a)16.2(nd)-274.5(2)16.8(-)0(a)29.8(r)18.5(a)16.2(c)14.5(hi)29.8(d)15.7(o)0(n)23.1(o)17.5(yl)-266.6(gl)29.8(yc)27.2(er)32.9(ol)-269.5(a)16.2(t)-285(G)15.2(A)0(B)29.6(A)0(A)-271.6(r)0(e)25.3(c)14.5(e)22(p)15.7(to)28.4(rs)26.5(.)-281(P)15(ha)29.4(rm)24.4(a)16.2(c)14.5(o)17.5(l)]TJ
0 -1.1988 TD
-.0163 Tc
[(Re)-16.3(s)13.7(.)-304.9(2017)-16.3(;)7.8(119:3)-16.3(5)9.7(8)-16.3(3)14.9(7).5(0)-16.3(.)]TJ
-1.7224 -1.1988 TD
.0152 Tc
[(3)15.2(2)15.2(.)-490.2(Blessing)-297.8(E)3.4(M)-2.3(,)-296.2(S)3.4(te)6.8(enk)5.2(a)1(mp)-303(M)5.3(M)-2.3(,)-296.2(M)-2.3(an)5.7(zanar)3.3(e)-.8(s)-295.4(J)-.2(,)-303.8(e)6.8(t)-300.2(a)1(l.)-303.8(Cann)5.7(abidiol)-302.1(a)1(s)-295.4(a)]TJ
1.7224 -1.1988 TD
.0138 Tc
[(pot)-5.6(e)5.4(ntial)-303.5(t)1.9(r)-5.6(e)5.4(at)-5.6(ment)-294(f)-6.3(o).9(r)-301.6(a)-.4(nx)-6.2(ie)5.4(t)-5.6(y)-299.7(disorders.)-305.2(Neuro)-6.7(t)1.9(her)-5.6(a)-.4(pe)5.4(ut)-5.6(ics.)-297.6(2015;12:)]TJ
T*
(825836.)Tj
-1.7224 -1.1988 TD
0 Tc
[(33.)-505.4(Loin)-307.8(MJ,)-298.7(Babson)-306.5(KA,)-304.5(Bonn-Miller)-307.5(MO.)-302(Cannabino)-11.9(ids)-301.2(as)-302.1(therapeutic)-307.8(for)]TJ
1.7224 -1.1988 TD
[(PTSD.)-308.9(Curr)-299.3(Opi)-9.2(n)-297.8(Psychol.)-304.9(2017;14:)-13.6(7883.)]TJ
-1.7224 -1.2064 TD
[(34.)-505.4(Bergamas)-11.6(chi)-244(MM,)-247.7(Queiroz)-250.9(RH,)-250.8(Chagas)-248.9(MH,)-245.3(et)-247.9(al.)-248.3(Cannabidiol)-257.1(reduces)-253.7(the)]TJ
1.7224 -1.1988 TD
[(anxiety)-307.8(induced)-302.2(by)-305.4(simulated)-310.9(public)-305.7(speaking)-299.7(in)-304(treatment-na)]TJ
26.2074 0 TD
[()25.4(v)0(e)-295.7(social)]TJ
-26.2074 -1.1988 TD
[(phobia)-307.4(patients.)-304.2(Neurop)-11.7(sychopharmacology.)-318.2(2011;36:12191226)-16.6(.)]TJ
-1.7224 -1.1988 TD
[(35.)-505.4(Campos)-305.6(AC,)-303.9(Guimaraes)-311.7(FS.)-299.4(Involvement)-307.9(of)-306.1(5HT1A)-307.4(receptors)-307.8(in)-296.4(the)]TJ
1.7224 -1.1988 TD
[(anxiolytic-li)-13.2(ke)-299.1(effects)-304.3(of)-306.2(cannabidiol)-306.3(injected)-306.3(into)-306(the)-302.9(dorsolateral)-307(peria)-9.8(-)]TJ
T*
