Subjective and Physiological Effects After Controlled Sativex and Oral THC Administration
Open accessAbstract
Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses.
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Oral cannabinoids avoid concentration peaks and with chronic administration, individual differences in bioavailability are overcome.
“The oral cannabinoids administration, on the other hand, avoids concentration peaks and with chronic administration, the individual differences in bioavailability are overcome [23, 33].”
From Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial (2012) · cites this paper as [33]
Oral administration of cannabinoid drugs shows poorer bioavailability than inhalation.
“The oral administration of cannabinoid drugs shows poorer bioavailability than when these drugs are administered by inhalation.”
From Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial (2012) · cites this paper as [33]
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“In our previous Sativex studies, which evaluated cannabis plant extracts rich in CBD and THC, we did not find any significant interaction with THC’s physiological or psychotropic effects [12, 13].”
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“However, the possible effects of CBD or nearly 1:1 combinations of THC and CBD on cannabis-related addictive behaviors remain unclear (Karschner et al., 2011; Prud’homme et al., 2015).”
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“2002), but it may also produce undesired feelings such as anxiety (Arkell et al. 2019; Bhattacharyya et al. 2010; D'Souza et al. 2004; Hunault et al. 2014; Karschner et al. 2011; Zuardi et al. 1982).”
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Salviato, B. Z., Raymundi, A. M., da Silva, T. R., Salemme, B. W., Sohn, J. M. B., de Araujo, F. S., Guimarães, F. S., Bertoglio, L. J., & Stern, C. A. J. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108684 · Cited by 35 · see citing works
Priority Considerations for Medicinal Cannabis-Related Research
Bonn‐Miller, M. O., Pollack, C. V., Casarett, D., Dart, R. C., ElSohly, M. A., Good, L. I., Guzmán, M., Hanuš, L., Hill, K. P., Huestis, M. A., et al. (2019) · Cannabis and Cannabinoid Research · doi:10.1089/can.2019.0045 · Cited by 32 · see citing works
Self-citationTranslational models of cannabinoid vapor exposure in laboratory animals
Moore, C. F., Stiltner, J. W., Davis, C. M., & Weerts, E. M. (2020) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000592 · Cited by 31 · see citing works
“However, multiple human studies using oral or intravenous administration have found no effects of cannabidiol on plasma THC and THC metabolite levels in blood (Nadulski et al., 2005; Bhattacharyya et al., 2010; Karschner et al., 2011).”
BackgroundSchaub, M. P., Haug, S., Wenger, A., Berg, O., Sullivan, R., Beck, T., & Stark, L. (2013) · BMC Psychiatry · doi:10.1186/1471-244x-13-305 · Cited by 30 · see citing works
“recommendations for medical cannabis use [29,30]) will be provided in an appendix accessible after login, along with frequently asked questions and their corresponding answers.”
BackgroundAbuhasira, R., Haviv, Y. S., Leiba, M., Leiba, A., Ryvo, L., & Novack, V. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.01.005 · Cited by 29 · see citing works
Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis
Podda, G., & Constantinescu, C. S. (2012) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2012.721765 · Cited by 29 · see citing works
“It is an inhibitor of the liver CYP3A11, blocking the hydroxylation of THC to its psychoactive metabolite 11-hydroxy-THC, so that THC amounts can be adjusted [20].”
BackgroundInfluentialPabon, E., Rockwood, F., Norman, G. J., & de Wit, H. (2021) · Psychophysiology · doi:10.1111/psyp.13955 · Cited by 30 · see citing works
Ballard, M. E., Gallo, D. A., & de Wit, H. (2013) · Psychopharmacology · doi:10.1007/s00213-012-2924-5 · Cited by 32 · see citing works
“With respect to THC, it also is possible that whole plant cannabis, which contains other chemical compounds in addition to THC, would produce different effects (Zuardi et al. 1982, but see Ilan et al. 2005; Karschner et al. 2011).”
BackgroundGilman, J. M., Lee, S., Kuster, J. K., Lee, M. J., Kim, B. W., van der Kouwe, A. J. W., Blood, A. J., & Breiter, H. C. (2016) · Brain and Behavior · doi:10.1002/brb3.459 · Cited by 26 · see citing works
“…based on a four-item marijuana intoxication scale developed in our laboratory that was designed to assess four signs of acute intoxication (Karschner et al. 2011): increased resting heart rate (>100 beats per minute), congestion of the conjunctival blood vessels (red eyes), slowed…”
MethodJanero, D. R., Lindsley, L., Vemuri, K. V., & Makriyannis, A. (2011) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2011.608063 · Cited by 25 · see citing works
“The main phytocannabinoid agonist of the Cannabis plant, D(9)-THC, can induce subjective feelings of anxiety and euphoria as well as symptoms of psychoses in human subjects [193,194].”
