CANNABIS, HIV, &

NEUROPSYCHOLOGICAL

FUNCTIONING

Good Medicine?

Raul Gonzalez, PhDAssociate Professor of Psychology, Psychiatry, & ImmunologyDirector, Substance Use and HIV Neuropsychology (SUHN) Lab

The Spread of Legal Marijuana

in the United States

http://www.thewire.com/politics/2013/04/map-shows-dramatic-spread-legal-weed-us/63997/

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

…. 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)

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

HIV, Cannabis, and NP

Cannabis and NP

HIV and NP

Current Studies

HIV & INFECTED T-CELLS ENTER

BRAIN

Illustration by Lydia Kibiuk. Adapted Lipton, 1994.

HIV-ASSOCIATED

NEUROCOGNITIVE DISORDERS

Antinori et al., 2007; Grant and Sacktor in Gendelman et al., 2012

Antinori et al., 2007; Grant and Sacktor in Gendelman et al., 2012

HAD SinceCART

HAND SinceCART

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

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

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

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

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

CB1

CB1 IS ABUNDANT IN BRAIN

Basal Ganglia

Hippocampal Formation

Amygdaloid Nucleus

Cingulate Cortex

Cerebellum Herkenham et al., 1990

Egan & Lewis, 2006

ENDOCANNABINOIDS

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

MARIJUANA

AS

MEDICINE?

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

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

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.

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)

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

CANNABIS AND HIV ON PROCEDURAL MEMORY AND

COMPLEX MOTOR SKILLS

Gonzalez et al, 2011; JCEN

HIV-

(n = 44)

All currently abstinent polydrug users

N = 86

MJ-

(n = 46)

HIV+

(n = 42)

MJ+

(n = 40)

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)

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

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

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

CANNABIS AND NEUROCOGNITION

IN HIV

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

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+

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%

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

Ongoing

Studies

@

FIU

http://suhn.fiu.edu