Cannabis use is common among people living with HIV (PLWH). Some observational studies of PLWH have linked cannabis use to lower immune markers; however, this is yet to be confirmed. In addition, whether HIV affects the endogenous cannabinoid system has not been studied. Our objective was to examine changes in immune-related biomarkers and endocannabinoids as a function of cannabis use frequency in people living with and without HIV.
Materials and Methods:
Data were obtained from a longitudinal study of men who have sex with men living in Los Angeles with, or at risk for, HIV. By design, half were PLWH. Those eligible for the parent study were willing and able to return for follow-up every 6 months. Those eligible for inclusion in this study reported varying levels of current cannabis use at follow-up. Specifically, one visit corresponded to a period of daily use and another to a period of infrequent use (weekly, monthly, or less than monthly). Banked serum from all eligible participants was analyzed for immune-related biomarkers, endocannabinoids, and paracannabinoids.
Results:
The analysis included 36 men, 19 of whom were PLWH. PLWH reported greater lifetime methamphetamine or amphetamine use (68% vs. 0%) and current cigarette use (55% vs. 20%) than people without HIV. Serum levels of HIV-related immune biomarkers including tumor necrosis factor receptor 2 (TNFR2; p=0.013) and CD27 (p=0.004) were greater in PLWH, alongside lower anandamide (AEA) (F1,34=5.337, p=0.027) and oleoylethanolamide (OEA) (F1,34=8.222, p=0.007) levels relative to people without HIV. Frequency of cannabis use did not impact the serum analytes in our study.
Conclusions:
Higher levels of TNFR2 and CD27 and lower levels of AEA and OEA in PLWH underscore the role of the TNF/TNFR superfamily in HIV, while highlighting a new role for the enzymatic activity of fatty acid amide hydrolase (the enzyme that hydrolyzes AEA and OEA) in HIV. Findings that cannabis frequency did not impact the immune phenotype may not generalize to other populations of PLWH. Additional work is required to further clarify the relationship between immune markers and endocannabinoids as a function of cannabis use frequency in PLWH. ClinicalTrials.gov ID: NCT01201083.
Get full access to this article
View all access options for this article.
References
1.
CostiniukCT, BrunetL, Rollet-KurhajecKC, et al.Tobacco smoking is not associated with accelerated liver disease in human immunodeficiency virus-hepatitis C coinfection: A longitudinal cohort analysis. Open Forum Infect Dis, 2016; 3(2):ofw050; doi: 10.1093/ofid/ofw050
2.
FulcherJA, JavanbakhtM, ShoverCL, et al.Comparative impact of methamphetamine and other drug use on viral suppression among sexual minority men on antiretroviral therapy. Drug Alcohol Depend, 2021; 221:108622; doi: 10.1016/j.drugalcdep.2021.108622
3.
CintiS. Medical marijuana in HIV-positive patients: What do we know?. J Int Assoc Physicians AIDS Care (Chic), 2009; 8(6):342–346; doi: 10.1177/1545109709351167
4.
CostiniukCT, SaneeiZ, SalahuddinS, et al.Cannabis consumption in people living with HIV: Reasons for use, secondary effects, and opportunities for health education. Cannabis Cannabinoid Res, 2019; 4(3):204–213; doi: 10.1089/can.2018.0068
5.
HarrisGE, DupuisL, MugfordGJ, et al.Patterns and correlates of cannabis use among individuals with HIV/AIDS in Maritime Canada. Can J Infect Dis Med Microbiol, 2014; 25(1):e1–e7; doi: 10.1155/2014/301713
6.
ChandraLC, KumarV, TorbenW, et al.Chronic administration of Δ9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute simian immunodeficiency virus infection of rhesus macaques. J Virol, 2015; 89(2):1168–1181; doi: 10.1128/jvi.01754-14
7.
MolinaPE, AmedeeAM, LeCapitaineNJ, et al.Modulation of gut-specific mechanisms by chronic δ(9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: A systems biology analysis. AIDS Res Hum Retroviruses, 2014; 30(6):567–578; doi: 10.1089/aid.2013.0182
8.
