Peter Reynolds

The life and times of Peter Reynolds

Posts Tagged ‘British Pharmacological Society

Bringing Cannabis Back Into The Medicine Cabinet

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Professor Les Iversen delivers the Inaugural President’s Public Lecture during the BPS Winter Meeting, London 2010.

Prof. Iversen is the current chairman of the Advisory Council on the Misuse of Drugs and a founder council member of the British Medicinal Cannabis Register.  He is also the author of many publications and books on cannabis.  He is famous for his article in The Times headlined “Cannabis.  Why It’s Safe” and for saying that cannabis is “one of the safer recreational drugs”.

He walks a courageous and tricky tightrope between science and his ACMD role.  He is the government’s chief drug adviser so at least we know they are getting good advice even if they don’t act on it.

You can watch the lecture here.

Professor Iversen has also provided me with a copy of his Powerpoint presentation from the lecture which you can download here.

Cannabis And Cannabinoids: Pharmacology, Medicalization And Recreational Use

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Reproduced from Pharmacology Matters,
the Newsletter of the British Pharmacological Society
Volume 3 Issue 2, December 2010

By Professor Roger Pertwee

Discovery of Δ9-tetrahydrocannabinol

Cannabis has been used as a medicine, for religious ceremonies and recreationally for over 5000 years. Indeed, an alcohol-containing tincture of cannabis (Figure 1) was a licensed medicine in the UK until its withdrawal in the early 1970’s.

In contrast, the discovery that cannabis contains (–)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and that many of the effects experienced when cannabis is taken recreationally are caused by this ‘phytocannabinoid’ was made less than 100 years ago (Pertwee, 2006). These effects include altered mood (usually euphoria); altered perception such that colours seem brighter, music more pleasant and ‘felt time’ appears to pass more slowly than ‘clock time’; an increased desire for sweet food (the ‘munchies’); changes in thought processes; impaired memory…and eventual drowsiness. They can also include increased heart rate, a lowering of blood pressure resulting in dizziness and, at high doses, hallucinations and feelings of paranoia. There is good evidence too that Δ9-THC targets the reward centres of the brain in a manner that can lead to psychological dependence, and that abrupt termination of repeated use of cannabis or Δ9-THC can trigger a transient physical withdrawal syndrome that in abstaining recreational cannabis users most commonly includes disturbed sleep, reduced appetite, restlessness, irritability, sweating, chills, a feverish feeling and nausea.

Some Cannabinoid Pharmacology

The discovery of Δ9-THC was followed by the development of synthetic compounds capable of inducing Δ9-THC-like effects. Results obtained from pharmacological research with some of these compounds culminated in the discovery that they produce many of their central effects by activating specific sites on nerve terminals called cannabinoid CB1 receptors in a manner that influences the normal functioning of the brain (Pertwee, 2006). This finding prompted a search for molecules within our own bodies that can activate these receptors and, in 1992, led to a second major discovery – that we do indeed produce and release such molecules. The first of these ‘endocannabinoids’ to be identified was an ethanolamide of the omega-6 unsaturated fatty acid, arachidonic acid. It was named
‘anandamide’, ananda being the Sanskrit word for internal bliss. It has subsequently emerged that there is at least one other cannabinoid receptor (CB2), that there are other endocannabinoids, and that this ‘endocannabinoid system’ of receptors and endogenous receptor activators plays major roles in the control of our health and in ameliorating unwanted symptoms such as pain.

The search is now on for additional cannabinoid receptors and endocannabinoids. Indeed, we have obtained evidence that ethanolamides, which are converted in our bodies from omega-3 polyunsaturated fatty acids that are found, for example, in fish oil, can both activate cannabinoid receptors and attack cancer cells (Brown et al., 2010).

The Medicalization Of Cannabinoids

Fig. 1. Tincture Of Cannabis

Individual cannabinoids first entered the clinic in the 1980’s (Crowther et al., 2010). The first of these was Nabilone (Cesamet), a synthetic Δ9-THC-like compound that is used to suppress nausea and vomiting produced by cancer chemotherapy. Synthetic Δ9-THC (Marinol) was licensed soon after Nabilone for the same purpose, and subsequently as an appetite stimulant, particularly for AIDS patients. Nabilone
and Marinol were recently joined in the clinic by Sativex: in Canada (2005) for the relief of multiple sclerosis and cancer pain and in the UK (2010) to treat spasticity due to multiple sclerosis. Sativex has also received regulatory authorisation in Spain. Its main constituents are two phytocannabinoids, Δ9-THC and cannabidiol, both extracted from cannabis.

