Cannabis-based Drugs Research Articles

Cannabidiol (CBD) Listed as a Drug of Abuse by the Italian Health Ministry: Expert Opinion

: In August 2023, the Italian Health Ministry listed cannabidiol (CBD) as a drug of abuse. This rekindled the debate on the medical and non-medical use of cannabis. The most discussed topics are risks related to the use of cannabis, the decriminalization/legalization of recreational cannabis, and use of cannabis-based drugs for medical purposes. The decision to include CBD in the “Unique Text for drugs of abuse” (DPR.309/1990), along with the already included main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), is not particularly relevant to such ongoing discussions. Even when it comes to cannabis-based drugs for medical purposes, such a decision will have a minimum impact on CBD-based medical prescriptions. Instead, a high economic impact is expected on CBD-based products sold online or in specific shops, including the so-called “cannabis-light”, formally sold as a “technological product” for collection purposes but used as over-the-counter drugs for the treatment of several medical conditions. Cannabis-light products have reduced regular drug consumption by about 10%. Also, they are not entirely safe, as the actual content of THC may significantly differ from the one stated, carrying unexpected health risks. Further, CBD is likely not a drug with addictive potential; however, its uncontrolled use for medical purposes needs to be regulated as the court battles are ongoing.

Medical cannabis use in oncology and associated outcomes: A scoping review.

Natural and synthetic cannabinoids are being used worldwide to treat various symptoms in cancer patients. This study aims to map the therapeutic benefits and adverse effects associated with the use of cannabis-based drugs in these outcomes. Following Joanna Briggs Institute guidelines a scoping review was conducted. The study protocol was available in the Open Science Framework public repository. An extensive search strategy involving databases like Cochrane Library, Embase, CINAHL, Medline/PubMed, Lilacs, Google Scholar, and Open Gray for gray literature analysis was executed by a skilled librarian. The inclusion criteria were primary studies (observational and randomized) that evaluated the efficacy and safety of cannabinoids in cancer patients. The review encompassed studies of diverse designs, publication years, and types, as long as they addressed cannabinoids' impact in oncology. Twenty-nine (82.86%) out of total of 35 were randomized and 6 (14.14%) were non-randomized. About 57.1% of studies utilized registered products as interventions, with THC being the most natural cannabinoid cited in variable doses and administration routes. Moreover, 62.85% of studies specified the cancer types (breast, lung, sarcomas, hematological and reproductive system), while only one study detailed cancer staging. The evaluated outcomes encompassed nausea and vomiting (77.14%), appetite (11.43%), pain (8.57%), and tumor regression (2.86%) across different proportions of studies. Cannabinoids show promise in managing pain, emesis, and anorexia/cachexia linked to cancer progression. New randomized clinical trials with a larger number of participants and observational studies on long-term safety are crucial to affirm their medicinal utility for cancer patients unresponsive to conventional drugs.

Computational Study on the Enzyme-Ligand Relationship between Cannabis Phytochemicals and Human Acetylcholinesterase: Implications in Alzheimer's Disease.

Cannabis has shown promise in treating various neurological disorders, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disorder that affects millions of people worldwide. Current treatments for AD are limited and are not very effective. This study investigated the enzyme-ligand relationship between nine active components of cannabis and human acetylcholinesterase (HuAChE) enzyme, which is significant in AD. Specifically, computational methods such as quantum mechanics, molecular docking, molecular dynamics, and free energy calculations were used to identify the cannabis phytochemicals with the highest HuAChE affinity and to understand the specific binding mechanisms involved. Our results showed that cannabichromene and cannabigerol were the cannabis phytochemicals with the highest affinity for HuAChE, with cannabichromene exhibiting the greatest binding energy. However, both substances showed lower affinity than that of the pharmaceutical drug donepezil. This study suggests that cannabichromene has a specific affinity for the peripheral anionic site (PAS) and acyl-binding pocket (ABP), while cannabigerol predominantly binds to PAS. Also, it was found that cannabichromene has a specific affinity for PAS and ABP, while cannabigerol predominantly binds to PAS. Our findings suggest that cannabichromene and cannabigerol are potential therapeutic agents, but further research is needed to validate their effectiveness. The specific binding mechanisms identified may also provide helpful information for the design of more effective cannabis-based drugs. Overall, this study provides valuable insights into the potential of cannabis-based drugs for treating neurological diseases.