[(queduc)-11.1(tal)-297.8(gray)-303.6(rats.)-303.3(Psy)-9.7(chopharmacology.)-316.2(2008;199:223230.)]TJ
-1.7224 -1.2064 TD
[(36.)-505.4(Norris)-243.8(C,)-232.6(Loureiro)-246.4(M,)-230.2(Kr)-9.6(amar)-231.6(C,)-240.2(et)-232.7(al.)-240.7(Cannabidiol)-242(modulates)-241.7(fear)-236.6(memory)]TJ
1.7224 -1.1988 TD
[(formation)-306.1(thr)-10.4(ough)-302.8(interactions)-307.6(with)-300.1(serato)-13.2(nergic)-304.1(transmission)-310.2(in)-296.4(the)]TJ
T*
[(mesolimbi)-12(c)-296.6(system.)-312.1(Neuropsychopharmacolo)-21.8(gy.)-300.5(2016;41:2839)-14.7(2850.)]TJ
-1.7224 -1.1988 TD
[(37.)-505.4(Indah)-304.5(Winarni)-307.1(T,)-300.4(Chonchaiya)-311.4(W,)-303(Adams)-306.3(E,)-300.4(et)-301(al.)-301.4(Sertraline)-305.1(may)-306.6(improve)]TJ
1.7224 -1.1988 TD
[(language)-304.4(developmental)-305.8(trajectory)-302.3(in)-296.4(young)-305.2(children)-294.6(with)-300.1(fragile)-304.1(x)-293.2(syn-)]TJ
T*
[(drome:)-239.4(a)-234.2(retro)-11.3(spective)-238.5(chart)-237.8(review)-10.5(.)-235.5(Autism)-240.1(Res)-235.7(Treat.)-240.5(2012;2012:104317)-15.8(.)]TJ
-1.7224 -1.1988 TD
[(38.)-505.4(Greiss)-306.3(Hess)-303.4(L,)-306.2(Fitzpatrick)-304.6(SE,)-304.6(Nguyen)-304.8(DV,)-302.2(et)-308.6(al.)-301.4(A)-298.9(randomized,)-312.3(double-)]TJ
1.7224 -1.2064 TD
[(blind,)-309.5(placebo-controlled)-312.6(trial)-300.8(of)-306.1(low-dose)-306(sertraline)-308.1(in)-304(young)-305.2(children)]TJ
0 -1.1988 TD
[(with)-307.7(Fragile)-298.2(X)-303(Syndrom)-11.7(e.)-297(J)-303.7(Dev)-299.9(Behav)-302(Pediat)-9.9(r.)-300.5(2016;37:6196)-15.5(28.)]TJ
-1.7224 -1.1988 TD
[(39.)-505.4(Leigh)-301.6(MJ,)-306.3(Nguyen)-304.8(DV,)-302.2(Mu)-303.5(Y,)-296.3(et)-301(al.)-301.4(A)-306.5(randomized)-304.4(double-blind,)-312.5(placebo-)]TJ
1.7224 -1.1988 TD
[(controlle)-12.2(d)-295.4(trial)-300.8(of)-298.6(minocycline)-307.2(in)-296.4(children)-302.2(and)-296.3(adolescents)-306(with)-300.1(fragile)-296.5(x)]TJ
T*
[(syndrome.)-311.6(J)-296.1(Dev)-307.4(Behav)-302(Pediatr.)-310.4(2013;34:147155.)]TJ
31.8829 60.0023 TD