BackgroundPereira, L. K. L., Núñez-Iglesias, M. J., Domínguez-Martís, E. M., López-Ares, D., González‐Peteiro, M., & Novío, S. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17072492 · Cited by 24 · see citing works
Recent Self-Reported Cannabis Use Is Associated With the Biometrics of Delta-9-Tetrahydrocannabinol
Smith, M. J., Alden, E., Herrold, A. A., Roberts, A. G., Stern, D., Jones, J., Barnes, A. J., O’Connor, K. P., Huestis, M. A., & Breiter, H. C. (2018) · Journal of Studies on Alcohol and Drugs · doi:10.15288/jsad.2018.79.441 · Cited by 24 · see citing works
“, 2014, 2016) to evaluate four signs of acute intoxication (Karschner et al., 2011): increased resting heart rate (>100 beats per minute), congestion of conjunctival blood vessels (red eyes), slowed speech response, and giddiness.”
BackgroundMethodSelf-citationIndustrial Applications of Hemp Fiber in Europe and Evolving Regulatory Landscape
Cortés, J. G., Ryu, B. R., Pauli, C. S., Royano, L., & Park, S. (2024) · Journal of Natural Fibers · doi:10.1080/15440478.2024.2435047 · Cited by 27 · see citing works
“Additionally, Nabiximols (Sativex®), an oral spray containing 2.5 mg CBD and 2.7 mg Δ9-THC per dose, was developed specifically to relieve pain (Karschner et al. 2011).”
InfluentialCardiac Complications of Common Drugs of Abuse: Pharmacology, Toxicology, and Management
Gagnon, L. R., Sadasivan, C., Perera, K., & Oudit, G. Y. (2021) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2021.10.008 · Cited by 23 · see citing works
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Current Cannabidiol Safety: A Review
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Pharmacokinetic evaluation of nabiximols for the treatment of multiple sclerosis pain
Tănăsescu, R., & Constantinescu, C. S. (2013) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2013.795542 · Cited by 18 · see citing works
“Recent empirical evidence shows the absence of significant differences in humans between similar oral THC and nabiximols doses with respect to subjective, physiological, and pharmacokinetic effects [44,45].”
BackgroundAnxiety Modulation by Cannabinoids—The Role of Stress Responses and Coping
Haller, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115777 · Cited by 17 · see citing works
“The absolute amount ∆ 9-THC and the baseline anxiety of participants is also relevant for the favorable effects of CBD [155,158].”
BackgroundZhou, H., Peng, X., Hou, T., Zhao, N., Qiu, M., Zhang, X., & Liang, X. (2019) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2019.112218 · Cited by 16 · see citing works
Cogan, P. S. (2019) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2019.1612743 · Cited by 14 · see citing works
“In many cultures, traditional exposure to CBD has come greatly as an artifact of THC dosing, and thus the present pursuit of high dose CBD is an emergent phenomenon with no clear historical point of reference to guide expectations of risk.”
InfluentialSantos, A. B., Scherf, J. R., & Mendes, R. D. C. (2019) · Acta Brasiliensis · doi:10.22571/2526-4338131 · Cited by 13 · see citing works
Medical Cannabis for Headache Pain: a Primer for Clinicians
Duarte, R., Dahmer, S., Sanguinetti, S. Y., Forde, G., Duarte, D. P., & Kobak, L. F. (2021) · Current Pain and Headache Reports · doi:10.1007/s11916-021-00974-z · Cited by 13 · see citing works
Routes of Administration, Pharmacokinetics and Safety of Medicinal Cannabis
O’Brien, K., & Blair, P. (2021) · Springer eBooks · doi:10.1007/978-3-030-78559-8_11 · Cited by 11 · see citing works
Morel, A., Lebard, P., Dereux, A., Azuar, J., Questel, F., Bellivier, F., Cynthia Marie-claire, A., Fatseas, M., Vorspan, F., & Bloch, V. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.565617 · Cited by 9 · see citing works
“Anxiety Another study (43) reported more classical outcome measures in terms of heart rate and blood pressure and several self-rated visual analog of mood states including good drug effect and high anxiety, but also the repetitive assessment state anxiety part of the Spielberger State–Trait Anxiety Inventory (38).”
BackgroundRobert, M., Graves, L. E., Allen, V. M., Dama, S., Gabrys, R. L., Tanguay, R. L., Turner, S. D., Green, C. R., & Cook, J. L. (2022) · Journal of Obstetrics and Gynaecology Canada · doi:10.1016/j.jogc.2022.01.012 · Cited by 8 · see citing works
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“THC has been shown to be associated with psychotropic effects as well as tachycardia, anxiety, dysphoria, sedation, and depression [41].”
BackgroundRole of Cannabis in the Incidence of Myocardial Infarction: A Review
Banerjee, A., Gandhi, A. B., Antony, I., Alexander, J., Hisbulla, M., Kannichamy, V., Kaleem, I., Mishra, V., & Khan, S. (2020) · Cureus · doi:10.7759/cureus.11097 · Cited by 7 · see citing works
“Acute exposure to marijuana will increase blood pressure and can also trigger atrial fibrillation [22].”
