Practical considerations in medical cannabis administration and dosing

Published:January 04, 2018DOI:


      • Cannabis need and tolerance depends on prior patient experience and underlying endocannabinoid tone.
      • ‘Start low and go slow!’
      • Doses >20–30 mg THC/day before tolerance risk psychoactive and other AEs.
      • Patients should never confuse psychoactivity with efficacy.
      • Correct dose is the lowest that produces therapeutic benefit without associated AEs.


      Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.

      Graphical abstract


      5-HT1A (serotonin 1A receptor), AE (adverse events), AIDS (acquired immunodeficiency syndrome), CB1 (cannabinoid-one receptor), CB2 (cannabinoid-two receptor), CBD (cannabidiol), CBDA (cannabidiolic acid), CRISP-R (Clustered Regularly Interspaced Short Palindromic Repeats), ECS (endocannabinoid system), GAP (Good Agricultural Practice), GCP (Good Clinical Practice), GMP (Good Manufacturing Practice), HIV (human immunodeficiency virus), MS (multiple sclerosis), PAH (polycyclic aromatic hydrocarbon), RCT (randomised controlled trial), THC (Δ9-tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), TRPV1 (transient receptor potential cation channel vanilloid subfamily receptor 1), USAN (United States Adopted Name)


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        • Russo E.B.
        The pharmacological history of Cannabis.
        in: Pertwee R. Handbook of cannabinoids. Oxford University Press, Oxford, United Kingdom2014: 23-43
        • Russo E.B.
        History of cannabis and its preparations in saga, science and sobriquet.
        Chem Biodivers. 2007; 4: 2624-2648
        • Pacher P.
        • Batkai S.
        • Kunos G.
        The endocannabinoid system as an emerging target of pharmacotherapy.
        Pharmacol Rev. 2006; 58: 389-462
        • Evanoff A.B.
        • Quan T.
        • Dufault C.
        • Awad M.
        • Bierut L.J.
        Physicians-in-training are not prepared to prescribe medical marijuana.
        Drug Alcohol Depend. 2017; 180: 151-155
        • Frieden T.R.
        Evidence for health decision making - beyond randomized, controlled trials.
        N Engl J Med. 2017; 377: 465-475
        • Upton R.
        • Craker L.
        • ElSohly M.
        • Romm A.
        • Russo E.
        • Sexton M.
        Cannabis inflorescence: Cannabis spp.: standards of identity, analysis and quality control.
        Scotts Valley, CA, USA, American Herbal Pharmacopoeia2013
        • Russo E.B.
        Current therapeutic cannabis controversies and clinical trial design issues.
        Front Pharmacol. 2016; 7: 309
        • Russo E.B.
        • Marcu J.
        Cannabis pharmacology: the usual suspects and a few promising leads.
        Adv Pharmacol. 2017; 80: 71-138
        • Di Marzo V.
        • Melck D.
        • Bisogno T.
        • De Petrocellis L.
        Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action.
        Trends Neurosci. 1998; 21: 521-528
        • Laprairie R.B.
        • Bagher A.M.
        • Kelly M.E.
        • Denovan-Wright E.M.
        Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.
        Br J Pharmacol. 2015; 172: 4790-4805
        • Russo E.B.
        Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.
        Br J Pharmacol. 2011; 163: 1344-1364
        • Lewis M.A.
        • Russo E.B.
        • Smith K.M.
        Pharmacological foundations of Cannabis chemovars: no “strain”, no gain.
        Planta Med. 2017; ([in press, PubMed:])
        • Potter D.J.
        • Clark P.
        • Brown M.B.
        Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology.
        J Forensic Sci. 2008; 53: 90-94
        • Mehmedic Z.
        • Chandra S.
        • Slade D.
        • Denham H.
        • Foster S.
        • Patel A.S.
        • et al.
        Potency trends of delta(9)-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008.
