Cannabis & Stress/Anxiety

In recent IDMU surveys, relaxation and stress relief were overwhelmingly the most commonly perceived benefits of cannabis use.  However, the Department of Health identifies panic attacks and anxiety as effects of acute cannabis intoxication, particularly among naive users, in justifying the refusal of the UK Government to permit the prescribing of cannabis..

Recent advances in fundamental cannabinoid research have been interpreted as indicating a common modality of action of cannabis and opiate drugs, in that naloxone (an opiate antagonist) blocks cannabinoid-induced dopamine release in the limbic system (a primitive brain structure associated with control of emotion and mood) [i] and the a cannabinoid antagonist administered to rats, pretreated with a powerful synthetic cannabinoid agonist, can precipitate corticotrophin releasing factor (CRF) which is held to be the mechanism responsible for mediating the psychological aspects of drug withdrawal symptoms, and leading to anxiety-type behaviours [ii] .  This was interpreted as demonstrating a cannabis withdrawal syndrome, however the potency of the synthetic cannabinoid used was many times that of THC, and the administration of an antagonist (blocker) would not effectively mimic the gradual decrease in plasma THC which occurs with cessation of normal use.  The fact that a potent cannabis blocker caused anxiety symptoms in rats would be consistent with a general diminution of anxiety levels arising from cannabis use.

Laurie [iii] reported that in a few cases 'anxiety, which may approach panic, often associated with a fear of death or an oppressive foreboding is infrequently seen, usually giving way to an increasing sense of calmness... to euphoria'.  Grinspoon refers to the initial state as a 'happy anxiety' where the experience is internally redefined as pleasurable.  Rosenthal et al [iv] report that panic reactions and anxiety are rare, and most commonly found with overdose (particularly from oral preparations), in na¹ve users, or in those who do not like the effects of marijuana, and attributed the incidence of anxiety reports with Marinol (dronabinol - pure THC) to the lack of CBD within the preparation.  Mikuriya [v] considered that 'the power of cannabis to fight depression is perhaps its most important property'.  Patients were reported to self-medicate with cannabis rather than use benzodiazepines as the former produced less dulling of mental activity.  The authors cited one study where marijuana was found to increase anxiety in na¹ve users, but to decrease anxiety in experienced users, and another of 79 psychotics who used marijuana recreationally and reported less anxiety, depression, insomnia or physical discomfort [vi] , and concluded that natural marijuana - containing CBD and THC - appeared more effective than THC alone in treating depression, and that patients suffering stress as a result of pain or muscle spasms would be most likely to be helped by the drug.  They differentiated the use of cannabis to cope with everyday life stresses from the use of benzodiazepines in treating 'severe anxiety disorders' with an organic aetiology.

Bello [vii] in a passionate treatise on the benefits of cannabis for physical and mental health, likened the anxiolytic effect of marijuana to a state of relaxed alertness brought on by 'balancing' the autonomic nervous system.

Explanations of the panic and anxiety experienced by some na¹ve users exposed to cannabis would include 'set and setting' i.e. a drug taken in the course of a laboratory experiment would provide different expectations of an experience to an informal party or gathering of friends, secondly the increase in heart rate can be interpreted by some older users as a heart attack and cause panic attacks [viii] , this 'tachycardia' is normally associated with a reduction in blood pressure, the combined effect is analogous to changing down a gear in a motor vehicle.  Some individuals may be more susceptible to the effects of cannabis than others, and those whose initial experience is unpleasant may be more likely to discontinue use of the drug.  By contrast, many first-time users fail to notice the influence of the drug.

Thompson & Proctor [ix] , treating withdrawal conditions, noted the synthetic cannabinoid pyrahexyl to produce significant increases in alpha brain waves, indicating increased relaxation, and Adams reported similar results [x] .  However Williams et al found no significant increase in alpha activity either with parahexyl or smoked marijuana [xi] .

Davies et al [xii] , in a study of cancer patients, considered the management of stressful patients to have been improved by oral THC.  However a study of intravenous THC used as a premedication for oral-facial surgery [xiii] found that patients showed pronounced elevation of anxiety, and considered noxious stimuli to be more painful.  Mechoulam [xiv] considered a number of synthetic cannabinoids to be worthy of investigation as potential sedative-relaxants.

