Increased use of illicit drugs in a Dutch cluster headache population

Cluster headache is an uncommon primary headache disorder marked by very severe unilateral attacks lasting 15–180 minutes, often accompanied by ipsilateral cranial autonomic symptoms. Most people experience an episodic form with remission periods, while about 14% have a chronic form without remissions longer than one month. Although standard treatments are effective for many patients, 10–20% remain refractory and often try alternative approaches, including illicit drugs. Prior small and uncontrolled studies have reported that substances such as cannabis, psilocybin mushrooms (PSI), lysergic acid diethylamide (LSD), gamma-hydroxybutyrate (GHB) and others have been used acutely or as prophylaxis, with mixed and inconclusive self-reported effects; however, systematic investigation in a Dutch population had not been performed. De Coo and colleagues set out to systematically assess lifetime use of illicit drugs and self-reported effects on attack frequency and attack duration in a representative Dutch cluster headache population. The study compared prevalence and patterns of drug use in people screened for cluster headache within the nationwide LUCA programme to age- and sex-matched data from the Dutch general population, and explored differences by gender, age cohort, and episodic versus chronic disease.

This was an explorative cross-sectional study nested in the nationwide Leiden University Cluster Headache neuro-analysis (LUCA) programme. Adults (≥18 years) were recruited across the Netherlands through programme promotion and invitations at headache clinics. Potential participants completed a validated web-based screening questionnaire based on ICHD-II criteria (reported specificity 0.89); those screening positive subsequently received a more extensive questionnaire. For the present analysis, people screened positive for cluster headache were emailed an additional author-designed questionnaire about lifetime use of illicit drugs and about perceived effects on attack frequency and attack duration when used during a cluster episode. The drug list included cannabis, cocaine, heroin, PSI, MDMA, LSD, amphetamine and GHB. Responses were collected online, with paper option for those unable to use the internet, and non-responders received multiple reminders including phone contact. Only respondents who completed all drug-use items were included. Comparison data for the Dutch general population came from Statistics Netherlands' annual health survey (random sample of ~15,000 people yearly); the authors restricted those data to individuals aged 18 and older and used anonymous categorical variables. For analysis the general-population data were partitioned into three categories: all respondents, those classified as having headache (migraine or regular severe headache in the prior 12 months), and those classified as having chronic pain in the prior 12 months. Ethical approval was obtained for LUCA from the Leiden University Medical Center ethics committee; the Statistics Netherlands survey was exempt from separate ethical approval. Statistical analyses used Chi-square tests for categorical variables (with Yates' correction where appropriate) and independent t-tests for continuous variables; Fisher's Exact test was used when cell counts were <5. Analyses were performed in SPSS 23.0 with significance set at p < 0.05. The authors did not perform a prior power calculation.

