From Forensics to Clinics

Transcription

1 My Last 40 Years of Cannabis Research From Forensics to Clinics Rudolf Brenneisen, PhD, Prof University of Bern, Dept. Clin. Research Swiss Task Force for Cannabinoids in Medicine STCM Swiss Academy of Pharm. Sciences SAPhS

2 Scientific output the last 50 years N = 55 out of my lab

3 How and why it started in the 1970s - Forensics Police: «Swiss cannabis rather not as intoxicating as chocolate; THC content?»

4 HPLC requires standards a real challenge, as no cannabinoid acid standards available 2-step analysis required, before and after decarbox [Brenneisen, Pharm Acta Helv 1984]

5 Home-made THCA [Lehmann & Brenneisen, Phytochem Anal 1992]

6 Home-grown Cannabis to

7 start breeding and phytochemical research 4 Early ripe «Boliva» Total THC [%] Early ripe «Italia» Late ripe «Africa» Late ripe «Hellas» May June July August September Oct. THC content depending on genetic and ecological factors Swiss climate requires early ripening ecotypes for high THC [Brenneisen & Kessler, Pharm Acta Helv 1987]

8 Linking research and forensic service Lead Cannabinoid THC THC + CBD CBD THCV Drug Type Intermediate Type Fiber Type Propyl Isomer Type Chemotyping of forensic interest 3 lead cannabinoids, 4 chemotypes CBD type not scheduled [Brenneisen, Arch Kriminol 1986]

9 Linking research and forensic service Chemotyping and potency of Swiss Cannabis [Brenneisen, Arch Kriminol 1986]

10 Ideal places for a postdoc stay DEA Special Testing Lab, McLean VA to get the best forensic-analytical training Mahmoud A. ElSohly s Lab University of Mississippi, Oxford MS to get the best phytochemical and botanical training at the only legal US production facility

11 Tracing origin by chemical fingerprints GC/MS profiling pa 180 Int. Standard THC 160 Terpenoids Cannabinoids CBD CBN Time [min] min Only terpenoids suited for chemometrics [Brenneisen & ElSohly, J Forensic Sci 1988; DEA project; US patent no , 1993; Lehmann, PhD thesis 1995]

12 Tracing origin by chemical fingerprints GC/MS clustering by chemometrics/pca domestic vs. foreign Switzerland I-IV vs.nl Coffee shops PCA clusters enable tracing of origin [Brenneisen & ElSohly, J Forensic Sci 1988; DEA project; US patent no , 1993; Lehmann, PhD thesis 1995]

13 HPLC profiling chemotyping, qc, acids neutrals CBD-type artefacts THC-CBD-type HPLC ideal for full cannabinoids profiling and chemotyping [Lehmann & Brenneisen 1995]

14 but also useful in forensics [UNDCP 1987 & 1993]

15 THC solubility in water the challenge HP-β-CD [g/100 ml] THC [µg/ml] 0 n.d HP-β-CD + HPMC THC-CBD-type Complexing with cyclextrins or cellulose derivatives makes THC water souble [Jarho et al, Life Sci 1998]

16 Human pharmacokinetics oral vs. inh vs. iv Pulmonal application, liquid aerosol 1.6 mg THC mg CBD mg lidocaine Very fast and efficient absorption by lungs [Naef, PhD thesis, 2004; Naef et al, J Pharm Sci 2004; Meyer et al, Med Cann Cannabinoids 2018]

17 Human pharmacokinetics oral vs. inh vs. iv Parenteral application, injection solution 1.6 mg THC mg CBD THC carboxylic acid long-term metabolite [Naef, PhD thesis, 2004; Naef et al, J Pharm Sci 2004; Meyer et al, Med Cann Cannabinoids 2018]

18 Human pharmacokinetics oral vs. inh vs. iv THC plasma profiles, t max and C max Plasma conc. [ng/ml] mg THC orally 3.75 mg THC pulmonally 3.75 mg THC intravenously Time [min] T max inhal parenteral, oral much delayed

19 Human Pharmacokinetics inh vs. iv 1.6 mg THC mg CBD, bioavailability Pulmonal bioavailability 3-10 times higher than oral

20 Pulmonal tolerability 1.6 mg THC mg CBD mg lidocaine lidocaine CBD Psychological and physiological side-effects of inhaled THC reduced by CBD and lidocaine

21 THC better than the gold standard? Experimental acute pain conditions (electrical stimulation) Deviation from baseline [ MW ± SEM; % ] Baseline Time [min] Placebo THC Morphine THC + Morphine THC alone not effective, even producing hyperalgesia, in combination with morphine slightly analgesic [Naef et al, Pain 2003]

22 THC to treat spasticity (pilot) 2 paralyzed patients, mg oral THC, multiple dosing, mg rectal THC-hemisuccinate Oral and rectal THC increase passive mobility of paralyzed patients [Egli et al, Int J Clin Pharm Ther 1996]