Can cannabidiol (CBD) help with low back pain?

Low back pain (LBP) is a major cause of disability and the main reason why individual patients need medical attention. Pharmacological treatment options for LBP are limited and are often associated with serious side-effects. This makes it necessary to search for new painkillers. One potential therapeutic agent is cannabidiol (CDB). Cannabidiol and tetrahydrocannabinol are the most researched components of cannabis, the plant more commonly known as marijuana or hemp. To the best of our knowledge, this is the first narrative review of the effects of CBD alone on acute and chronic back pain. Based on the guidelines provided by the Primary Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA), the PubMed/ MEDLINE database was used to identify articles for analysis from the last 30 years. Due to the limited number of studies on this topic, all types of studies that met the inclusion criteria were included. After analysis, 10 studies were included in this review. Currently, the use of medical marijuana continues to increase and the Food and Drug Administration (FDA) has already approved four cannabis-based drugs. Cannabidiol (CBD) is a relatively safe substance for humans and generally well tolerated. It is a substance that is easily available and often taken by patients with LBP. Evidence for the effectiveness of CBD in the treatment of acute low back pain is lacking. There was only one clinical trial conducted in the Emergency Department that showed no superiority of CBD over placebo in acute LBP. The majority of studies concern chronic rather than acute LBP. Although most of the results suggest a beneficial effect of cannabinoids in relieving chronic LBP, hard evidence is lacking. Rigorous randomized controlled trials are needed.

Abstract 4935: Cannabidiol and cannabis extract protect cells against platinum-based chemotherapy via cellular uptake

Abstract Cannabinoids including cannabidiol belong between constituents of cannabis sp. (marijuana plant). Purified or as a part of cannabis products, the compounds are frequently used by cancer patients to attenuate chemotherapy-induced side effects such as pain, nausea, and vomiting. The presence of cannabis products on the public market expands each year while the illegality status weakens in an increasing number of countries. U.S. Food and Drug Administration has approved several cannabis-based drugs for seizures induced by Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex, also for the lost appetite of AIDS patients, and chemotherapy-induced nausea and vomiting. Oncological patients are further and strongly motivated to take the drugs in combination with chemotherapy by numerous reports demonstrating the anticancer effects of cannabinoids. Nevertheless, here we present unsettling data that cannabis extract together with CBD negatively interferes with worldwide approved platinum-based drugs cisplatin, carboplatin, and oxaliplatin. The phenomenon is proven across three cellular models including primary cells. Even low concentrations of cannabidiol or cannabis extract reduced the toxicity of platinum-based drugs using long-term colony forming assay and/or short-term crystal violet assay. Increased resistance of cells was also accompanied by decreased cellular stress as evaluated by quantitative immunofluorescence microscopy and immunoblotting. Most importantly, concomitant cannabidiol and cisplatin exposure results in the decreased presence of cisplatin-modified DNA. Following the information, we determined platinum content in cells by ICP-MS. The experiment uncovered significantly decreased intracellular platinum content indicating an effect on cellular transport. Furthermore, the mechanism is translational independent as shown by the experiment with cycloheximide. This study offers crucial information that patients and physicians should take into account regarding possible interactions between platinum-based drugs and cannabis-based products. Furthermore, the study on the contradictory effects of cannabis products in cancer treatment may be motivated by this project. Citation Format: Tereza Buchtová, Lucie Beresova, Katarina Chroma, Martin Mistrik. Cannabidiol and cannabis extract protect cells against platinum-based chemotherapy via cellular uptake. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4935.

