cannabis, hiv, & neuropsychological …cfar.med.miami.edu/documents/presentation_slides.pdflots...
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CANNABIS, HIV, &
NEUROPSYCHOLOGICAL
FUNCTIONING
Good Medicine?
Raul Gonzalez, PhDAssociate Professor of Psychology, Psychiatry, & ImmunologyDirector, Substance Use and HIV Neuropsychology (SUHN) Lab
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The Spread of Legal Marijuana
in the United States
http://www.thewire.com/politics/2013/04/map-shows-dramatic-spread-legal-weed-us/63997/
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LOTS OF PEOPLE HAVE TRIED IT….
ILLICIT DRUGS 48
Marijuana and Hashish 43
Cocaine 15
Crack 4
Heroin 2
Hallucinogens 15
Inhalants 8
Nonmedical Use of Psychotherapeutics 21
Pain Relievers 14
Tranquilizers 9
Stimulants 8
Methamphetamine 5
Sedatives 3
NSDUH 2013% of US Population over 12 [Lifetime Use]
7.4% used cannabis in the past month
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…. INCLUDING PERSONS LIVING WITH HIV
12 – 27% Recreational use in European samples(Garin et al., 2015)
39% Recreational use in Canadian samples(Harris et al., 2014)
24% Recent use in U.S. sample (4 cities)(Mimiaga et al., 2013)
14 – 21% Recent use in WIHS sample
(D’Souza et al., 2012)
72% Ever used in WIHS sample
(Kuo et al., 2004)
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CANNABIS USE DISORDERS
NSDUH 2010% of US Population over 12 [Lifetime Use]
ILLICIT DRUGS 2.8 [7.1 million Americans]
Marijuana and Hashish 1.8 [4.5 million]
Cocaine 0.4 [1 million]
Heroin 0.1
Hallucinogens 0.2
Inhalants 0.1
Nonmedical Use of Psychotherapeutics 0.9
Pain Relievers 0.8
Tranquilizers 0.2
Stimulants 0.1
Sedatives 0.1
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HIV, Cannabis, and NP
Cannabis and NP
HIV and NP
Current Studies
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HIV & INFECTED T-CELLS ENTER
BRAIN
Illustration by Lydia Kibiuk. Adapted Lipton, 1994.
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HIV-ASSOCIATED
NEUROCOGNITIVE DISORDERS
Antinori et al., 2007; Grant and Sacktor in Gendelman et al., 2012
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Antinori et al., 2007; Grant and Sacktor in Gendelman et al., 2012
HAD SinceCART
HAND SinceCART
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PATTERN OF DEFICITS IN HIV
• Primarily reflects prefrontal-striatal abnormalities
– Motor, psychomotor, processing speed
– Verbal learning & free recall (spared recognition)
– Executive
Reger et al., 2002
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HIV NEUROCOGNITIVE IMPAIRMENTS
AFFECT DAILY FUNCTIONING
• Deficits in:
– Driving ability Marcotte et al., 1999, 2004
– Standardized work samples Heaton et al., 1996
– Unemployment & vocational functioning Heaton et al., 1996
– Activities of daily living Heaton et al., 1995, 1996, 2004
– Medication management Albert et al., 1999, Hinkin et al., 2002
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CANNA
BIS
AND
NEURO
COGNI
TIVE
DEFICI
TS
14 Studies N = 1188 Cannabis Users = 704Non-Users = 484
Grant, Gonzalez, Carey, Natarajan, & Wolfson, JINS 2003
-1
-0.75
-0.5
-0.25
0
0.25
0.5
Simple RT Percp/Motor Attention Executive Motor Verbal Learning Recall/Retrieval
Domains 0.009 -0.065 -0.11 -0.15 -0.26 -0.28 -0.24 -0.27
CANNABIS AND NEUROCOGNITION
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PERSISTING NEUROCOGNITIVE DEFICITS? META-ANALYSES BASED
ON 33 STUDIES OF NONINTOXICATED MJ USERS AND SUBSET OF
13 STUDIES WITH MINIMUM 25 DAYS ABSTINENT
Effect Size
Schreiner & Dunn, 2012
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PERSISTING NEUROCOGNITIVE DEFICITS? META-
ANALYSES BASED ON 33 STUDIES OF
NONINTOXICATED MJ USERS AND SUBSET OF 13
STUDIES WITH MINIMUM 25 DAYS ABSTINENT
Schreiner & Dunn, Experimental and Clinical Psychopharmacology, 2012, 20(5):420-429.