MolinaPE, WinsauerP, ZhangP, et al.Cannabinoid administration attenuates the progression of simian immunodeficiency virus. AIDS Res Hum Retroviruses, 2011; 27(6):585–592; doi: 10.1089/aid.2010.0218
9.
MechoulamR, ShaniA, EderyH, et al.Chemical basis of hashish activity. Science, 1970; 169(3945):611–612; doi: 10.1126/science.169.3945.611
10.
KallianpurKJ, BirnR, NdhlovuLC, et al.Impact of cannabis use on brain structure and function in suppressed HIV infection. J Behav Brain Sci, 2020; 10(8):344–370.
11.
ManuzakJA, GottTM, KirkwoodJS, et al.Heavy cannabis use associated with reduction in activated and inflammatory immune cell frequencies in antiretroviral therapy-treated human immunodeficiency virus-infected individuals. Clin Infect Dis, 2018; 66(12):1872–1882; doi: 10.1093/cid/cix1116
12.
EllisRJ, PetersonSN, LiY, et al.Recent cannabis use in HIV is associated with reduced inflammatory markers in CSF and blood. Neurol Neuroimmunol Neuroinflamm, 2020; 7(5); doi: 10.1212/nxi.0000000000000809
13.
RizzoMD, CrawfordRB, HenriquezJE, et al.HIV-infected cannabis users have lower circulating CD16+ monocytes and IFN-γ-inducible protein 10 levels compared with nonusing HIV patients. AIDS, 2018; 32(4):419–429; doi: 10.1097/qad.0000000000001704
14.
CastroFOF, SilvaJM, DornelesGP, et al.Distinct inflammatory profiles in HIV-infected individuals under antiretroviral therapy using cannabis, cocaine or cannabis plus cocaine. AIDS, 2019; 33(12):1831–1842; doi: 10.1097/qad.0000000000002296
15.
ThamesAD, MahmoodZ, BurggrenAC, et al.Combined effects of HIV and marijuana use on neurocognitive functioning and immune status. AIDS Care, 2016; 28(5):628–632; doi: 10.1080/09540121.2015.1124983
16.
KrsakM, WadaNI, PlankeyMW, et al.Self-reported cannabis use and markers of inflammation in men who have sex with men with and without HIV. Cannabis Cannabinoid Res, 2021; 6(2):165–173; doi: 10.1089/can.2019.0083
17.
AbramsDI, HiltonJF, LeiserRJ, et al.Short-term effects of cannabinoids in patients with HIV-1 infection: A randomized, placebo-controlled clinical trial. Ann Intern Med, 2003; 139(4):258–266; doi: 10.7326/0003-4819-139-4-200308190-00008
18.
BredtBM, Higuera-AlhinoD, ShadeSB, et al.Short-term effects of cannabinoids on immune phenotype and function in HIV-1-infected patients. J Clin Pharmacol, 2002; 42(S1):82s–89s; doi: 10.1002/j.1552-4604.2002.tb06007.x
19.
ChaoC, JacobsonLP, TashkinD, et al.Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men. Drug Alcohol Depend, 2008; 94(1–3):165–171; doi: 10.1016/j.drugalcdep.2007.11.010
OrioL, AlenF, PavónFJ, et al.Oleoylethanolamide, neuroinflammation, and alcohol abuse. Front Mol Neurosci, 2018; 11:490; doi: 10.3389/fnmol.2018.00490
22.
TurcotteC, ChouinardF, LefebvreJS, et al.Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol, 2015; 97(6):1049–1070; doi: 10.1189/jlb.3RU0115-021R
23.
Cosenza-NashatMA, BaumanA, ZhaoML, et al.Cannabinoid receptor expression in HIV encephalitis and HIV-associated neuropathologic comorbidities. Neuropathol Appl Neurobiol, 2011; 37(5):464–483; doi: 10.1111/j.1365-2990.2011.01177.x
24.
McPartlandJM, GuyGW, Di MarzoV. Care and feeding of the endocannabinoid system: A systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One, 2014; 9(3):e89566; doi: 10.1371/journal.pone.0089566
25.