[(40.)-505.4(Klaiman)-300.1(C,)-300.9(Qu)-8.8(intin)-301.3(EM,)-302.7(Jo)-301.4(B,)-301.5(et)-301(al.)-301.4(Longi)-10.2(tudinal)-303.2(proles)-307.5(of)-298.6(adaptive)-310.9(be-)]TJ
1.7224 -1.2064 TD
[(havior)-304.1(in)-296.4(fragile)-304.1(X)-303(syndrome.)-311.6(Pediatrics.)-309.3(2014;134:315)-14.7(324.)]TJ
-1.7224 -1.1988 TD
[(41.)-505.4(Rohleder)-254.1(C,)-255.3(Muller)-252.7(JK,)-256.2(Lange)-256.4(B,)-256(et)-255.5(al.)-248.3(Cannabi)-12.3(diol)-252.5(as)-256.6(a)-249.4(potential)-262.7(new)-252.5(type)]TJ
1.7224 -1.1988 TD
[(of)-298.6(an)-304.4(antipsychotic.)-313(A)-298.9(critical)-308.3(review)-306.4(of)-298.6(the)-302.9(evidence.)-305.9(Front)-303.1(Pharmaco)-12(l.)]TJ
T*
(2016;7:422.)Tj
-1.7224 -1.1988 TD
[(42.)-505.4(Carlini)-301.7(EA,)-303.4(Mechoulam)-311.5(R,)-296.3(Lander)-303.8(N.)-307.9(Anticonvulsant)-311.8(activity)-302.9(of)-306.2(four)-300.6(oxy-)]TJ
1.7224 -1.1988 TD
[(genated)-304.1(cannabidiol)-306.3(derivatives.)-307.3(Res)-304(Commu)-11(n)-297.8(Chem)-304.9(Pathol)-305.2(Pharmacol.)]TJ
0 -1.2064 TD
(1975;12:115.)Tj
-1.7224 -1.1988 TD
[(43.)-505.4(Chagas)-218.5(MH,)-215(Eckeli)-225.4(AL,)-218.2(Zuardi)-221.1(AW,)-215(et)-217.5(al.)-218(Cannabidiol)-219.2(can)-221.6(improve)-221.6(complex)]TJ
1.7224 -1.1988 TD
[(sleep-related)-304(beha)-8.8(viours)-300.5(associat)-13.7(ed)-296.2(with)-307.7(rapid)-304.4(eye)-299.9(movement)-303.7(sleep)]TJ
T*
[(behaviour)-302.1(disorder)-307.8(in)-304(Parkinsons)-309(disease)-308.9(patients:)-304.2(a)-302.5(case)-303.5(series.)-307.4(J)-296.1(Cli)-9.5(n)]TJ
T*
[(Pharm)-302.9(Ther.)-299.8(2014;39)-13.3(:564566.)]TJ
-1.7224 -1.1988 TD
[(44.)-505.4(Viveros)-305.4(MP,)-298.6(Marco)-307.5(EM,)-302.7(File)-300.6(SE.)-304.6(Endocannabin)-13.5(oid)-299.3(system)-304.2(and)-303.9(stress)-303.9(and)]TJ
1.7224 -1.1988 TD
[(anxiety)-300.2(respon)-11.3(ses.)-303.7(Pharmacol)-306.6(Biochem)-302.6(Behav.)-309.9(2005;81:331342.)]TJ
-1.7224 -1.2064 TD
[(45.)-505.4(Osborne)-234.9(AL,)-233.4(Solowij)-235.4(N,)-232(Weston-Green)-240.4(K.)-225.6(A)-230.6(systematic)-246.1(review)-230.6(of)-230.3(the)-234.6(effect)]TJ