        J Forensic Sci. 2010; 55: 1209-1217
        • Verhoeckx K.C.
        • Korthout H.A.
        • van Meeteren-Kreikamp A.P.
        • Ehlert K.A.
        • Wang M.
        • van der Greef J.
        • et al.
        Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways.
        Int Immunopharmacol. 2006; 6: 656-665
        • Rock E.M.
        • Sticht M.A.
        • Parker L.A.
        Effects of phytocannabinoids on nausea and vomiting.
        in: Pertwee R.G. Handbook of cannabis. Oxford University Press, Oxford, UK2014: 435-454
        • Nadal X.
        • Del Rio C.
        • Casano S.
        • Palomares B.
        • Ferreiro-Vera C.
        • Navarrete C.
        • et al.
        Tetrahydrocannabinolic acid is a potent PPARgamma agonist with neuroprotective activity.
        Br J Pharmacol. 2017; 174: 4263-4276
        • Sulak D.
        • Saneto R.
        • Goldstein B.
        The current status of artisanal Cannabis for the treatment of epilepsy in the United States.
        Epilepsy Behav. 2017; 70: 328-333
        • Bolognini D.
        • Rock E.M.
        • Cluny N.L.
        • Cascio M.G.
        • Limebeer C.L.
        • Duncan M.
        • et al.
        Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation.
        Br J Pharmacol. 2013; 168: 1456-1470
        • Rock E.M.
        • Limebeer C.L.
        • Petrie G.N.
        • Williams L.A.
        • Mechoulam R.
        • Parker L.A.
        Effect of prior foot shock stress and Delta9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats.
        Psychopharmacology (Berl). 2017; 234: 2207-2217
        • Huestis M.A.
        Human cannabinoid pharmacokinetics.
        Chem Biodivers. 2007; 4: 1770-1804
        • Russo E.B.
        • Hohmann A.G.
        Role of cannabinoids in pain management.
        in: Deer T. Gordin V. Comprehensive treatment of chronic pain by medical, interventional and behavioral approaches. Springer, New York2013: 181-197
        • Tashkin D.P.
        Effects of marijuana smoking on the lung.
        Ann Am Thorac Soc. 2013; 10: 239-247
        • Abrams D.I.
        • Vizoso H.P.
        • Shade S.B.
        • Jay C.
        • Kelly M.E.
        • Benowitz N.L.
        Vaporization as a smokeless cannabis delivery system: a pilot study.
        Clin Pharmacol Ther. 2007; 82: 572-578
        • Bloor R.N.
        • Wang T.S.
        • Spanel P.
        • Smith D.
        Ammonia release from heated ‘street’ cannabis leaf and its potential toxic effects on cannabis users.
        Addiction. 2008; 103: 1671-1677
        • Earleywine M.
        • Smucker Barnwell S.
        Decreased respiratory symptoms in cannabis users who vaporize.
        Harm Reduct J. 2007; 4: 11
        • Loflin M.
        • Earleywine M.A.
        New method of cannabis ingestion: the dangers of dabs?.
        Addict Behav. 2014; 39: 1430-1433
        • National Academies of Sciences Engineering and Medicine (U.S.)
        Committee on the health effects of marijuana: an evidence review and research agenda. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research.
        the National Academies Press, Washington, DC2017: 1 (online resource, xviii, 468 pages)
        • Devinsky O.
        • Cross J.H.
        • Laux L.
        • Marsh E.
        • Miller I.
        • Nabbout R.
        • et al.
        Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.
        N Engl J Med. 2017; 376: 2011-2020
        • Leweke F.M.
        • Piomelli D.
        • Pahlisch F.
        • Muhl D.
        • Gerth C.W.
        • Hoyer C.
        • et al.
        Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.
        Transl Psychiatry. 2012; 2e94
        • Hill M.N.
        • Bierer L.M.
        • Makotkine I.
        • Golier J.A.
        • Galea S.
        • McEwen B.S.
        • et al.
        Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks.
        Psychoneuroendocrinology. 2013; 38: 2952-2961
        • Volicer L.
        • Stelly M.
        • Morris J.
        • McLaughlin J.
        • Volicer B.J.
        Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease.
        Int J Geriatr Psychiatry. 1997; 12: 913-919
        • Bergamaschi M.M.
        • Queiroz R.H.
        • Chagas M.H.
        • de Oliveira D.C.
        • De Martinis B.S.
        • Kapczinski F.
        • et al.
        Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients.
        Neuropsychopharmacology. 2011; 36: 1219-1226
        • Ware M.A.
        • Wang T.
        • Shapiro S.
        • Collet J.P.
        • team Cs
        Cannabis for the management of pain: assessment of safety study (COMPASS).
        J Pain. 2015; 16: 1233-1242
        • Russo E.B.
        • Mathre M.L.
        • Byrne A.
        • Velin R.
        • Bach P.J.
        • Sanchez-Ramos J.
        • et al.
        Chronic cannabis use in the compassionate investigational new drug program: an examination of benefits and adverse effects of legal clinical cannabis.
        J Cannabis Ther. 2002; 2: 3-57
        • Russo E.
        Cannabis treatments in obstetrics and gynecology: a historical review.
        J Cannabis Ther. 2002; 2: 5-35
        • Grant K.S.
        • Petroff R.
        • Isoherranen N.
        • Stella N.
        • Burbacher T.M.
        Cannabis use during pregnancy: pharmacokinetics and effects on child development.
        Pharmacol Ther. 2017; ([in press])
        • Conner S.N.
        • Bedell V.
        • Lipsey K.
        • Macones G.A.
        • Cahill A.G.
        • Tuuli M.G.
        Maternal marijuana use and adverse neonatal outcomes: a systematic review and meta-analysis.
        Obstet Gynecol. 2016; 128: 713-723
        • Sellers E.M.
        • Schoedel K.
        • Bartlett C.
        • Romach M.
        • Russo E.B.
        • Stott C.G.
        • et al.
        A multiple-dose, randomized, double-blind, placebo-controlled, parallel-group QT/QTc study to evaluate the electrophysiologic effects of THC/CBD spray.
        Clin Pharmacol Drug Dev. 2013; 2: 285-294
        • Herkenham M.
        • Lynn A.B.
        • Little M.D.
        • Johnson M.R.
        • Melvin L.S.
        • de Costa B.R.
        • et al.
        Cannabinoid receptor localization in brain.
        Proc Natl Acad Sci U S A. 1990; 87: 1932-1936
        • Wang T.
        • Collet J.P.
        • Shapiro S.
        • Ware M.A.
        Adverse effects of medical cannabinoids: a systematic review.
        CMAJ. 2008; 178: 1669-1678
        • Russo E.B.
        • Etges T.
        • Stott C.
        • Wright S.
        • Mohammed A.
        • Robson P.
        Sativex safety profile is improving over time. 21st Annual Symposium on the Cannabinoids.
        International Cannabinoid Research Society, St. Charles, IL, USA2011: GW1
        • Novotna A.
        • Mares J.
        • Ratcliffe S.
        • Novakova I.
        • Vachova M.
        • Zapletalova O.
        • et al.
        A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R))), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis.
        Eur J Neurol. 2011; 18: 1122-1131
        • Favrat B.
        • Menetrey A.
        • Augsburger M.
        • Rothuizen L.
        • Appenzeller M.
        • Buclin T.
        • et al.
        Two cases of “cannabis acute psychosis” following the administration of oral cannabis.
        BMC Psychiatry. 2005; 5: 17
        • Zendulka O.
        • Dovrtelova G.
        • Noskova K.
        • Turjap M.
        • Sulcova A.
        • Hanus L.
        • et al.
        Cannabinoids and cytochrome P450 interactions.
        Curr Drug Metab. 2016; 17: 206-226
        • Stott C.