BackgroundCannabinoids and Their Role in Chronic Pain Treatment: Current Concepts and a Comprehensive Review.
Shehata, I., Hashim, A., Elsaeidy, A., Nair, A. M., Urits, I., Viswanath, O., Kaye, A., & Habib, M. (2022) · Health Psychology Research · doi:10.52965/001c.35848 · Cited by 7 · see citing works
Drug/Natural Products-Related problems in Elderly
Zailani, I. S., Moshawih, S., Kifli, N., Wahab, M. S. A., Lee, K. S., & Ming, L. C. (2022) · Progress in Drug Discovery & Biomedical Science · doi:10.36877/pddbs.a0000312 · Cited by 6 · see citing works
Cannabis Use Disorder as a Developmental Disorder
Tomko, R., Williamson, A., McRae-Clark, A., & Gray, K. M. (2018) · Cannabis Use Disorders · doi:10.1007/978-3-319-90365-1_18 · Cited by 6 · see citing works
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“High doses of THC increased anxiety in humans as well [105–111].”
BackgroundBudney, A. J., & Stanger, C. (2012) · Cited by 5 · see citing works
A Systematic Review of Cannabis and Anxiety: Chicken or Egg?
Blyth, L. G., Seal, C., Sorkhou, M., Lowe, D. J. E., & George, T. P. (2025) · Current Addiction Reports · doi:10.1007/s40429-025-00650-x · Cited by 4 · see citing works
“Several studies in this review support this finding, including the demonstration that higher doses of THC are linked to more pronounced anxiety symptoms [32, 33, 56].”
Part I: Current Legislation, Scientific Literature Review, and Nursing Implications
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Endocannabinoid system components: A crucial role in regulation of disease
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“THC-infused edible products and other oral formulations are also available, and at least one company has developed an oral-mucosal cannabis extract spray [11].”
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“Studies conducted in humans have shown no significant differences from the effects observed in animal studies (31, 32).”
ResultLisano, J. K., Flores, V. A., Kisiolek, J. N., & Stewart, L. K. (2022) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0000000000004297 · Cited by 3 · see citing works
“19.3 6 4.2 18.3 6 4.5 20.3 6 3.8 0.85 0.48 Waist-to-hip ratio 0.74 6 0.03 0.74 6 0.02 0.74 6 0.05 0.26 0.11 Resting SBP (mm Hg) 115.3 6 11.7 111 6 13.3 119.7 6 8.3 0.07 0.80 Resting DBP (mm Hg) 71.3 6 6.8 70.3 6 7.4 72.3 6 6.4 0.50 0.29 *CU 5 cannabis users; NU 5 noncannabis users.”
BackgroundInfluentialCaring for Patients Using Medical Marijuana
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“Sublingual and mucosal sprays directly access the bloodstream and, as a result, oromucosal doses have less dosage variability than smoked cannabis and edibles but are limited by slower absorption and lower rate of THC delivery to the brain (Karschner et al., 2011).”
BackgroundAPRNs Certifying a Medical Marijuana Qualifying Condition
(2018) · Journal of Nursing Regulation · doi:10.1016/s2155-8256(18)30097-8 · Cited by 2 · see citing works
Medical Marijuana Education in APRN Nursing Programs
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Treatment of Psychosomatic Symptoms
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Cannabidiol: de nieuwe haarlemmerolie of een hype?
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Cardiac Disorders Associated with Cannabis: A Review of Literature
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Cannabinoids Pharmacology, Abuse, and Addiction
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Self-citation
- Authors
- Karschner, E. L., Darwin, W. D., McMahon, R. P., Liu, F., Wright, S., Goodwin, R. S., & Huestis, M. A.
- Affiliations
- National Institutes of Health (US)
- GW Pharmaceuticals (United Kingdom) (GB)
- Corresponding author
- Huestis, M A
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2011-02-02
- Volume
- 89
- Issue
- 3
- Pages
- 400-407
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- PMC
- PMC3836266
- OpenAlex
- W2143261008
- Cited by
- 117
- References
- 33
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 15 · 2021: 12 · 2020: 13 · 2019: 8 · 2018: 13 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 9 · 2013: 6 · 2012: 8
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (ZIADA000541)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Keywords
- Sativex, cannabidiol, tetrahydrocannabinol, pharmacodynamics, heart rate, anxiety, euphoria, cannabis smoking, drug delivery routes, adverse events
- MeSH terms
- Administration, Oral, Adult, Anxiety, Brain, Cannabidiol, Dose-Response Relationship, Drug, Double-Blind Method, Drug Combinations, Female, Heart Rate, Humans, Male, Mouth Mucosa, Plant Extracts, Psychotropic Drugs, Dronabinol, Tissue Distribution, Young Adult
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