Cannabis bei Krebs – für welchen Einsatz haben wir Evidenz?

The general use of “medical cannabis” and “cannabis-based drugs” in the treatment of cancer patients cannot be recommended due to the currently, still insufficient amount of data available. However, taking into account the legal framework, it is possible to consider its use in selected cases. Patients must be informed in detail about treatment goals, relevant side effects to be expected, and the character of a “therapy attempt”. Further the effectiveness and safety of the treatment should be critically re-evaluated after a few weeks and, if necessary, be terminated in the event of insufficient clinical improvement or if intolerable side effects occur. Smoking cannabis should be avoided and oral or oromucosal preparations should be used. Due to the narrow therapeutic range, the lowest possible starting dose is recommended, particularly for older patients, in the case of comorbidities, or in patients taking centrally acting drugs. Little is known about the clinically relevant interaction risks of cannabis. Especially in the context of modern cancer treatment, increased attention is required.

The Therapeutic Potential of Synthetic and Natural Cannabinoids in Treating Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the most prevalent and debilitating neurodegenerative diseases in the world, highlighting the need for research on novel treatments and therapies. Previous studies have found that the body’s endocannabinoid system (ECS) interacts closely with its neural system, making it a potential avenue for the treatment of neurological disorders. One hallmark of AD is the accumulation of amyloid-beta (Aβ) in the brain and its potentially detrimental effects on cognitive function. Cannabis-based drugs have been observed to regulate Aβ modifications and inhibit AD progression. Furthermore, cannabinoids have been noted to reduce inflammation and neurotoxicity. Synthetic cannabinoids were able to rescue memory deficits and neurodegeneration, and reduce immunoreactivity. Similarly, natural cannabinoids like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) demonstrate therapeutic potential by interacting with the cholinergic system, and reversing the symptoms of AD. Although further research and testing are needed, it is evident that the use of cannabinoids shows promise for future treatment in AD patients.

Impact of Cannabis-Based Medicine on Alzheimer’s Disease by Focusing on the Amyloid β-Modifications: A Systematic Study

Deposition of Amyloid-beta (Aβ) peptide in the brain is the leading source of the onset and progression of Alzheimer's Disease (AD). Recent studies have suggested that anti-amyloidogenic agents may be a suitable therapeutic strategy for AD. The current review was proposed to address the beneficial effects of cannabis-based drugs for the treatment of AD, focusing primarily on Aβ modifications. Keywords related to AD, Aβ, and cannabis-based on MeSH were identified and were searched in PubMed, Google Scholar, Scopus, Ovid-Medline, and Web of Science from inception until 15 March 2020. The full text of identified papers was obtained and assessed based on exclusion and inclusion criteria. The review is based on articles that have focused on AD and the amyloidogenic pathway. A total of 17 studies were identified based on the inclusion criteria; however, nine studies qualified for this systematic review. The maximum and minimum cannabis dosages, mostly CBD and THC in animal studies, were 0.75 and 50 mg/kg, respectively. Cannabis (CBD and THC) was injected for 10 to 21 days. The findings of the 9 articles indicated that cannabis-based drugs might modulate Aβ modifications in several AD models. Our findings establish that cannabis-based drugs inhibited the progression of AD by modulating Aβ modifications.