        • White L.
        • Wright S.
        • Wilbraham D.
        • Guy G.A.
        Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers.
        2. SpringerPlus, 2013: 236
        • Ujvary I.
        • Hanus L.
        Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy.
        Cannabis Cannabinoid Res. 2016; 1: 90-101
        • Wade D.T.
        • Makela P.M.
        • House H.
        • Bateman C.
        • Robson P.J.
        Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis.
        Mult Scler. 2006; 12: 639-645
        • Notcutt W.
        • Langford R.
        • Davies P.
        • Ratcliffe S.
        • Potts R.
        A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex(R) (nabiximols).
        Mult Scler. 2012; 18: 219-228
        • Serpell M.G.
        • Notcutt W.
        • Collin C.
        Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis.
        J Neurol. 2013; 260: 285-295
        • Russo E.B.
        Cannabis and epilepsy: an ancient treatment returns to the fore.
        Epilepsy Behav. 2017; 70: 292-297
        • Devinsky O.
        • Marsh E.
        • Friedman D.
        • Thiele E.
        • Laux L.
        • Sullivan J.
        • et al.
        Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
        Lancet Neurol. 2016; 15: 270-278
        • Russo E.B.
        • Guy G.W.
        • Robson P.J.
        Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine.
        Chem Biodivers. 2007; 4: 1729-1743
        • Johnson J.R.
        • Burnell-Nugent M.
        • Lossignol D.
        • Ganae-Motan E.D.
        • Potts R.
        • Fallon M.T.
        Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.
        J Pain Symptom Manage. 2010; 39: 167-179
        • Portenoy R.K.
        • Ganae-Motan E.D.
        • Allende S.
        • Yanagihara R.
        • Shaiova L.
        • Weinstein S.
        • et al.
        Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial.
        J Pain. 2012; 13: 438-449
        • Guzman M.
        • Duarte M.J.
        • Blazquez C.
        • Ravina J.
        • Rosa M.C.
        • Galve-Roperh I.
        • et al.
        A pilot clinical study of delta(9)-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.
        Br J Cancer. 2006; 95: 197-203
        • Foroughi M.
        • Hendson G.
        • Sargent M.A.
        • Steinbok P.
        Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas–possible role of Cannabis inhalation.
        Childs Nerv Syst. 2011; 27: 671-679
        • Singh Y.
        • Bali C.
        Cannabis extract treatment for terminal acute lymphoblastic leukemia with a Philadelphia chromosome mutation.
        Case Rep Oncol. 2013; 6: 585-592
        • GW Pharmaceuticals
        GW pharmaceuticals achieves positive results in phase 2 proof of concept study in glioma.
        • Torres S.
        • Lorente M.
        • Rodriguez-Fornes F.
        • Hernandez-Tiedra S.
        • Salazar M.
        • Garcia-Taboada E.
        • et al.
        A combined preclinical therapy of cannabinoids and temozolomide against glioma.
        Mol Cancer Ther. 2011; 10: 90-103
        • Caffarel M.M.
        • Andradas C.
        • Mira E.
        • Perez-Gomez E.
        • Cerutti C.
        • Moreno-Bueno G.
        • et al.
        Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition.
        Mol Cancer. 2010; 9: 196
        • Holdcroft A.
        • Maze M.
        • Dore C.
        • Tebbs S.
        • Thompson S.
        A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.
        Anesthesiology. 2006; 104: 1040-1046
        • Hampson A.J.
        • Grimaldi M.
        • Axelrod J.
        • Wink D.
        Cannabidiol and (−)delta9-tetrahydrocannabinol are neuroprotective antioxidants.
        Proc Natl Acad Sci U S A. 1998; 95: 8268-8273
        • Fernandez-Ruiz J.
        • Moreno-Martet M.
        • Rodriguez-Cueto C.
        • Palomo-Garo C.
        • Gomez-Canas M.
        • Valdeolivas S.
        • et al.