1.7224 -1.1988 TD
[(of)-298.6(cannabidio)-11.7(l)-294.5(o)0(n)-303.1(cognitive)-307.1(functoin:)-311.6(relevance)-301.8(to)-305.5(schizophren)-12.4(ia.)-301.4(Neu-)]TJ
T*
[(rosci)-304.4(Biobehav)-305.4(Rev.)-303.7(2017;72:310324.)]TJ
-1.7224 -1.1988 TD
[(46.)-505.4(Mead)-297.5(A.)-306.8(The)-302.8(legal)-302.5(status)-300.3(of)-306.1(cannabis)-303.7(\(marijua)-11.5(na\))-296.6(and)-303.9(cannab)-9.6(idiol)-296.6(\(CB)-9.7(D\))]TJ
1.7224 -1.1988 TD
[(under)-300.1(U.S.)-308.2(law.)-300.9(Epilepsy)-306.7(Behav.)-302.3(2017;70)-13.3(\(Pt)-300.1(B\):288291.)]TJ
-1.7224 -1.1988 TD
[(47.)-505.4(Bonn-Miller)-307.5(MO,)-302(Loin)-300.2(MJE,)-310.5(Thomas)-300(BF,)-308.1(et)-301(al.)-301.4(Labeling)-306.3(accuracy)-308(of)-298.6(can)-9.2(-)]TJ
1.7224 -1.2064 TD
[(nabidiol)-304.6(extracts)-306.1(sold)-306.5(online.)-303.4(JAMA.)-304.8(2017;318:1708170)-16.6(9.)]TJ
-1.7224 -1.1988 TD
[(48.)-505.4(Thiele)-209.8(EA,)-212.4(Marsh)-219.5(ED,)-213.5(French)-213.4(JA,)-216(et)-217.5(al.)-210.4(Cannabidiol)-219.2(in)-213(patients)-220.4(with)-209.1(seizu)-9.8(res)]TJ
1.7224 -1.1988 TD
[(associated)-302.3(wit)-9.9(h)-297.8(Lennox-Gasta)-13(ut)-297.9(syndrome)-311.3(\(GWPCARE4\):)-313(a)-294.9(rando)-10(mized,)]TJ
T*
[(double-blind,)-304.9(placebo)-11(-controlled)-309.1(phase)-304.3(3)-301.9(trial.)-301(Lancet.)-305.3(2018;391)-11.7(:1085)]TJ
T*
(1096.)Tj
/F4 1 Tf
-.7891 -3.7331 TD
[(Cite)-301.7(this)-306(article)-307(as:)]TJ
/F9 1 Tf
8.5739 0 TD
[(Tartaglia)-304.9(N,)-300.3(Bonn-Miller)-307.5(M,)-306.1(Hagerman)-304.5(R)-303.6(\(2019\))]TJ
-8.5739 -1.1988 TD
[(Treatment)-248.8(of)-245.4(frag)-10.1(ile)-240.8(X)-242.3(s)0(y)-9.6(ndrome)-248.6(with)-247(cannabidiol:)-253.4(a)-241.8(case)-250.4(series)-246.4(study)]TJ
0 -1.2064 TD
[(and)-250.8(brief)-258.5(review)-253.3(of)-253(the)-249.8(literature,)]TJ
/F10 1 Tf
13.9535 0 TD
[(Cannabis)-257.9(and)-250(Cannabinoid)-267(Research)]TJ
/F9 1 Tf
-13.9535 -1.1988 TD
[(4:1)-300.5(39,)-301.3(DOI:)-310(10.1089/can.2018.0053)-18.6(.)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 390.8976 381.3164 Tm