Safety and pharmacokinetics of medical cannabis preparation in a monocentric series of young patients with drug resistant epilepsy

ObjectivesTo evaluate safety and pharmacokinetic parameters (PK) of medical cannabis in add-on for children and young adults with drug-resistant epilepsy. Design, settingTen patients (4 females, 6 males, age 2.5–23.2 years) were enrolled in a prospective open trial with a galenic preparation (decoction) of Italian cannabis (FM2, ratio THC:CBD = 3:5, range THC 5.2–7.2 %; CBD 8.2–11.1 %). Patients received the first dose in Hospital, progressively augmented by CBD dose titration (from 1 to 4 mg/kg/day). Outcome measuresIn order to assess safety, blood parameters, heart rates and electrocardiograms (ECGs) were evaluated before the enrollment and during the follow up. The PK study was performed measuring THC and CBD concentrations by UHPLC–MS/MS in plasma samples collected during the first administration and at each follow-up visit. ResultsTwo out of ten patients stopped the treatment for adverse events (detected in 6/10: gastroenteric, sleep or behavioral disorders) and difficulties in drug supply. We observed minor ECG alterations in two patients and asymptomatic transient reductions of fibrinogen after 6 months of therapy. The PK study during follow-up revealed statistically significant correlations between THC-CBD blood concentrations and: volumes of decoction, FM2 and THC-CBD daily dosages. ConclusionsThe present study, although with some limitations, shows a good safety profile of medical cannabis in children and young patients with drug-resistant epilepsy and encourages the possibility of further studies with oral cannabis-based drugs. The correlations between THC-CBD plasma concentrations and their administered dosages underline the need of a therapeutic drug monitoring for cannabinoids therapy.

Ein Positionspapier zu medizinischem Cannabis und cannabisbasierten Medikamenten in der Schmerzmedizin

Since March 2017, the prescription of medical cannabis at the expense of the statutory health insurance is possible after approval by the respective medical services. Chronic pain is the most common indication, as health claims data and the accompanying survey show. From the point of view of the law, a prescription is indicated in cases of serious illness, missing or not indicated established therapeutic approaches and a not entirely remote prospect of improvement of the illness or its symptoms. This describes a broader indication spectrum than can currently be based on randomised controlled clinical trials. There is weak evidence of low efficacy for neuropathic pain. For pain related to spasticity and cancer-related pain there is evidence of improvements in quality of life, but effects on pain are of little relevance. For all other indications, only an individual therapeutic trial can be justified based on the available external evidence. However, this usually corresponds to the demand of "anot entirely remote prospect" of a noticeably positive effect of medical cannabis. It is also problematic that almost no long-term studies for the application and efficacy of flowers and extracts are available.Current knowledge on the use of cannabis-based drugs and, more clearly, medical cannabis for chronic pain is insufficient. The increase in the number of countries with marketing authorisations or exemptions for medicinal cannabis or cannabis-based drugs for chronic pain will also pave the way for larger empirical and population-based studies that will further improve the evidence base of research and clinical use.

Dronabinol in geriatric pain and palliative care patients : Aretrospective evaluation of statutory-health-insurance-covered outpatient medical treatment

Geriatric patients often suffer from along history of pain and have alimited life expectancy. Cannabinoid receptor agonists like dronabinol may be an effective, low-risk treatment option for geriatric patients with chronic pain. The effectiveness and side effects of dronabinol therapy in geriatric patients are analyzed. The effects of the approval requirement are presented. In our retrospective monocentric cohort study, the study population comprised all geriatric patients over the age of 80years who were treated in our office since the cannabis law came into effect on 10March2017 until 17July2018 (evaluation date). Geriatric, nonpalliative pain patients (groupA) and geriatric palliative patients (groupB) were investigated. The basis of the evaluation was aquestionnaire sheet that we use in our office with details of dosages, pain intensity, treatment effects and side effects from dronabinol therapy. By using dronabinol, 21 of the 40geriatric patients (52.5%) achieved pain relief of more than 30%, 10% of the patients of more than 50%. On average, about four symptoms or side effects related to previous treatment were positively influenced. 26%of patients reported side effects. The rejection rates on the part of the health insurances were 38.7% (groupA) and 10.3% (groupB). This study is one of the few analyses of the use ofDronabinol in geriatric patients. We show that cannabis-based drugs (in this case dronabinol) are an effective, low-risk treatment option that should be consideredearly in therapy. Regarding the indication spectrum, further clinical studies and an approval-free test phase are necessary.