Effect Size
Schreiner & Dunn, 2012
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CB1
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CB1 IS ABUNDANT IN BRAIN
Basal Ganglia
Hippocampal Formation
Amygdaloid Nucleus
Cingulate Cortex
Cerebellum Herkenham et al., 1990
Egan & Lewis, 2006
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ENDOCANNABINOIDS
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ENDOCANNABINOID SYSTEM
FUNCTION
• Modulation of signaling activity– Best understood for GABA & Glutamate (Pertwee, 1997)
• Implicated in various behaviors/functions– Feeding, nursing (Fride et al., 2001)
– Pain regulation (Hohmann & Herkenham, 1999)
– Addiction (Maldonado, 2006)
– Immune Functioning (Cabral 2006)
– Emesis (van Sickle et al., 2001)
• Neuroprotective Properties (Guzman et al., 2001; Marsicano et al., 2002; Mechoulam 2002)
– Inhibit release of glutamate
– Dampens excitotoxic injury
– Potent antioxidant
– Reduce damage from experimentally induced ischemia
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MARIJUANA
AS
MEDICINE?
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MEDICAL BENEFITS
Disorder Symptom Evidence
Cancer Nausea P. Effective
Cancer; HIV Anorexia P. Effective
HIV Pain P. Effective
Multiple Sclerosis Spasticity P. Effective
Pain P. Effective
Urinary Dysfunction P. Effective
Tremor P. Ineffective
Parkinson’s Disease Dyskinesia P. Ineffective
Huntington’s Disease; Tourette Syndrome; Epilepsy
unknown
Koppel et al., Neurology, 2014Borgelt et al., Pharmacotherapy, 2013
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Whiting et al., 2015
79 Clinical Trials6,462 Participants4 studies were judged as low risk for bias
Benefitsless nausea & vomitingPain reductionLess spasticity
Side EffectsDizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, hallucination
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Level of Confidence in the Evidence for Adverse Effects of Marijuana on Health and Well-Being.
VOLKOW ND ET AL. N ENGL J MED 2014;370:2219-2227.
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CURRENT RESEARCH ON HIV & CANNABIS INTERACTIONS
• Non-human primates• Chronic THC administration decreased mortality and associated with
less viral load and retention of body mass (Molina et al., 2011)
• THC administration increased T-cell survival and reduced HIV infection-related inflammation in GI tract of macaques (Molina et al.,
2014)
• No immunological or mortality related differences in THC-treated female macaques, but less weight gain (Molina et al., 2014)
• Human Subjects• Daily marijuana users in WIHS cohort had higher adherence, CD4
count, quality of life, being underweight, and having more mental health & medical comorbidities (D’Souza et al., 2012)
• Lower viral load among daily cannabis users during first year after serconversion (Milloy et al., 2015)
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Study Participants Results
Abrams et al., (2003) N = 62, clinical trial cannabis vs dronabinol, placebo
No adverse effects on NP
Cristiani, Pukay-Martin, & Bornstein (2004)
N = 288, stratified by HIV and history of cannabis use
Symptomatic HIV+ frequent cannabis users performed most poorly
Chang, Cloak, Yakupov, & Ernst (2006)
N = 96, stratified by HIV and history of cannabis use
No additive effects on NP, MRS metabolic abnormalities in basal ganglia and thalamus
Byrd et al., (2011) N = 399 HIV+ substance using individuals
No difference in HAND prevalence
Gonzalez, et al., (2011) N = 86 SDIs, stratified by HIV and hx of cannabis dependence
Poorer complex motor skills in those with hx of cannabis dependence
STUDIES ON CANNABIS USE &
NEUROCOGNITION IN HIV
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CANNABIS AND HIV ON PROCEDURAL MEMORY AND
COMPLEX MOTOR SKILLS
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Gonzalez et al, 2011; JCEN
HIV-
(n = 44)
All currently abstinent polydrug users
N = 86
MJ-
(n = 46)
HIV+
(n = 42)
MJ+
(n = 40)
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20
40
60
80
100
120
140
1 2 3 4
MST Blocks
se
co
nd
s t
o c
om
ple
te
MJ+ (n = 42)
MJ- (n = 52)
5
6
7
8
9
10
11
12
13
1 2 3 4
RPT Blocks
se
co
nd
s o
n t
arg
et
HIV+ (n = 47)
HIV- (n = 47)
20
40
60
80
100
120
140
1 2 3 4
MST Blocks
seco
nd
s t
o c
om
ple
te
HIV+ (n = 47)
HIV- (n = 47)
5
6
7
8
9
10
11
12
13
1 2 3 4
RPT Blocks
seco
nd
s o
n t
arg
et
MJ+ (n = 42)
MJ- ( n = 52)
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2RF < 0 RF
2RF < 1RF
2RF < 0 RF
RPT by Group
5
6
7
8
9
10
11
12
13
MJ+ AND HIV+ (2RF) MJ+ OR HIV+ (1RF) MJ- AND HIV- (0RF)
seco
nd
s o
n t
arg
et
MST by Group
20
40
60
80
100
120
140
MJ+ AND HIV+ (2RF) MJ+ OR HIV+ (1RF) MJ- AND HIV- (0RF)
se
co
nd
s t
o c
om
ple
te
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Study Participants ResultsAbrams et al., (2003) N = 62, clinical trial cannabis vs dronabinol,
placeboNo adverse effects on NP
Cristiani, Pukay-Martin, & Bornstein (2004) N = 288, stratified by HIV and history of cannabis use
Symptomatic HIV+ frequent cannabis users performed most poorly
Chang, Cloak, Yakupov, & Ernst (2006) N = 96, stratified by HIV and history of cannabis use
No additive effects on NP, MRS metabolic abnormalities in basal ganglia and thalamus
“These results indicate that chronic delta-9-THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression.”