[(Abbreviations)-336.5(Used)]TJ
/F9 1 Tf
7.4718 0 0 7.4718 364.8755 369.0141 Tm
(AEA)Tj
/F11 1 Tf
1.8665 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(N-arachidonoylethan)-15(olamine)-301.9(\(anan)-9.2(damide\))]TJ
-3.1716 -1.2064 TD
(2-AG)Tj
/F11 1 Tf
2.2307 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(2-arachidonoylglycer)-17.7(ol)]TJ
-2.8833 -1.1988 TD
[(CB)-10(D)]TJ
/F11 1 Tf
1.9424 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
(cannabidiol)Tj
-3.7634 -1.1988 TD
(CBD)Tj
/F5 1 Tf
1.9348 0 TD
(+)Tj
/F11 1 Tf
.8877 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
(CBD-enriched)Tj
-2.7315 -1.1988 TD
(EEG)Tj
/F11 1 Tf
1.7907 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(electroencephalo)-15.7(graphy)]TJ
-3.4296 -1.1988 TD
(FMR1)Tj
/F11 1 Tf
2.4887 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(fragile)-304.1(X)-303(mental)-302.2(retardation)-309.6(1)]TJ
-3.4523 -1.1988 TD
(FMRP)Tj
/F11 1 Tf
2.5115 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(fragile)-304.1(X)-303(mental)-302.2(retardation)-309.6(protein)]TJ
-2.6405 -1.2064 TD
(FXS)Tj
/F11 1 Tf
1.6996 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(fragile)-304.1(X)-303(syndrome)]TJ
-2.337 -1.1988 TD
(KO)Tj
/F11 1 Tf
1.3961 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
(knockout)Tj
-2.7239 -1.1988 TD
(LTD)Tj
/F11 1 Tf
1.7831 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(long-term)-308.6(depression)]TJ
-2.6708 -1.1988 TD
(MRI)Tj
/F11 1 Tf
1.73 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(magnetic)-304.8(resonance)-310.2(imaging)]TJ
-2.2535 -1.1988 TD
(SD)Tj
/F11 1 Tf
1.3126 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(standard)-303(deviatio)-12.8(n)]TJ
-2.815 -1.1988 TD
(THC)Tj
/F11 1 Tf
1.8741 0 TD
()Tj
/F9 1 Tf
.9409 0 TD
[(tetrahydrocannabino)-18.8(l)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 59.7543 753.8455 Tm
[(TREA)-10.3(TMENT)-305.4(OF)-302.7(FX)-8.4(S)-299.8(WITH)-303.3(CBD)]TJ
48.6485 0 TD
(9)Tj
ET
endstream
endobj
63 0 obj