Kearney-RamosT, HerrmannES, BelluomoI, et al.The relationship between circulating endogenous cannabinoids and the effects of smoked cannabis. Cannabis Cannabinoid Res, 2022; doi: 10.1089/can.2021.0185
26.
MorganCJ, PageE, SchaeferC, et al.Cerebrospinal fluid anandamide levels, cannabis use and psychotic-like symptoms. Br J Psychiatry, 2013; 202(5):381–382; doi: 10.1192/bjp.bp.112.121178
27.
JavanbakhtM, RagsdaleA, ShoptawS, et al.Transactional sex among men who have sex with men: Differences by substance use and HIV status. J Urban Health, 2018; doi: 10.1007/s11524-018-0309-8
28.
FulcherJA, ShoptawS, MakgoengSB, et al.Brief report: Recent methamphetamine use is associated with increased rectal mucosal inflammatory cytokines, regardless of HIV-1 serostatus. J Acquir Immune Defic Syndr, 2018; 78(1):119–123; doi: 10.1097/QAI.0000000000001643
29.
OkaforCN, GorbachPM, RagsdaleA, et al.Correlates of preexposure prophylaxis (PrEP) use among men who have sex with men (MSM) in Los Angeles, California. J Urban Health, 2017; 94(5):710–715; doi: 10.1007/s11524-017-0172-z
30.
SharmaP, MurthyP, BharathMM. Chemistry, metabolism, and toxicology of cannabis: Clinical implications. Iran J Psychiatry, 2012; 7(4):149–156.
31.
BrenchleyJM, PriceDA, SchackerTW, et al.Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med, 2006; 12(12):1365–1371; doi: 10.1038/nm1511
32.
De MilitoA, AlemanS, MarenziR, et al.Plasma levels of soluble CD27: A simple marker to monitor immune activation during potent antiretroviral therapy in HIV-1-infected subjects. Clin Exp Immunol, 2002; 127(3):486–494; doi: 10.1046/j.1365-2249.2002.01786.x
33.
FrenchMA, KingMS, TschampaJM, et al.Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells. J Infect Dis, 2009; 200(8):1212–1215; doi: 10.1086/605890
NeuhausJ, JacobsDRJr, BakerJV, et al.Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis, 2010; 201(12):1788–1795; doi: 10.1086/652749
36.
SandlerNG, WandH, RoqueA, et al.Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis, 2011; 203(6):780–790; doi: 10.1093/infdis/jiq118
37.
AhmedF, TorrensA, MahlerSV, et al.A Sensitive Ultrahigh-Performance Liquid Chromatography/Tandem Mass Spectrometry Method for the Simultaneous Analysis of Phytocannabinoids and Endocannabinoids in Plasma and Brain. Cannabis Cannabinoid Res, 2022 [Epub ahead of print]; doi: 10.1089/can.2022.0216
38.
RuizCM, TorrensA, CastilloE, et al.Pharmacokinetic, behavioral, and brain activity effects of Δ9-tetrahydrocannabinol in adolescent male and female rats. Neuropsychopharmacology, 2021; 46(5):959–969; doi: 10.1038/s41386-020-00839-w
39.
RuizCM, TorrensA, LallaiV, et al.Pharmacokinetic and pharmacodynamic properties of aerosolized (“vaped”) THC in adolescent male and female rats. Psychopharmacology, 2021; 238(12):3595–3605; doi: 10.1007/s00213-021-05976-8
40.
TorrensA, VozellaV, HuffH, et al.Comparative pharmacokinetics of Δ(9)-tetrahydrocannabinol in adolescent and adult male mice. J Pharmacol Exp Ther, 2020; 374(1):151–160; doi: 10.1124/jpet.120.265892
41.
VozellaV, ZibardiC, AhmedF, et al.Fast and sensitive quantification of Δ(9)-tetrahydrocannabinol and its main oxidative metabolites by liquid chromatography/tandem mass spectrometry. Cannabis Cannabinoid Res, 2019; 4(2):110–123; doi: 10.1089/can.2018.0075
42.