23 THC to treat spasticity (main) 25 paralyzed patients, 30 mg/d oral THC, 40 mg/d rectal THC-HS, placebo, 6 weeks Oral and rectal THC decrease muscle spasms of paralyzed patients [Hagenbach et al, Spinal Cord 2007]

24 THC to treat PONV Gynecology patients, 10 mg iv THC after last suture iv THC decreases post-anesthesia side-effects [Kleine-Brueggeney et al, Anesth Analg 2015]

25 THC to treat RLS Outpatients, positive experience after smoking cannabis before sleeping, self-treatment No significant effect after 20 mg oral THC, controlled clinical setting No significant effect after oral THC, trial should be repeated with Cannabis-based medicine [Mathys et al, IACM Conference, Leiden 2005]

26 THC to treat ALS 9 ALS patients, 5 and 10 mg oral THC PK-PD population modeling Psychological and somatic adverse effects dosedepending High interindividual PK variability requires individual dose titration in ALS patients [Joerger et al, Drug Metab Lett 2012; Fagagnini, MD thesis]

27 First and last Swiss clinical trial with joints WADA 2004: Cannabis listed as doping Switzerland: 50% of pos. doping cases due to cannabis Performance-enhancing or rather medication to treat training-stress symptoms or recreational use? Should Cannabis be revised as wrong target analyte? [Brenneisen et al, Anal Bioanal Chem 2010]

28 The kinetic Cannabis doping trap 12 THC THC-OH THC-COOH 10 No. Subjects of subjects [N] Proposed target analyte (active, short-term) WADA target analyte (long-term, inactive) Time Time [h] [h] THC and not THC-COOH should be the target analyte in urine to detect recent Cannabis doping [Brenneisen et al, Anal Bioanal Chem 2010]

29 THC-glucuronide as doping target analyte No prediction of Cannabis application time-based on carboxy-thc metabolite, also resulting from out-of-competition use THC-glucuronide recommended LC-MS/MS target analyte as indicator for in-competition Cannabis use [Mareck et al, Drug Test Anal 2009]

30 THC and the brain (1): dopamine release 11 healthy subjects, 2.5 mg iv THC vs placebo, double-blind, SPET scans Positive psychotic symptoms not related to dopamine release No significant increase of dopamine release Dopamine does not play a central role for THC-elicited psychoses [Barkus et al, J Psychopharmacol 2010]

31 THC and the brain (2): pro-psychotic? 16 healthy subjects, 1.25 mg iv THC vs placebo, double-blind, EEG THC evoked positive and negative psychotic symptoms Pro-psychotic effects might be related to impaired neuronal network dynamics and frontal lobes communication [Morrison et al, Neuropsychopharmacol 2011]

32 THC and the brain (3): schizophrenigenic? Synchronisation of neuronal oszillation is significantly impaired after 1.25 mg iv THC Degree of disorder in relation to THC-induced symptoms (anxiety, paranoia, perceptual disorders, etc.) Does THC modulate a neuronal substrate similar to schizophrenia? Biomarker for development of new antipsychotic drugs? [Stone et al, Mol Psych 2012]

33 THC and the brain (4): can Cannabis cause paranoia? 121 vulnerable subjects, 1.5 mg iv THC THC increases negative effects - such as anxiety, worry, depression, negative thoughts, anomalous experiences - and decreases working memory capacity as well as triggers paranoia soughts [Freeman et al, Schizophrenia Bull 2015]

34 THC and the brain (5): CBD + THC anti-psychotic State Social Paranoia Scale, SSPS Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment [Englund et al, J Psychopharmacol 2013]

35 Vaporization good option? Vaporizers should be validated by their vapor release and decarboxylation performance [Lanz & Brenneisen, Plos one 2016]

36 ECS and liver diseases

37 ECS and liver diseases CB1-R modulates alcohol-induced liver fibrosis AEA and 2-AG in plasma of patients with chronic hepatitis C Hepatitis C viral infection directly affects ECS ECS or in chronic liver damage? Endocannabinoids immunosuppressive and profibrogenic? ECS a therapeutic target in chronic HCV infection? [Patsenker et al, Mol Med 2011; Patsenker et al, Int J Mol Sci 2015]

38 ECS analytical pitfalls and challenges GC/MS of Eendocannabinoids in blood of healthy subjects AG AEA Min on ice In vivo and in vitro factors, such as food and plasma handling, influence the endocannabinoid plasma levels [Lanz et al, Med Cann Cannabinoids 2018]

39 What next? A migraine project to come CB 1 X Aimovig Novartis (immunization) THC Calcitonin generelated peptide (CGRP) Anti-migraine effect of THC via pathological key-mechanism, similar to aimovig? [Durham 2004; Akerman 2004]

40 What next? A new journal [MCA Karger]

41 What next? STCM Conference 3.0

42 Take-home message From a very personal perspective: In contrast to the controlled therapeutic and recreational use of Cannabis its research implicates a significant addiction potential!

43 The famous spider experiment LSD Cannabis Mescalin Coffee [Mardikar 1969]

44 Thank you for listening! Cannabis is also good for digestion, no study needed