<>stream
h\{0\w]?&76d["hkuIm!Zj=fwRzum.ELx+DBL'ښHM:˟33=砈9AQԞ/<-#z'^(sbU~s5AQUaἣ^xOHHQR%MU2!i銌t4"YR2
RI
*i<[g$LͰilOm"(D9"("Br9!҂Cǚ#\rQ3v
Ǧ:QMÑr}wh5yWJaQ
|ꐷ\DGCKhÅ'_1i^i">%u+N\ _XڵE/e-~QyFY4%i%B74O;|- #kj*2ks/24nABR~
S u_|}tܮǴ4%c&i 94wsػr-{m N*:]Vޠ "*Q$抩 V+=OA$3;0fj[iǺլ+r
@[O1?;l /2
;Y0*|β,h44|Dt^뀣pG]D|zx`8
xK?.S} 41 nb ?Fb3t*]|*Zʿijf`!Y_MjwVc4MtŦ42Zyiz0A7e2ujZaQ=XE2"
yO:ǵE1yQa7
I;݁%p!䳶"SP206d@2ƙgꪒJڰRCwYp°pց`ɦܡ͕wQtlmO@O&θ19=^rd2QGlM) T
endstream
endobj
65 0 obj
<>stream
hTMo
;@M'\MaZ)8BI3vclcT[3jpXqf.yڨi=Ũz逓Y ڶ']_`gw 4s?أ -WdPs~=hTQR@߱"9.%eĮ9m|b{'$r 8 <(\/֫1fCmnpد (
endstream
endobj
67 0 obj
<>stream
hbd`ad`ddrpvvL)0q6q57+i ^!FR :"~|WXtesWnXr)R'5f+jjXؾJnUi
'뒗HO4n}vµsp6yA%ݭ|?t~[tּ+kf./=Kǫa3!25^@df WD]B
endstream
endobj
69 0 obj
<>stream
hTP1n0
):lxu]hW@M <'E#wl\atdApr֙wͬ$%衮L%7'lMpW"5"T4`q=p3,?cn-.AdMB=HFY6mD٬<9+>|^į i
endstream
endobj
71 0 obj
<>stream
8;X]O>EqN@%''O_@%e@?J;%+8(9e>X=MR6S?i^YgA3=].HDXF.R$lIL@"pJ+EP(%0
b]6ajmNZn*!='OQZeQ^Y*,=]?C.B+\Ulg9dhD*"iC[;*=3`oP1[!S^)?1)IZ4dup`
E1r!/,*0[*9.aFIR2&b-C#soRZ7Dl%MLY\.?d>Mn
6%Q2oYfNRF$$+ON<+]RUJmC0InDZ4OTs0S!saG>GGKUlQ*Q?45:CI&4J'_2j$XKrcYp0n+Xl_nU*O(
l[$6Nn+Z_Nq0]s7hs]`XX1nZ8&94a\~>
endstream
endobj
73 0 obj
<>stream
8;Z\7$"Cdp%.jMVdf9)(lc*?A5!gr;g/Voi64tLL5uY]T:&r]MT)TtA=)(%#ZrEso
Jq-2&[1^o#5eSf\!918mq?cMmN?8.t`L4_tVB<)S[40WMVBu5'="3gGC-$JB1nWl8
e^T!Qo%rHW,(8+eiqf+=IHo>ZjlV[D6Lm%Td)I="D\'$^9FNRm(XTD@YIjCp-)f/M
4KcfX$/Ccs46A&F=6G1`*c]eZ]o8;qpg*LAPI+(kam6*Y9ootY(!5e%@=!fSOScZR
,4TYoGd'@cX.^H>3'!nsGYIYUcD/J'dqJ3].k7'i3UO!6Ha!ml?,sBf^QtVLe/0F#
7RAQb6Pn>!0b_.0B#1NL3Aaeof&;bD&/nZnN)&b()!)E\G6BQ,$;[,Lf.=KO^[Is.qH,/L!cDX28.U5TB.*(i
endstream
endobj
27 0 obj
<>stream
8;Z\7;6n(^#jhLCaE9Q.1l9:+TOOf@iT%m@j0FRG;<4u"HVH'ef^Yo
3VM9s#$CM?1EgL4)h8Z0Y/Z^<&RLF:Z&*\s!D.p_KZKt/OtC[*h!k^tWY\&4NVjWp
d)+^E?D?Qk>TGK5:8J[)/;?"X)-.u;C@lbEiAY=_&j54Y[iBHMru*F4;[`p3/0)i>=69GUU\;7IVhb-mH\>Q'Y,dC`5Gf
KGgUn.L'sV!q^Ctl<8e"[=-Uf'Dq!OlTLT_W284hT5aZb&n:k4hL<=]IV+5"ruk^2
`kUua'>2PHi(3d27ba%T^Xj4\C'>@:29,_L*?XC1eAA6tGZa1bk&pN-o5!Nc0?&j_
7Bl82EE;M85\#$]GZ]BC\]&Ti7X2U]=AdKYY9i2Z'-La'$J=XKY[UIAITA^',HRig