In laboratory animals, the cannabinoid receptor has been linked to modulation of emotional behaviour [xv] , reinforcement [xvi] , learning [xvii] and memory [xviii] [xix]   Musty [xx] compared the effects of THC, CBD (cannabidiol) and diazepam (valium) on anxiety-related behaviours in mice.   THC produced similar reductions in anxiety behaviours to diazepam, however the effect of CBD was more pronounced than either in measures of shock-avoidance, grooming and reduction of delerium tremens in alcohol-withdrawn mice.  Both THC and CBD produced dose-related reductions in ulcer formation in stressed mice.  However in all tests the CBD dosages used were higher than THC dosages.

Mechoulam reviewed studies of Nabilone (synthetic cannabinoid) on anxiety, finding two studies which suggested a superior effect on anxiety, mood and concomitant depression, whereas two other studies found little or no effect.  Benowitz & Jones [xxi] reported initial tachycardia and hypertension in volunteer subjects administered up to 210mg THC per day, but found development of tolerance to tachycardia and CNS effects over the 20 day experiment, with blood pressure reduced and stabilised at around 95/65.  Fabre & McLendon [xxii] reported a dramatic improvement in anxiety in the nabilone-treated group compared to placebo.  Nakano et al [xxiii] reported anti anxiety effects of nabilone and diazepam in a controlled trial of experimentally-induced stress, but was unable to conclude which was more effective due to differences in dosage and metabolism.  Hollister [xxiv] reported these and other nabilone studies [xxv] indicating significant anti-anxiety effects of low doses, and commented on the scarcity of studies of potential anti-anxiety effects of cannabinoids.

Post-Traumatic Stress Disorder:  I am unaware of any controlled scientific studies in published journals which investigate the use of cannabis as a treatment option for post-traumatic stress disorder, although several studies of this condition make reference to cannabis use by patients.  In a study of female drug clinic patients with histories of post-traumatic stress disorder following physical or sexual abuse, Gil-Revas et al [xxvi] reported "contrary to expectation, PTSD is not associated with relapse to drug use".  Clark et al [xxvii] found PTSD to be a common diagnosis among a group of alcoholic adolescents, who also showed high rates of cannabis and hallucinogen use, considering the relationship to reflect a comorbid disorder.  DeFazio et al [xxviii] studied Vietnam veterans, finding a higher incidence of PTSD symptoms among combat, compared to non-combat groups, the relationship to cannabis use is unclear, but may reflect a coping strategy, where the use of marijuana by US troops during combat has been widely-documented, which typically ceased upon return to civilian life.

Cannabis and Depression

Depression is a term used to describe a variety of different disorders characterised by lowering of mood, disinterest in ones surroundings or condition, fatigue, and loss of appetite and/or personal neglect.  For most people, depression is a passing mood, for others it is a debilitating condition with severe emotional and physical symptoms.  Only when depression is serious is it normally considered a psychiatric disorder requiring treatment.  Most drug treatments for clinical depression involve use of tricyclic antidepressants (e.g. amitriptyline), monoamine oxidase inhibitors (e.g. isocarboxazid) or more recently fluotexine (prozac), both of which boost levels of brain catecholamines (stimulant neurotransmitters including noradrenalin or serotonin). 

Cannabis products have long been considered to be effective in the treatment of depressive disorders, in 1845 it was recommended for melancholia (with obsessive rumination) and mental disorder in general [xxix] .  In 1947 Stockings [xxx] found improvements in 36 out of 50 depressed mental patients treated with a synthetic cannabinoid.  Grant et al [xxxi] in a US population study, commented "cannabis might be used to self-medicate major depression."  Schnelle et al [xxxii] found depression to be the most common reason for self-medication in a study of German-speaking medicinal cannabis patients.

In a case study Bolls [xxxiii] reported a case of post-natal depression successfully treated by a large oral dose (4g of alcoholic cannabis tincture) and counselling.  The subject reported anxiety at the peak of the drugs effect, however the study involved a single case, was not controlled under current scientific methodology, and it could not now be concluded whether any recovery was due to the drug, the psychotherapy, or would have occurred in any event.  Conversely Payne [xxxiv] reported a case history where cannabis use was considered to worsen the patientòs mood disorder.