        Prospects for cannabinoid therapies in basal ganglia disorders.
        Br J Pharmacol. 2011; 163: 1365-1378
        • Venderova K.
        • Ruzicka E.
        • Vorisek V.
        • Visnovsky P.
        Survey on cannabis use in Parkinson's disease: subjective improvement of motor symptoms.
        Mov Disord. 2004; 19: 1102
        • Wong S.S.
        • Wilens T.E.
        Medical cannabinoids in children and adolescents: a systematic review.
        Pediatrics. 2017; 140 (pii: e20171818)
        • Lorenz R.
        On the application of cannabis in paediatrics and epileptology.
        Neuroendocrinol Lett. 2004; 25 ([In Press])
        • Gottschling S.
        Cannbinoide bei Kindern. Gute Erfahrungen bei Schmerzen, Spastik und in der Onkologie. Angewandte Schmerztherapie und Palliativmedizin.
        2011: 55-57
        • Abrahamov A.
        • Mechoulam R.
        An efficient new cannabinoid antiemetic in pediatric oncology.
        Life Sci. 1995; 56: 2097-2102
        • Muller-Vahl K.R.
        • Emrich H.M.
        Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia.
        Expert Rev Neurother. 2008; 8: 1037-1048
        • Robson P.J.
        • Guy G.W.
        • Di Marzo V.
        Cannabinoids and schizophrenia: therapeutic prospects.
        Curr Pharm Des. 2014; 20: 2194-2204
        • Russo E.B.
        Handbook of psychotropic herbs: A scientific analysis of herbal remedies for psychiatric conditions.
        Haworth Press, Binghamton, NY2001
        • Russo E.B.
        The role of cannabis and cannabinoids in pain management.
        in: Cole B.E. Boswell M. Weiner's pain management: a practical guide for clinicians. 7th ed. CRC Press, Boca Raton, FL2006: 823-844
        • Cichewicz D.L.
        Synergistic interactions between cannabinoid and opioid analgesics.
        Life Sci. 2004; 74: 1317-1324
        • Lucas P.
        • Walsh Z.
        Medical cannabis access, use, and substitution for prescription opioids and other substances: a survey of authorized medical cannabis patients.
        Int J Drug Policy. 2017; 42: 30-35
        • Reiman A.
        Cannabis as a substitute for alcohol and other drugs.
        Harm Reduct J. 2009; 6: 35
        • Haroutounian S.
        • Ratz Y.
        • Ginosar Y.
        • Furmanov K.
        • Saifi F.
        • Meidan R.
        • et al.
        The effect of medicinal cannabis on pain and quality of life outcomes in chronic pain: a prospective open-label study.
        Clin J Pain. 2016; 32: 1036-1043
        • Bachhuber M.A.
        • Saloner B.
        • Cunningham C.O.
        • Barry C.L.
        Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999–2010.
        JAMA Intern Med. 2014; 174: 1668-1673
        • Bradford A.C.
        • Bradford W.D.
        Medical marijuana laws reduce prescription medication use in Medicare part D.
        Health Aff (Millwood). 2016; 35: 1230-1236
        • Bradford A.C.
        • Bradford W.D.
        Medical marijuana laws may be associated with a decline in the number of prescriptions for Medicaid enrollees.
        Health Aff (Millwood). 2017; 36: 945-951
        • Johnson J.R.
        • Lossignol D.
        • Burnell-Nugent M.
        • Fallon M.T.
        An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.
        J Pain Symptom Manage. 2013; 46: 207-218
        • Abrams D.I.
        • Couey P.
        • Shade S.B.
        • Kelly M.E.
        • Benowitz N.L.
        Cannabinoid-opioid interaction in chronic pain.
        Clin Pharmacol Ther. 2011; 90: 844-851
        • Rekand T.T.H.C.
        CBD spray and MS spasticity symptoms: data from latest studies.
        Eur Neurol. 2014; 71: 4-9