U[=\bPY#Qt5/]=8)4eHfpHI*m>iGA.@nD"X!0o:7CB~>
endstream
endobj
37 0 obj
<>stream
8;Z\7!KP)@#k\-=j?&]5eV_-b+0.T&7n6.b>:";1'CE
Nm$I%QD9ufQi9HZ"LD;9Im*Hb3dnhlXbJeRPQ7k0]Ssfj9rcG\N.k($`>jHS-f5q:
hrhe0*/TOOQhNCaFqg9@[H3M`976OQm@r(e^W4aj)^B["ZN#GJGs)/_30lJ]'R?mo
F^S!Xbs-Bp7Teo3-Q^+C@`]E2)b5$Zb@fuh8)G;+*U@1nBN=B8..n*[\FV79Q;jE_
>EnE;'tDDV@9cAQN6>RjNSkE`>GfS\1o+&7f^8AZh;I(!kIMeIop[-bg/(h820dX1
MSo5UZR,<$!0$kOpA~>
endstream
endobj
43 0 obj
<>stream
8;Z]">8Di6$q/eK#2)b4[C&+D&(1UU+hlG>
WE`]o4.L%H@QCtr_^]$)nOde)hMbb6gteoF5qK-=0I)d):LDFmorfbG>BQ95)Ee#0
+>%4qL3'hmo.;u4\Ytc#X]BKZ`[AO&*J!_LRbnAqN[\,#023]?S.Upm9_5>OV>a1d5@
6X%Rr5E*PI\^o+U,;+VV/F$dOcnMc''>27q/8j<:]=#"aM:N;;ogL)8;>"3f2_VI*
XpFAE&X-G,5DCt[o*F2g)6s,l(mXLjI?;2$.Q;,$Z(6lOoAr%]"T9KNreq5F:?57@
L7kYdbJRM."-5fKO$2p@`g>Z.,Vs2S>T&5.2U3_qY6Bldr]DDQ:(Zq6!-"X7If~>
endstream
endobj
47 0 obj
<>stream
8;Z\7>8"js#j_FBaE@3O%p):eSHWY=b"lei0hDCCjL#.QN6Qa?#4&\!VF/36OV'_D*1/6bf@u&ebff
hiDAs"naC,,-=WQY*sgVL'GThV"@2`23cP`%d##4l]AWWQUAWV+O,:GXobTCTsh[:
&fKU.NmsDEQHjIS(PN$T\)I>cMe!3)I,`F9G6E[B2K.kL,]19?$6\.OS1`f
R*0T3Pf*o!F)J\f(uOLoNqTm.hIIA4!sZp3#o-:lSO7MX&GKdA/NBP3VY4jJpGKX&
bRmV_?T:b:a8Z$"MIo"IK>CO`/[A-C#6i`9NA&ocDU"lR2sJB\">]#\2V[mEn(d#d
F)eneg1-`U!#np_^A~>
endstream
endobj
52 0 obj
<>stream
8;Z\7>EZlX#ikn#j>o@sN=ZTpeTARKc8:a'!?oY%WrDA'jPZ6F?C0j6r9OaeE+@ao
g[)W2r#jebj%L-c1:,uNKt%4X1-<[C?HX,qH]FG57L.ZX7m^q!18-eGO,h:qf:Pii(gUkc\
B3b4,>,iuMFnkOPEct,M%r.H*1e0$ci[G2d_K@LI(T#f_[2o`X4S)/H>KbF.^/eqE
NGg`K,Quk(Rcd1$JoAH\hrHLXtcZI4,V^J7'mTY3mk8R^%6KsmI/f)aT.f6
)f5.6XdZ;5(5sW7EMLb:fS,_()nJpK]7EVW5J$d[_9kI_jr^PE/Fg/B(:^:Kk1o!.
]oP.'Jq""8LR!j[-38o'N+)^5)q]lSoOT5.2KIcZBk52J]2Yt]D>17DRBn4'CRm'+
6S'sZ/R>`[lU`odPO&!^]\
7BiM&(2Ojt\W89m"%hTr<"k&WcjrKB:2g[=O$:NWmo9:#>@6E?s(I-s=A385gO
_cqU]H`O=G!e!UCOG49#MVf(s?tWC'bM9g?-E)Vp%,7)[:/Gk2-<>I+?Vt7:E+"BX
b.0Sr76WN$KI*cNeU(Brnp^N'B+t.]!+6K=VZ~>
endstream
endobj
59 0 obj
<>stream
8;Z\6d;B%@#ikr70Y]EO(MlH0G+!Z)=cbOak'Fp^R%Uu4t
[+uHfM'4;'fcP24Sc-3*W#m>)b_S\8feZO\(&'*`!6%rZXkE`M@5,j*S/ZR2bo-)$#:OFRa797h"sa`,N??2FL`./OYX>`at_jJ-VtV
n+p[q9o6JRad01SVRXp1oo1o?