The German medical cannabis law of 2017

PurposeThe purpose of this paper is to give a review on the developments leading to the 2017 law on the medical use of cannabis and cannabinoids in Germany, and to present the major advances arising from this law for the supply of patients with cannabis-based drugs and its major limitations.Design/methodology/approachThis paper used an Analysis of the major political statements and documents as well as court decisions of the past 20 years, which can be regarded as the major steps of this development.FindingsSince 1998, when dronabinol/THC was made available in Germany on prescription there have been continuous improvements of the access to cannabis-based medicines. The law of 2017, which made cannabis flowers available to patients on a doctor’s prescription and forced health insurers to pay for a treatment under certain circumstances was a major step. However, many patients, who profit from a treatment with cannabis still do not get access.Originality/valueThe German law on the medical use of cannabis and cannabinoids of 2017 is unique in its kind in the world. Compared to the legal framework in other countries it has several disadvantages, for example with regard to the high prices of cannabis flowers (€20-€25 per gram), and several advantages, for example with regard to the role of health insurers.

Cannabinoid therapy in practice

In recent years, the media and scientists have shown increased interest in cannabis-based drugs. Background information about cannabis-based drugs and their mechanism of action as well as discussion of possible applications as supportive therapy or in palliative medicine, respectively, are presented. The recent literature was examined and evaluated. In many medical fields, we do not have sufficient evidence for the efficacy of cannabinoids. In German pharmaceutical legislation, the use of nabiximols for the treatment of intermediate to severe, therapy-resistant spasticity in multiple sclerosis is the only approved indication for cannabis-based drugs. Furthermore, in view of the current evidence cannabinoids, combined with established treatments and as part of an individual therapeutic attempt, can be used for neuropathic pain, cancer-associated pain and human immunodeficiency virus (HIV)-related cachexia. In most cases, today's assessment of cannabinoids relies on studies that are classified as low evidence. Therefore, further studies which involve more participants and evaluate long-term effects are needed.

Cannabis as a Possible Treatment for Spasticity in Multiple Sclerosis / Kanabis Kao Moguci Tretman U Lecenju Spasticnosti Kod Multiple Skleroze

Abstract The therapeutic potential of cannabis has been known for centuries. Cannabinoids express their effects through two types of receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Present studies indicate that cannabis-based drugs can make a positive impact in the treatment of different diseases. For many years, multiple sclerosis patients have self-medicated with illegal street cannabis to alleviate spasticity, a common and debilitating symptom that impairs quality of life. Nabiximols is the cannabis-based medicine approved in many countries as an add-on therapy for symptom improvement in patients with spasticity who have not responded adequately to other medications. Adverse events such as dizziness, diarrhoea, fatigue, nausea, headache and somnolence occur quite frequently with nabiximols, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual uptitration. The prerequisite for the therapeutic use of cannabis in Serbia arerequires legal clarification for the use of the drug in a clinical environment

A portable electronic nose system for the identification of cannabis-based drugs

We report on a research aimed at evaluating the capacity of a simple, low-cost, portable electronic nose system based on commercially available metal oxide gas sensors to classify different types of drugs. Five drugs, namely cannabis buds, cannabis plants, hashish, snuff tobacco and tobacco leaves were employed. A dedicated real-time data acquisition system based on dynamic headspace sampling, a microcontroller and a laptop computer have been designed and constructed for this application. To demonstrate its discrimination capability, unsupervised and supervised classification models have been built and validated. Principal Component Analysis (PCA) of volatile profiles revealed five distinct groups corresponding to the five different drugs analyzed. This was further confirmed by a multivariate analysis of variance (MANOVA) test. Support Vectors Machines (SVMs) were applied to build a classifier and reached a 98.5% success rate in the recognition of the different drugs analyzed. This work demonstrates for the first time that the electronic nose technology could be successfully applied to the identification of illegal drugs.