Kotin et al [xxxv] , in a double-blind experiment, found no effect on moderate to severe depression from relatively high doses (0.3mg/kg) of THC.  Grinspoon considered cannabinoids to be of promise where depression is secondary to some life event (reactive depression) rather than a primary diagnosis, but did not consider general optimism about such treatment to be justified by the state of knowledge in 1977.

Regelson et alia [xxxvi] reported a number of significant effects in a controlled study of THC in terminal cancer patients, including a reduction in depression, greater emotional stability, more self-reliant/less dependent, less suspiciousness, increased forthrightness, less apprehension, more normal level of control and more tranquil/relaxed, however two patients who discontinued the study reported fear and anxiety, confused thinking and dissociation.  The authors commented that such effects would appear to be confined to a susceptible population.

Grinspoon [xxxvii] considered some patients who fail to respond to traditional antidepressant drugs, or who find the side-effects of these unbearable, to have been helped by illicit marijuana use, quoting 3 case studies all involving long histories of severe clinical depression, all treated unsuccessfully with all types of antidepressive medication, and all now living normally through use of cannabis, twice daily in one case, on re-appearance of symptoms in the others, each attributing the improvement to greater self-insight, a reduction of a negative self-image, and/or a general euphoria arising from cannabis intoxication.

Several recent studies have highlighted the association between depression, conduct disorder and substance  (including cannabis & alcohol) abuse [xxxviii] .  Rey et al [xxxix] considered this to represent "a malignant pattern of comorbidity that may lead to negative outcomes".  Lynskey et al [xl] noted major depression to be a correlate of cannabis dependence, but noted "genetic risk factors are important determinants of risk of cannabis dependence among men". Bovasso [xli] , following a large-scale longitudinal survey of depressive patients,  considered cannabis use to be a risk factor for depressive symptoms:  "In participants with no baseline depressive symptoms, those with a diagnosis of cannabis abuse at baseline were four times more likely than those with no cannabis abuse diagnosis to have depressive symptoms at the follow-up assessment, after adjusting for age, gender, antisocial symptoms, and other baseline covariates. In particular, these participants were more likely to have experienced suicidal ideation and anhedonia during the follow-up period. Among the participants who had no diagnosis of cannabis abuse at baseline, depressive symptoms at baseline failed to significantly predict cannabis abuse at the follow-up assessment." In a case study of a brain-damaged patient, Payne [xlii] noted "The impact of cannabis use in this individual appeared to have a detrimental effect on his mood."

In a survey of young Austrialian adults, Degenhardt et al [xliii] concluded "Cannabis use did not appear to be directly related to depression or anxiety when account was taken of other drug use. However, the association between heavier involvement with cannabis use and affective and anxiety disorders has implications for the treatment of persons with problematic cannabis use." Dhossche et al [xliv] noted "Detection of alcohol, cocaine, or cannabis in about 40% of suicides supports the clinical practice of discouraging consumption of these substances in depressed patients".  However  in a clinical trial of synthetic cannabinoids (CB1-agonists) Tramer et al found these enhanced mood among cancer  patients: "In selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness." [xlv]   Nunn et al [xlvi] reported "Neither anxiety or depression scores were higher in cannabis users...", and Dumas et al [xlvii] reported "The co-occurrence of cannabis use and schizotypal traits appeared to be independent of anxiety and depression dimensions".