Importantly, whereas exogenously administered cannabis and individual cannabinoids such as Δ9-THC and Nabilone target all cannabinoid receptors in the body and so ‘flood’ the whole endocannabinoid system, endocannabinoids released endogenously are somewhat more selective since they seem to be released in a manner that only targets subpopulations of their receptors. Although such release is often ‘autoprotective’ it can sometimes be ‘autoimpairing’, leading for example to CB1 receptor-mediated obesity. There is, however, currently little interest in developing medicines from compounds that block CB1 receptors, as such a blockade could well also suppress CB1 receptor-mediated autoprotection. Indeed, the CB1 receptor blocking drug, Rimonabant, was recently withdrawn from the clinic because of an increased incidence of depression and suicidality in patients taking it as an anti-obesity agent.

The fact that Cesamet, Marinol and Sativex are all in the clinic is of course an indication that, as prescribed, these medicines do significantly more good than harm. Even so, there is considerable interest in developing a second generation of cannabinoid medicines that display even greater ‘benefit-torisk ratios’ (Pertwee, 2009). Possibilities include compounds that avoid the production of unwanted cannabinoid CB1 receptor-mediated effects by:

(1) Only activating cannabinoid receptors that are located outside the brain and spinal cord.

(2) Only activating cannabinoid receptors in particular tissues such as skin or spinal cord by being administered directly into these tissues.

(3) Activating cannabinoid CB2 but not cannabinoid CB1 receptors.

(4) Being administered at low doses that produce a cannabinoid receptor-mediated enhancement of the sought after effects of  non-cannabinoid medicines but are insufficient to produce significant cannabinoid receptor-mediated unwanted side effects.

(5) Boosting the levels of endocannabinoids when these are being released in an ‘autoprotective’ manner, for example to relieve pain.

(6) Targeting ‘allosteric’ sites that we have discovered to be present on cannabinoid CB1 receptors in a manner that will boost the ability of autoprotectively released endocannabinoids to activate these receptors.

Cannabis: A Complex Scenario

Δ9-THC is synthesized in the cannabis plant from a nonpsychoactive precursor, Δ9-THC acid. This process can be greatly accelerated by heat which is why cannabis is usually smoked, often with tobacco, consumed in preheated food or inhaled from ‘volcano’ vaporizers that create fumes by heating cannabis without burning it or producing smoke. Other pharmacologically active phytocannabinoids can also be
formed from their acids by heating cannabis. These include the non-psychoactive yet pharmacologically active compounds, cannabidiol (CBD), Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG), each of which has actual (CBD) or potential medical applications. Some of these phytocannabinoids are really ‘fighto’ cannabinoids, their presence in cannabis making it a pharmacological ‘battlefield’. Thus
we have discovered that although CB1 receptors are activated by Δ9-THC, they can be blocked by Δ9-THCV. It has also been found that CBD can oppose certain effects produced by cannabis or Δ9-THC. Indeed, whilst there is evidence that the presence of Δ9-THC in cannabis increases the risk of developing schizophrenia for certain individuals, there is also strong evidence that cannabidiol is a potential medicine for the treatment of schizophrenia. A further complication is that the relative concentrations of different phytocannabinoids are not the same in all strains of cannabis, in all parts of the same cannabis plant or in male and femalecannabis plants, the female flowering heads of sinsemilla (‘without seeds’) being particularly rich in Δ9-THC. This may have important consequences for those who take cannabis either recreationally or for the quite different purpose of self-medication, as high CBD:THC or THCV:THC ratios may lessen the risk from cannabis of developing schizophrenia or cannabis dependence…although probably also alter the perceived nature of a cannabis-induced ‘high’.