Managing neuropathic pain with Sativex®: a review of its pros and cons

Background: Although not new, the use of cannabis-based drugs for treating chronic pain patients is becoming a hot topic for pain physicians and other specialists due to the constant flow of medical information regarding this pharmacological therapy. Its indication is becoming more clearly targeted towards pain syndromes arising from nerve damage. The number of cases reported, clinical trials and reviews published on this subject exponentially increase year by year. A possible explanation for this may be the fact that neuropathic pain is a highly disabling symptom and, consequently, there is a demand from patients and health professionals for a definitive remedy to treat this pain. Methods: Parallel to the number of articles on the effectiveness, recent articles describing the tolerability of cannabis-based drugs along with a more accurate characterisation of its side-effect profile and/or lack of effectiveness have been published, and they are placing a cautious stop for a more precise prescription of these medications. Conclusion: This article reviews the current knowledge on the use of Sativex® for treating neuropathic pains of different origin, and analyses the balance between the advantages and drawbacks of this therapy.

Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis

IntroductionCannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB1) and receptor 2 (CB2) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA.MethodsThirty-two OA and 13 RA patients undergoing total knee arthroplasty were included in this study. Clinical staging was conducted from x-rays scored according to Kellgren-Lawrence and Larsen scales, and synovitis of synovial biopsies was graded. Endocannabinoid levels were quantified in synovial fluid by liquid chromatography-mass spectrometry. The expression of CB1 and CB2 protein and RNA in synovial biopsies was investigated. Functional activity of these receptors was determined with mitogen-activated protein kinase assays. To assess the impact of OA and RA on this receptor system, levels of endocannabinoids in the synovial fluid of patients and non-inflamed healthy volunteers were compared. The activity of fatty acid amide hydrolase (FAAH), the predominant catabolic endocannabinoid enzyme, was measured in synovium.ResultsCB1 and CB2 protein and RNA were present in the synovia of OA and RA patients. Cannabinoid receptor stimulation of fibroblast-like cells from OA and RA patients produced a time-dependent phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2 which was significantly blocked by the CB1 antagonist SR141716A. The endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) were identified in the synovial fluid of OA and RA patients. However, neither AEA nor 2-AG was detected in synovial fluid from normal volunteers. FAAH was active in the synovia of OA and RA patients and was sensitive to inhibition by URB597 (3'-(aminocarbonyl) [1,1'-biphenyl]-3-yl)-cyclohexylcarbamate).ConclusionOur data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.

Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex

Cannabinoid agonists modulate a variety of behavioral functions by activating cannabinoid receptors that are widely distributed throughout the central nervous system. In the present study, norepinephrine efflux was assessed in the frontal cortex of rats that received a systemic administration of the cannabinoid agonist, WIN 55,212-2. The synthetic cannabinoid agonist dose-dependently increased the release of norepinephrine in this brain region. Pretreatment with the cannabinoid receptor antagonist, SR 141716A, blocked the increase in norepinephrine release. To identify sites of cellular activation, immunocytochemical detection of c-Fos was combined with detection of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in the brainstem nucleus locus coeruleus (LC), a region that is the sole source of norepinephrine to the frontal cortex. Systemic administration of WIN 55,212-2 significantly increased the number of c-Fos immunoreactive cells within TH-containing neurons in the LC compared to vehicle-treated rats. Pretreatment with SR 141716A inhibited the WIN 55,212-2 induced c-Fos expression, while the antagonist alone did not affect c-Fos expression. Taken together, these data indicate that systemically administered cannabinoid agonists stimulate norepinephrine release in the frontal cortex by activating noradrenergic neurons in the coeruleo-frontal cortex pathway. These effects may partially underlie changes in attention, arousal and anxiety observed following exposure to cannabis-based drugs.

Pharmacokinetics and Pharmacodynamics of Cannabinoids

Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.