OTHER KEY STUDIES
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Gonzalez et al., 2004
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Exec Attn/WM VF SIP Lrn Rec/Ret Motor
GD
S
Meth-/MJ- Meth+/MJ+ Meth+/MJ-
METHAMPHETAMINE & CANNABIS
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CANNABIS AND NEUROCOGNITION
IN HIV
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PRELIMINARY DATA FROM THE
MIND MATTERS PROJECT
HIV-/CB- (n = 67)
HIV-/CB+ (n = 55)
HIV+/CB- (n = 47)
HIV+/CB+ (n = 28)
Age 35.2 (9.5) 32.0 (8.4) 38.0 (10.1) 37.3 (9.4) HIV-/CB+ < HIV+/CB-
% Male 54% 60% 51% 79% ns
Years of Education 14.4 (2.2) 13.0 (2.0) 13.6 (2.4) 13.8 (2.3) HIV-/CB- > HIV-/CB+
% African American 54% 64% 70% 64% ns
Estimated IQ 97.7 (9.9) 92.1 (12.5) 94.8 (11.9) 96.4 (12.5) HIV-/CB- > HIV-/CB+
Lifetime MDD 15% 13% 9% 21% ns
Past Dependence
Alcohol 3% 15% 6% 7% ns Cocaine 0% 7% 11% 11% <.01
Cannabis 0% 58% 2% 14% <.001
THCOOH + 0% 96% 0% 82% <.001
CD4 count 608 [395, 774] 583 [346, 704] ns
nadir CD4 252 [38, 368] 239 [105, 405] ns
HIV viral load (Log10 plasma) 0 [0, 1.7] 0 [0, 1.7] ns
% undetectable viral load 72% 61% ns
% AIDS Diagnosis 34% 36% ns
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PRELIMINARY BETWEEN GROUP COMPARISONS ON NP: MIND MATTERS
30
35
40
45
50
Processing Speed Motor Learning Memory Executive Global
HIV-/CB- HIV-/CB+ HIV+/CB- HIV+/CB+
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REASONS FOR CANNABIS USE
Teens (n = 173) Adults: HIV- (n = 12) Adults: HIV+ (n = 15)
Get High 94% [25%] 92% [33%] 93% [13%]
Have Fun 94% [21%] 92% 93%
Socialize 81% 83% 93% [53%]
Relax, Reduce Stress 80% [29%] 92% [33%] 80%
Feel Happier 61% 83% 60%
Feel Less Bored 52% 50% 20%
Sleep Better 49% 75% 80%
Feel Less Sad 37% 50% 40%
Increase Appetite 33% 50% 40%
Reduce Pain 29% 58% 53%
Reduce Nausea 17% 25% 27%
Fit In 8% 8% 12%
Reduce Muscle Spasms 4% 42% 20%
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ACKNOWLEDGEMENTS
• FIU
– Gianna Perez Gomez, PhD
– Brenda Lerner, PsyD, RN
– Jessica Arguello
– Ingrid Gonzalez
– Diana Martinez
– Melanie Vega
– Karen Granja
– Robert Malow, PhD
– William Pelham, PhD
– SUHN Lab Team!
• UIC– Eileen Martin, PhD
– Jasmin Vassileva, PhD
– Robin Mermelstein, PhD
– Randi Schuster
– Natania Crane
• UCSD– Igor Grant, MD
– Robert Heaton, PhD
– Susan Tapert, PhD
SUBSTANCE USE AND HIV NEUROPSYCHOLOGY
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Ongoing
Studies
@
FIU
http://suhn.fiu.edu