By August 2014, 756 people with self-reported cluster headache were invited and 643 (85.1%) completed all necessary questionnaires; of these, 613/643 (95.3%) had a physician diagnosis of cluster headache. From the Statistics Netherlands cohorts of 2014–2015, 14,542/24,396 (59.6%) respondents aged 18+ were included as the general-population comparison; within that sample 3,457 (23.8%) reported chronic pain and 2,269 (15.6%) reported headaches. Compared with the general population, the cluster headache sample was more often male, had higher education levels, were more often smokers and consumed alcohol less frequently. Lifetime illicit drug use was higher in the cluster headache group than in the general population: 31.7% versus 23.8% (p < 0.001). Specific substances with higher lifetime use in the cluster headache group included cannabis (29.5% vs. 22.7%; p < 0.001), cocaine (8.9% vs. 4.8%; p < 0.001), amphetamine (6.4% vs. 4.2%; p = 0.011), psilocybin mushrooms (PSI) (9.3% vs. 3.9%; p = 0.000), and heroin (1.1% vs. 0.5%; p = 0.037). When compared specifically to the general-population headache subgroup, cluster headache patients used all listed drugs more frequently except GHB; compared to the chronic pain subgroup, cannabis, cocaine, MDMA, amphetamine and PSI were used more often by the cluster headache group. Gender analyses showed higher prevalence of illicit drug use in males than females in both samples (cluster headache: 34.7% vs. 23.7%; p = 0.008; general population: 29.2% vs. 18.5%; p < 0.001). Within the cluster headache sample, males reported greater use of cannabis (33.0% vs. 20.2%; p = 0.028) and LSD (3.25% vs. 0.0%; p = 0.044). Compared with males in the general population, males with cluster headache reported higher lifetime use of illicit drugs (34.7% vs. 29.2%; p = 0.013), notably cannabis, cocaine and PSI. Among females, there was no overall difference in illicit drug use between those with and without cluster headache except for PSI (5.8% vs. 2.3%; p = 0.008). Age-cohort patterns of lifetime illicit drug use in the cluster headache group mirrored those of the general population, with increased use in most age groups; the 18–24 and 25–30 cohorts did not reach significance, but these groups were small. Comparing episodic and chronic cluster headache, overall illicit drug use did not differ (34.4% vs. 30.9%; p = 0.413). Two exceptions were higher reported lifetime use of MDMA (13.9% vs. 7.5%; p = 0.027) and GHB (4.6% vs. 1.2%; p = 0.015) in chronic versus episodic patients. Respondents who had used illicit drugs during a cluster episode reported perceived effects on attack frequency and duration. A decrease in attack frequency was reported most often for LSD (60.0%; n = 3) and PSI (56.4%; n = 22). GHB was reported by a small number to increase attack frequency (18.2%; n = 2). For reduction in attack duration, PSI (46.2%; n = 18) and heroin (50.0%; n = 2) were most often reported to shorten individual attacks. The extracted text truncates the reporting for cocaine (it lists 10.3%, n = 3, but the outcome is incomplete), and the authors emphasise that these effect data derive from small subgroups and are self-reported.

De Coo and colleagues interpret their findings as showing a higher lifetime prevalence of illicit drug use in a Dutch cluster headache population compared to the general Dutch population, with notable excesses for cannabis, amphetamine, heroin and cocaine. Despite the higher prevalence, most users reported no effect of illicit drugs on attack frequency or duration when used during a cluster episode. A small number of respondents reported perceived beneficial effects of PSI and LSD on frequency and of PSI and heroin on duration, but these observations derive from very small subgroups and must be treated cautiously. The authors propose several non-mutually exclusive explanations for the observed increase in drug use. First, some substances might have true acute or prophylactic effects through neurobiological mechanisms relevant to cluster headache—for example, cannabinoids acting at hypothalamic receptors—but evidence from this and prior studies is limited and inconsistent. Second, a shared predisposition to addictive or risk-taking behaviours among people with cluster headache could partly explain higher usage rates; this hypothesis is concordant with the higher smoking prevalence observed in the cohort. Third, heightened awareness and endorsement of certain illicit substances within cluster headache communities, blogs and media may encourage patients to try them. Fourth, placebo effects or reporting biases could have inflated perceived benefits in uncontrolled reports. The authors acknowledge several limitations. The general-population data were categorical and prevented adjustment for age and gender as continuous covariates; analyses therefore required stratification, and residual confounding by demographic or socioeconomic factors is possible. Small numbers of users for certain drugs limited statistical power for subgroup comparisons. Internet-based recruitment likely produced a sample with higher education levels, which could bias estimates (higher education is typically associated with lower drug use and thus might have attenuated the observed differences). The headache subgroup in the general-population sample could have included a small number of undiagnosed cluster headache cases, but the authors judge this would not materially affect the results. Crucially, the study relied on self-reported lifetime use and self-assessed effects without data on timing relative to attacks, motives for use, dose, route of administration or objective clinical outcomes, so causal inferences cannot be drawn. In summary, the study finds an increased prevalence of illicit drug use among Dutch people with cluster headache compared with the general population; however, most users report no effect on their attacks, and the limited positive reports for certain substances require further controlled research to determine whether any true therapeutic or prophylactic effects exist or whether alternative explanations account for the association.