However Aharonovitch et al [xlviii]   postulated "the self-medication hypothesis  of substance abuse...  that drug abuse is driven by an attempt to alleviate specific psychological distress".  Abraham & Fava [xlix]   studying the order of onset of depression and substance abuse  in an attempt to resolve the "cause or self-medicationò question, reached no conclusions concerning cannabis alone, but noted "Among polydrug-dependent patients, each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression." In a study of patients with bipolar disorder (manic depressive psychosis),  Strakowski  et al [l] found "The duration of alcohol abuse during follow-up was associated with the time patients experienced depression. The duration of cannabis abuse was associated with the duration of mania."  In schizophrenia patients, Hambrecht & Hafner [li]   identified three subtypes of patient in relation to cannabis use: "Group 1 might suffer from the chronic deteriorating influence of cannabis reducing the vulnerability threshold and/or coping resources. Group 2 consists of individuals which are already vulnerable to schizophrenia. Cannabis misuse then is the (dopaminergic) stress factor precipitating the onset of psychosis. Group 3 uses cannabis for self-medication against (or for coping with) symptoms of schizophrenia, particularly negative and depressive symptoms. These patients probably learn to counterbalance a hypodopaminergic prefrontal state by the dopaminergic effects of cannabis."  In an American epidemiological study of cannabis use, dependence and co-morbidity, Grant & Pickering [lii] concluded "cannabis might be used to self-medicate major depression."

A Canadian study of self-medicating cannabis users by Ogborne  et al [liii] reported patients used for a variety of conditions including: "HIV-AIDS-related problems, chronic pain, depression, anxiety, menstrual cramps, migraine, narcotic addiction as well as everyday aches, pains, stresses and sleeping difficulties."  In a similar German study, Schnelle et al [liv]   found "The most frequently mentioned indications for medicinal cannabis use were depression (12.0%), multiple sclerosis (10.8%), HIV-infection (9.0%), migraine (6.6%), asthma (6.0%), back pain (5.4%), hepatitis C (4. 8%), sleeping disorders (4.8%), epilepsy (3.6%), spasticity (3.6%), headache (3.6%), alcoholism (3.0%), glaucoma (3.0%), nausea (3.0%), disk prolapse (2.4%), and spinal cord injury (2.4%)."

In a learned review, Williamson & Evans [lv] reported "Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this." and concluded "Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety."

In November 2002, the British Medical Journal published the results of three separate longitudinal ("cohortò) studies into mental health outcomes of adolescent cannabis users.

(a)          Swedish Conscripts ¸ a cohort study by Zammitt et al [lvi] of 50,000 Swedish male conscripts in 1969 were followed up at intervals between 1970 and 1996.  Of the 5391 subjects who had ever used cannabis, 73 had developed schizophrenia (1.4%) compared to 215 out of 36429 subjects (0.6%) who had never used (or denied using) the drug.  The study suggested that all cannabis users are 50% more likely to develop schizophrenia, and regular users three times as likely, after controlling for social factors including use of other drugs.  However the study had data on cannabis use only at the outset of the study, and the control cohort would not have excluded subjects who subsequently started to use cannabis after age 18-20, or users of cannabis who denied using the drug.  It is unclear whether  the rigour in assessing the mental health history of control subjects matched that for cannabis-using subjects. 

(b)          Australian Students ¸ A seven year follow-up study of 1601 secondary school students in Australia by Patton et al [lvii] found that weekly or more frequent use of cannabis during adolescence predicted a two-fold increase in later development of depression and anxiety, with young women being at particular risk, although for young men the effect was not statistically significant, if anything they showed lower rates of depression than controls.  Young women were statistically 60% more likely to develop depression than men in the absence of cannabis use. The authors found no relationship between adolescent anxiety and depression and later cannabis use, which they interpreted as excluding the "self-medicationò hypothesis.

(c)          New Zealand Birth Cohort ¸ A longitudinal study by Arsenault et al [lviii] of 1037 individuals born in 1972-3 was followed up at ages 11, 15, 18 and 26.  They found cannabis use by age 15 (n=29) to be associated with a four-fold increase in the likelihood of developing schizophreniform symptoms by age 26 (p<.05), although use by age 18 (n=236) showed no significantly increased risk.  A weakly significant association was found between cannabis use by age 18 and depressive symptoms by age 26, the odds ratio falling closer to the boundary of significance when the data was controlled for pre-existing psychopathologies and use of other drugs.  Again, no relationship was found between adolescent symptomatology and later cannabis use, and the authors rejected the "self-medicationò hypothesis.

It may well be that common factors predispose an individual both to schizophrenia and to early use of cannabis, particularly in a country like Sweden with a very strong prohibitionist enforcement policy and anti-drug social attitudes, where early cannabis use may be considered more "deviantò than in countries with more tolerant social attitudes to the drug.