CohenP, WestSG, AikenLS. Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences. Psychology Press: New York; 2014.
43.
HendriksJ, GravesteinLA, TesselaarK, et al.CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol, 2000; 1(5):433–440; doi: 10.1038/80877
44.
YangS, WangJ, BrandDD, et al.Role of TNF-TNF receptor 2 signal in regulatory t cells and its therapeutic implications. Front Immunol, 2018; 9:784; doi: 10.3389/fimmu.2018.00784
45.
SkapenkoA, LeipeJ, LipskyPE, et al.The role of the T cell in autoimmune inflammation. Arthritis Res Ther, 2005; 7Suppl 2(Suppl 2):S4–S14; doi: 10.1186/ar1703
46.
KumarA, AbbasW, HerbeinG. TNF and TNF receptor superfamily members in HIV infection: New cellular targets for therapy?. Mediators Inflamm, 2013; 2013:484378; doi: 10.1155/2013/484378
47.
AhnK, McKinneyMK, CravattBF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev, 2008; 108(5):1687–1707; doi: 10.1021/cr0782067
48.
WeiBQ, MikkelsenTS, McKinneyMK, et al.A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem, 2006; 281(48):36569–36578; doi: 10.1074/jbc.M606646200
49.
UedaN, TsuboiK, UyamaT. N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog Lipid Res, 2010; 49(4):299–315; doi: 10.1016/j.plipres.2010.02.003
50.
TaylorBK. N-acylethanolamine acid amidase (NAAA), a new path to unleash PPAR-mediated analgesia. Pain, 2013; 154(3):326–327; doi: 10.1016/j.pain.2012.12.012
51.
LuHC, MackieK. An introduction to the endogenous cannabinoid system. Biol Psychiatry, 2016; 79(7):516–525; doi: 10.1016/j.biopsych.2015.07.028
52.
HermesDJ, XuC, PoklisJL, et al.Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS. Neuropharmacology, 2018; 141:55–65; doi: 10.1016/j.neuropharm.2018.08.013
53.
NasirinezhadF, JergovaS, PearsonJP, et al.Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy. Neuropharmacology, 2015; 95:100–109; doi: 10.1016/j.neuropharm.2014.11.024
54.
LowinT, ApitzM, AndersS, et al.Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner. Arthritis Res Ther, 2015; 17:321; doi: 10.1186/s13075-015-0845-5
55.
SchlosburgJE, KinseySG, LichtmanAH. Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J, 2009; 11(1):39–44; doi: 10.1208/s12248-008-9075-y
56.
ChaillonA, NakazawaM, AndersonC, et al.Effect of cannabis use on human immunodeficiency virus DNA during suppressive antiretroviral therapy. Clin Infect Dis, 2020; 70(1):140–143; doi: 10.1093/cid/ciz387
57.
MilloyMJ, MarshallB, KerrT, et al.High-intensity cannabis use associated with lower plasma human immunodeficiency virus-1 RNA viral load among recently infected people who use injection drugs. Drug Alcohol Rev, 2015; 34(2):135–140; doi: 10.1111/dar.12223
58.
OkaforCN, ZhouZ, BurrellLE, 2nd, et al. Marijuana use and viral suppression in persons receiving medical care for HIV-infection. Am J Drug Alcohol Abuse, 2017; 43(1):103–110; doi: 10.1080/00952990.2016.1191505
59.
RieraR, PachecoRL, Bagattini ÂM, et al. Efficacy and safety of therapeutic use of cannabis derivatives and their synthetic analogs: Overview of systematic reviews. Phytother Res, 2022; 36(1):5–21; doi: 10.1002/ptr.7263
60.
YinL, DinasarapuAR, BorkarSA, et al.Anti-inflammatory effects of recreational marijuana in virally suppressed youth with HIV-1 are reversed by use of tobacco products in combination with marijuana. Retrovirology, 2022; 19(1):10; doi: 10.1186/s12977-022-00594-4
61.
MurrayCH, ChristianDT, MilovanovicM, et al.mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving. Neuropharmacol, 2021; 186:108452; doi: 10.1016/j.neuropharm.2021.108452