One notable recent event has been the arrival in the recreational cannabis world of herbal mixtures laced with synthetic cannabinoids (‘designer drugs’) such as JWH-018 (e.g. Spice or K2, named after the second highest mountain on earth). These little-investigated synthetic cannabinoids share the ability of Δ9-THC to activate cannabinoid CB1 receptors and hence to produce a ‘high’. Moreover, any of them that
activate these receptors more strongly than Δ9-THC will most likely produce a more intense ‘high’ and perhaps also more serious unwanted effects than usually experienced by recreational cannabis users. They probably also differ from THC in other ways. Thus, although Δ9-THC shares its ability to target cannabinoid receptors with many synthetic compounds, the additional pharmacological actions it possesses provide it  with a unique ‘pharmacological fingerprint’ that distinguishes it from many of these other compounds.

Harm Minimization For Recreational Cannabis

One important challenge for the International Narcotics Control Board that monitors and implements United Nations drug control conventions is to select an optimal but workable strategy for minimizing the harm that is now being caused both to themselves and to Society by some of the many  millions of people world-wide who currently take cannabis (or Spice) recreationally and also, indeed, by some of those who self-medicate with ‘street’ cannabis. For the UK, options include leaving the present law unchanged and increasing or
decreasing current penalties for the supply and/or possession of ‘street’ cannabis. It would also be advisable to develop strategies directed (i) at discouraging cannabis from being taken by adolescents or other individuals who are thought to be at particular risk from cannabis-induced harm and (ii) at providing advice (a) about combinations and levels of cannabinoids in cannabis that are thought to be the least
harmful and (b) about how to take cannabis as an inhaled unburnt vapour or in other ways that avoid the lung damage caused by smoked cannabis. It will be important that policy makers have discussions with cannabinoid pharmacologists whilst considering these and any other potential strategies for minimizing the harm caused by recreational cannabis.

Brown I, Cascio MG, Wahle KWJ, Smoum R, Mechoulam R, Ross RA, Pertwee RG and Heys SD. Cannabinoid receptor dependent and independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor positive and negative prostate cancer cell lines.
Carcinogenesis 2010; 31: 1584-1591.
Crowther, SM, Reynolds, LA and Tansey, EM (eds). The Medicalization of Cannabis. Witness Seminar Transcript. Volume 40. The Wellcome Trust Centre for the History of Medicine, at UCL. 2010;
Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 2006; 147: S163-S171.
Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 2009; 156: 397-411.
Professor Roger Pertwee has three degrees from the University of Oxford: MA (in biochemistry), D.Phil. (in pharmacology) and D.Sc. (in physiological sciences). He is Professor of Neuropharmacology at the University of Aberdeen, Director of Pharmacology for GW Pharmaceuticals, co-chairman of the International Union of Pharmacology (IUPHAR) Subcommittee on Cannabinoid Receptors, a co-ordinator of the British Pharmacological Society’s Special Interest Group on Cannabinoids and visiting Professor at the University of Hertfordshire. He has also served as chairman of the International Association for Cannabis as Medicine (IACM; 2005-2007) and as President of the International Cannabinoid Research Society (ICRS; 2007-2008; 1997-1998) and is currently ICRS International Secretary and a member of the IACM board of directors. He was the recipient of the 2002 Mechoulam Award “for his outstanding contributions to cannabinoid research” and in 2005 was recognized to be an “ISI Highly Cited Researcher” and hence among “the world’s most cited and influential researchers” (see Pertwee at His research has focused mainly on the pharmacology of  cannabinoids. This he began in 1968 at Oxford University and continued when he moved to Aberdeen in 1974. His research has played major roles in:
• the discovery of endocannabinoids and the endocannabinoid system;
• the recent discovery that ethanolamides formed from omega-3 polyunsaturated fatty acids seem to be endocannabinoids;
• the gathering of evidence supporting cannabinoids for the management of multiple sclerosis;
• the discovery that tetrahydrocannabivarin (THCV) is a phytocannabinoid;
• the pharmacological characterization of certain phytocannabinoids and of novel synthetic cannabinoids, e.g. the phytocannabinoids THCV, cannabidiol and cannabigerol, the first water-soluble cannabinoid (O-1057), the first CB1 receptorselective agonists (e.g. methanandamide), and a widely-used CB2 receptor antagonist (AM630);
• the discovery of a cannabinoid CB1 receptor allosteric site;
• the development of cannabinoid bioassays, some widely used (e.g. the “ring test”).
See also