X:[[:HCEi.`R%S2698dHP6il&qirg.E84Ut(W!:a/PPtLrKC=`T_jT6S!m`%nOT[o
+tc'^A,4pTJk[/]iYK$4>4AM*ng%mkg`,omjT/fU@ioX.+su,P5RF%h4fLnXKK)s/
+!Toa+D`sjZ5>:]JZiJgD/4:_G.8/a$3Bb8[W!6KG3mkdA&jW.Du1CPpbf_)~>
endstream
endobj
77 0 obj
<>
endobj
99 0 obj
<>stream
hdV PSYNw~=>߳CE]@E$@Xd @"M(;Ȣ,슸Έ2vT'Ūy睊TJwwE(0BumۼJR팈8;|eڅF&-4h!AP0d=Ph6qvԝN'K3[kkO$qooZ<2>+!"Q(GJ\R3YL>y,29Rn%##f{|;[:O!
H@ Ke
Y p /!
V"TS_C.=S
zIzsCOhD Qh7:~ي"E;
y9s*\k>7yY
'H|g.D6b|5=[|4l ?TC<qL
aɎ Z>i1/diLP{AS
ӬUII$|C7Kυņr$y'`&p@8cA
[:`q89^XO
̰
Wznc(;M{&/sL`vkXǵL~բAЯӀx/vvOf;쉺ցqf%`rذMǻ(y _z}mIZk=3d(іne
ݲa/k3>]⛭u'e<@ 8|]ӳj"eZFQqUӽ)%ʨ({0iUƢ7%ZF0[bv^ qLG+F$퉉NNO(8:zm*kE~.0:9ܝr#aLD?*
k+*Me0wNK,@8qƑ6K?:{4-5.e]eԨTRRwT{nL w:=y̽-=nI'ױ->6o%.TQul aOpl
nqkV'IL=Z- 2cw)l,+J_v9'Bsʅ{JLc&UM)h?B
8RxQD<4.;nƈE&`$:
ٿF*mAJMa87DfuxĀ;5lٴKjGgfձM}Un^r_p;DpSҶ zgXZﭚ K@0}d1DC?A LxڀԽi:y/dg+aJ7]0mJʵۡ[NMfkWgZN0*oExS!zcvMl:G>:ҬKcT܂\v_@F"=;/կU_RJ?e,+*y[[kBx./
p]0ueKCdteqR\]J,
g6_^5v۔pg!^-o7+9rPp&JQGM6jv*`Z&J DV!Z@g,UvAȬ
&:%eZQ,m2DR<.~m3?¿]+{شDVdDбsLj\Cyp4h_ՉkoTU$J/eΊ#ҽTr"bRf(o3D]=_a%ٝ:o_}j)dEz˼}X7
_:9JfC3#Cuw~
HQMUV+
0<8ܠ)X_Y%M6SʲRУ%\;L<3
;M):?\P "#`9=`7"l3S.P }rw#F
sa'xR]Ńnhia5vY>|e^`"y@zX.vlaVFʹta`ťAn?OA#G0"ti(܂
~?OXW`Kl[45Su{x;cj$}Пw6pS:Dk
!T)?f&z<l^%*S$^2v8sL,@$R+f3>CUA`
Gr"s#xRtf^\GMIVE&U]Ml{Yɀqd
]ϐfd2g4kխ 5]`YV`B %eΣ(I ɇdiԼŦCU=W^܅j
47ppCyE=T5&Z 5imftr"Ybj,oY|_i_
endstream
endobj
100 0 obj
<>stream
hlViTTז.{
"MV# <@1 "P" ̣TY0 Ȍ
JDQq@C/$&&%ݻӫ]묻>GK-Zd.0*"&0^Dj?7@,X,wd?Y&Ҋne:K3ja]c&ZK";"eQQARpilh8ilP\PlF$Ҁc=DlW[^kii hH4_KP,Z+2DVDkE"gJAEuB"` %nkmj^]=>4n?t,9sN:*f;!X!5Ѝms҃=g|s>9